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Pajares MÁ. Posttranslational Regulation of Mammalian Sulfur Amino Acid Metabolism. Int J Mol Sci 2025; 26:2488. [PMID: 40141131 PMCID: PMC11942099 DOI: 10.3390/ijms26062488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/05/2025] [Accepted: 03/09/2025] [Indexed: 03/28/2025] Open
Abstract
Metabolism of the mammalian proteinogenic sulfur amino acids methionine and cysteine includes the methionine cycle and reverse transsulfuration pathway, establishing many connections with other important metabolic routes. The main source of these amino acids is the diet, which also provides B vitamins required as cofactors for several enzymes of the metabolism of these amino acids. While methionine is considered an essential amino acid, cysteine can be produced from methionine in a series of reactions that also generate homocysteine, a non-proteinogenic amino acid linking reverse transsulfuration with the methionine and folate cycles. These pathways produce key metabolites that participate in synthesizing a large variety of compounds and important regulatory processes (e.g., epigenetic methylations). The impairment of sulfur amino acid metabolism manifests in many pathological processes, mostly correlated with oxidative stress and alterations in glutathione levels that also depend on this part of the cellular metabolism. This review analyzes the current knowledge on the posttranslational regulation of mammalian sulfur amino acid metabolism, highlighting the large number of modification sites reported through high-throughput studies and the surprisingly limited knowledge of their functional impact.
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Affiliation(s)
- María Ángeles Pajares
- Department of Molecular and Cellular Biosciences, Centro de Investigaciones Biológicas Margarita Salas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
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Polar Interactions at the Dimer-Dimer Interface of Methionine Adenosyltransferase MAT I Control Tetramerization. Int J Mol Sci 2021; 22:ijms222413206. [PMID: 34948004 PMCID: PMC8703375 DOI: 10.3390/ijms222413206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 11/29/2021] [Accepted: 12/06/2021] [Indexed: 11/17/2022] Open
Abstract
Catalytic MATα1 subunits associate into kinetically distinct homo-dimers (MAT III) and homo-tetramers (MAT I) that synthesize S-adenosylmethionine in the adult liver. Pathological reductions in S-adenosylmethionine levels correlate with MAT III accumulation; thus, it is important to know the determinants of dimer–dimer associations. Here, polar interactions (<3.5 Å) at the rat MAT I dimer–dimer interface were disrupted by site-directed mutagenesis. Heterologous expression rendered decreased soluble mutant MATα1 levels that appeared mostly as dimers. Substitutions at the B1–B2 or B3–C1 β-strand loops, or changes in charge on helix α2 located behind, induced either MAT III or MAT I accumulation. Notably, double mutants combining neutral changes on helix α2 with substitutions at either β-strand loop further increased MAT III content. Mutations had negligible impact on secondary or tertiary protein structure, but induced changes of 5–10 °C in thermal stability. All mutants preserved tripolyphosphatase activity, although AdoMet synthesis was only detected in single mutants. Kinetic parameters were altered in all purified proteins, their AdoMet synthesis Vmax and methionine affinities correlating with the association state induced by the corresponding mutations. In conclusion, polar interactions control MATα1 tetramerization and kinetics, diverse effects being induced by changes on opposite β-sheet loops putatively leading to subtle variations in central domain β-sheet orientation.
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Vatsalya V, Gala KS, Hassan AZ, Frimodig J, Kong M, Sinha N, Schwandt ML. Characterization of Early-Stage Alcoholic Liver Disease with Hyperhomocysteinemia and Gut Dysfunction and Associated Immune Response in Alcohol Use Disorder Patients. Biomedicines 2020; 9:biomedicines9010007. [PMID: 33374263 PMCID: PMC7823569 DOI: 10.3390/biomedicines9010007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Revised: 12/18/2020] [Accepted: 12/22/2020] [Indexed: 01/11/2023] Open
Abstract
Heavy alcohol consumption can cause hyperhomocysteinemia, which could be consequential in the proinflammatory response and worsening of the neurobehavioral domains of alcohol use disorder (AUD), such as alcohol withdrawal. We examined the role of heavy drinking, hyperhomocysteinemia, gut dysfunction and inflammation in early-stage alcoholic liver disease (ALD) in AUD patients. A total of 110 AUD patients without clinical manifestations of liver injury were grouped by the serum homocysteine levels (SHL): normal ≤ 13 µmol/L (Group 1 (Gr.1); n = 80), and elevated > 13 µmol/L (Group 2 (Gr.2), n = 30). A comprehensive metabolic panel, SHL, a nutritional assessment, and drinking history assessed by the timeline followback questionnaire were evaluated. A subset analysis was performed on 47 subjects (Gr.1 n = 27; Gr.2 n = 20) for additional measures: Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score, plasma cytokines (interleukin-1β (IL-1β)), gut dysfunction markers (lipopolysaccharide (LPS), and LPS-binding protein (LBP)); 27% of the AUD patients exhibited hyperhomocysteinemia. SHL was significantly associated (p = 0.034) with heavy drinking days (HDD90). Subset analyses showed that the withdrawal ratings were both clinically and statistically (p = 0.033) elevated and significantly associated with hyperhomocysteinemia (p = 0.016) in Gr.2. LBP, IL1-β, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.627) on withdrawal ratings in Gr.2 subset. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher in all Gr.2 patients; AUROC showed a fair level of true positivity for ALT (0.676), and AST (0.686). Il1-β, LBP, SHL, and HDD90 showed significant cumulative effects (adjusted R2 = 0.554) on the elevated ALT in Gr.2 subset as well. The gut-brain derived proinflammatory response, patterns of heavy drinking, and hyperhomocysteinemia were closely associated with clinically elevated alcohol withdrawal and elevated liver injury. Hyperhomocysteinemia could have a potential phenotypic marker response indicative of early-stage ALD along with AUD.
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Affiliation(s)
- Vatsalya Vatsalya
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; (K.S.G.); (A.Z.H.); (J.F.)
- Correspondence: ; Tel.: +1-502-852-8928
| | - Khushboo S. Gala
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; (K.S.G.); (A.Z.H.); (J.F.)
| | - Ammar Z. Hassan
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; (K.S.G.); (A.Z.H.); (J.F.)
| | - Jane Frimodig
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; (K.S.G.); (A.Z.H.); (J.F.)
| | - Maiying Kong
- Department of Biostatistics and Bioinformatics, University of Louisville, Louisville, KY 40202, USA;
| | - Nachiketa Sinha
- Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, NS B3H 4R2, Canada;
| | - Melanie L. Schwandt
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA;
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S-Adenosylmethionine Deficiency and Brain Accumulation of S-Adenosylhomocysteine in Thioacetamide-Induced Acute Liver Failure. Nutrients 2020; 12:nu12072135. [PMID: 32709137 PMCID: PMC7400803 DOI: 10.3390/nu12072135] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 07/09/2020] [Accepted: 07/15/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Acute liver failure (ALF) impairs cerebral function and induces hepatic encephalopathy (HE) due to the accumulation of neurotoxic and neuroactive substances in the brain. Cerebral oxidative stress (OS), under control of the glutathione-based defense system, contributes to the HE pathogenesis. Glutathione synthesis is regulated by cysteine synthesized from homocysteine via the transsulfuration pathway present in the brain. The transsulfuration-transmethylation interdependence is controlled by a methyl group donor, S-adenosylmethionine (AdoMet) conversion to S-adenosylhomocysteine (AdoHcy), whose removal by subsequent hydrolysis to homocysteine counteract AdoHcy accumulation-induced OS and excitotoxicity. METHODS Rats received three consecutive intraperitoneal injections of thioacetamide (TAA) at 24 h intervals. We measured AdoMet and AdoHcy concentrations by HPLC-FD, glutathione (GSH/GSSG) ratio (Quantification kit). RESULTS AdoMet/AdoHcy ratio was reduced in the brain but not in the liver. The total glutathione level and GSH/GSSG ratio, decreased in TAA rats, were restored by AdoMet treatment. CONCLUSION Data indicate that disturbance of redox homeostasis caused by AdoHcy in the TAA rat brain may represent a deleterious mechanism of brain damage in HE. The correction of the GSH/GSSG ratio following AdoMet administration indicates its therapeutic value in maintaining cellular redox potential in the cerebral cortex of ALF rats.
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Eudy BJ, McDermott CE, Fernandez G, Mathews CE, Lai J, da Silva RP. Disruption of hepatic one-carbon metabolism impairs mitochondrial function and enhances macrophage activity in methionine-choline-deficient mice. J Nutr Biochem 2020; 81:108381. [PMID: 32422424 PMCID: PMC7338047 DOI: 10.1016/j.jnutbio.2020.108381] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 01/24/2020] [Accepted: 03/13/2020] [Indexed: 02/05/2023]
Abstract
One-carbon metabolism is a collection of metabolic cycles that supports methylation and provides one-carbon bound folates for the de novo synthesis of purine and thymidine nucleotides. The methylation of phosphatidylethanolamine to form choline has been extensively studied in the context of fatty liver disease. However, the role of one-carbon metabolism in supporting nucleotide synthesis during liver damage has not been addressed. The objective of this study is to determine how the disruption of one-carbon metabolism influences nucleotide metabolism in the liver after dietary methionine and choline restriction. Mice (n=8) were fed a methionine-choline-deficient or control diet for 3 weeks. We treated mice with the compound alloxazine (0.5 mg/kg), a known adenosine receptor antagonist, every second day during the final week of feeding to probe the function of adenosine signaling during liver damage. We found that concentrations of several hepatic nucleotides were significantly lower in methionine- and choline-deficient mice vs. controls (adenine: 13.9±0.7 vs. 10.1±0.6, guanine: 1.8±0.1 vs. 1.4±0.1, thymidine: 0.0122±0.0027 vs. 0.0059±0.0027 nmol/mg dry tissue). Treatment of alloxazine caused a specific decrease in thymidine nucleotides, decrease in mitochondrial content in the liver and exacerbation of steatohepatitis as shown by the increased hepatic lipid content and altered macrophage morphology. This study demonstrates a role for one-carbon metabolism in supporting de novo nucleotide synthesis and mitochondrial function during liver damage.
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Affiliation(s)
- Brandon J Eudy
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL.
| | - Caitlin E McDermott
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL.
| | - Gabriel Fernandez
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
| | - Clayton E Mathews
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL.
| | - Jinping Lai
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL; Department of Pathology and Laboratory Medicine, Kaiser Permanente, Sacramento, CA.
| | - Robin P da Silva
- Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL.
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Pajares MA, Pérez-Sala D. Mammalian Sulfur Amino Acid Metabolism: A Nexus Between Redox Regulation, Nutrition, Epigenetics, and Detoxification. Antioxid Redox Signal 2018; 29:408-452. [PMID: 29186975 DOI: 10.1089/ars.2017.7237] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
SIGNIFICANCE Transsulfuration allows conversion of methionine into cysteine using homocysteine (Hcy) as an intermediate. This pathway produces S-adenosylmethionine (AdoMet), a key metabolite for cell function, and provides 50% of the cysteine needed for hepatic glutathione synthesis. The route requires the intake of essential nutrients (e.g., methionine and vitamins) and is regulated by their availability. Transsulfuration presents multiple interconnections with epigenetics, adenosine triphosphate (ATP), and glutathione synthesis, polyol and pentose phosphate pathways, and detoxification that rely mostly in the exchange of substrates or products. Major hepatic diseases, rare diseases, and sensorineural disorders, among others that concur with oxidative stress, present impaired transsulfuration. Recent Advances: In contrast to the classical view, a nuclear branch of the pathway, potentiated under oxidative stress, is emerging. Several transsulfuration proteins regulate gene expression, suggesting moonlighting activities. In addition, abnormalities in Hcy metabolism link nutrition and hearing loss. CRITICAL ISSUES Knowledge about the crossregulation between pathways is mostly limited to the hepatic availability/removal of substrates and inhibitors. However, advances regarding protein-protein interactions involving oncogenes, identification of several post-translational modifications (PTMs), and putative moonlighting activities expand the potential impact of transsulfuration beyond methylations and Hcy. FUTURE DIRECTIONS Increasing the knowledge on transsulfuration outside the liver, understanding the protein-protein interaction networks involving these enzymes, the functional role of their PTMs, or the mechanisms controlling their nucleocytoplasmic shuttling may provide further insights into the pathophysiological implications of this pathway, allowing design of new therapeutic interventions. Antioxid. Redox Signal. 29, 408-452.
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Affiliation(s)
- María A Pajares
- 1 Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC) , Madrid, Spain .,2 Molecular Hepatology Group, Instituto de Investigación Sanitaria La Paz (IdiPAZ) , Madrid, Spain
| | - Dolores Pérez-Sala
- 1 Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas (CSIC) , Madrid, Spain
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Pérez-Sala D, Martínez-Costa ÓH, Aragón JJ, Pajares MA. Alterations in Nucleocytoplasmic Localization of the Methionine Cycle Induced by Oxidative Stress During Liver Disease. THE LIVER 2018:21-41. [DOI: 10.1016/b978-0-12-803951-9.00003-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Grattagliano I, Oliveira P, Vergani L, Portincasa P. Oxidative and Nitrosative Stress in Chronic Cholestasis. LIVER PATHOPHYSIOLOGY 2017:225-237. [DOI: 10.1016/b978-0-12-804274-8.00017-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Proteomics-Based Identification of the Molecular Signatures of Liver Tissues from Aged Rats following Eight Weeks of Medium-Intensity Exercise. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:3269405. [PMID: 28116034 PMCID: PMC5223045 DOI: 10.1155/2016/3269405] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Revised: 09/05/2016] [Accepted: 11/28/2016] [Indexed: 02/07/2023]
Abstract
Physical activity has emerged as a powerful intervention that promotes healthy aging by maintaining the functional capacity of critical organ systems. Here, by combining functional and proteomics analyses, we examined how hepatic phenotypes might respond to exercise treatment in aged rats. 16 male aged (20 months old) SD rats were divided into exercise and parallel control groups at random; the exercise group had 8 weeks of treadmill training with medium intensity. Whole protein samples of the liver were extracted from both groups and separated by two-dimensional gel electrophoresis. Alternatively objective protein spots with >2-fold difference in expression were selected for enzymological extraction and MS/MS identification. Results show increased activity of the manganese superoxide dismutase and elevated glutathione levels in the livers of exercise-treated animals, but malondialdehyde contents obviously decreased in the liver of the exercise group. Proteomics-based identification of differentially expressed proteins provided an integrated view of the metabolic adaptations occurring in the liver proteome during exercise, which significantly altered the expression of several proteins involved in key liver metabolic pathways including mitochondrial sulfur, glycolysis, methionine, and protein metabolism. These findings indicate that exercise may be beneficial to aged rats through modulation of hepatic protein expression profiles.
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Pérez C, Pérez-Zúñiga FJ, Garrido F, Reytor E, Portillo F, Pajares MA. The Oncogene PDRG1 Is an Interaction Target of Methionine Adenosyltransferases. PLoS One 2016; 11:e0161672. [PMID: 27548429 PMCID: PMC4993455 DOI: 10.1371/journal.pone.0161672] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 06/03/2016] [Indexed: 12/15/2022] Open
Abstract
Methionine adenosyltransferases MAT I and MAT III (encoded by Mat1a) catalyze S-adenosylmethionine synthesis in normal liver. Major hepatic diseases concur with reduced levels of this essential methyl donor, which are primarily due to an expression switch from Mat1a towards Mat2a. Additional changes in the association state and even in subcellular localization of these isoenzymes are also detected. All these alterations result in a reduced content of the moderate (MAT I) and high Vmax (MAT III) isoenzymes, whereas the low Vmax (MAT II) isoenzyme increases and nuclear accumulation of MAT I is observed. These changes derive in a reduced availability of cytoplasmic S-adenosylmethionine, together with an effort to meet its needs in the nucleus of damaged cells, rendering enhanced levels of certain epigenetic modifications. In this context, the putative role of protein-protein interactions in the control of S-adenosylmethionine synthesis has been scarcely studied. Using yeast two hybrid and a rat liver library we identified PDRG1 as an interaction target for MATα1 (catalytic subunit of MAT I and MAT III), further confirmation being obtained by immunoprecipitation and pull-down assays. Nuclear MATα interacts physically and functionally with the PDRG1 oncogene, resulting in reduced DNA methylation levels. Increased Pdrg1 expression is detected in acute liver injury and hepatoma cells, together with decreased Mat1a expression and nuclear accumulation of MATα1. Silencing of Pdrg1 expression in hepatoma cells alters their steady-state expression profile on microarrays, downregulating genes associated with tumor progression according to GO pathway analysis. Altogether, the results unveil the role of PDRG1 in the control of the nuclear methylation status through methionine adenosyltransferase binding and its putative collaboration in the progression of hepatic diseases.
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Affiliation(s)
- Claudia Pérez
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
| | - Francisco J. Pérez-Zúñiga
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
| | - Francisco Garrido
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
| | - Edel Reytor
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
| | - Francisco Portillo
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
- Instituto de Investigación Sanitaria La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid, Spain
- Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid, Spain
| | - María A. Pajares
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
- Instituto de Investigación Sanitaria La Paz (IdiPAZ), Paseo de la Castellana 261, 28046 Madrid, Spain
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Rambaldi A, Gluud C, Cochrane Hepato‐Biliary Group. WITHDRAWN: S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database Syst Rev 2015; 2015:CD002235. [PMID: 26560497 PMCID: PMC10734257 DOI: 10.1002/14651858.cd002235.pub3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The review is withdrawn as it was abandoned and has not been updated since its last edition in 2008. A new team of authors resumed the work on the review, and so far, a major update to the protocol is published. The review is expected to be finalised towards the end of 2016. The editorial group responsible for this previously published document have withdrawn it from publication.
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Affiliation(s)
- Andrea Rambaldi
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University HospitalThe Cochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Mathematical analysis of the regulation of competing methyltransferases. BMC SYSTEMS BIOLOGY 2015; 9:69. [PMID: 26467983 PMCID: PMC4606511 DOI: 10.1186/s12918-015-0215-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 09/22/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND Methyltransferase (MT) reactions, in which methyl groups are attached to substrates, are fundamental to many aspects of cell biology and human physiology. The universal methyl donor for these reactions is S-adenosylmethionine (SAM) and this presents the cell with an important regulatory problem. If the flux along one pathway is changed then the SAM concentration will change affecting all the other MT pathways, so it is difficult for the cell to regulate the pathways independently. METHODS We created a mathematical model, based on the known biochemistry of the folate and methionine cycles, to study the regulatory mechanisms that enable the cell to overcome this difficulty. Some of the primary mechanisms are long-range allosteric interactions by which substrates in one part of the biochemical network affect the activity of enzymes at distant locations in the network (not distant in the cell). Because of these long-range allosteric interactions, the dynamic behavior of the network is very complicated, and so mathematical modeling is a useful tool for investigating the effects of the regulatory mechanisms and understanding the complicated underlying biochemistry and cell biology. RESULTS We study the allosteric binding of 5-methyltetrahydrofolate (5 mTHF) to glycine-N-methyltransferase (GNMT) and explain why data in the literature implies that when one molecule binds, GNMT retains half its activity. Using the model, we quantify the effects of different regulatory mechanisms and show how cell processes would be different if the regulatory mechanisms were eliminated. In addition, we use the model to interpret and understand data from studies in the literature. Finally, we explain why a full understanding of how competing MTs are regulated is important for designing intervention strategies to improve human health. CONCLUSIONS We give strong computational evidence that once bound GNMT retains half its activity. The long-range allosteric interactions enable the cell to regulate the MT reactions somewhat independently. The low K m values of many MTs also play a role because the reactions then run near saturation and changes in SAM have little effect. Finally, the inhibition of the MTs by the product S-adenosylhomocysteine also stabilizes reaction rates against changes in SAM.
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Hathout L, Huang J, Zamani A, Morioka C, El-Saden S. White matter changes in chronic alcoholic liver disease: Hypothesized association and putative biochemical mechanisms. Med Hypotheses 2015; 85:825-34. [PMID: 26474927 DOI: 10.1016/j.mehy.2015.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Revised: 09/23/2015] [Accepted: 10/02/2015] [Indexed: 12/16/2022]
Abstract
Advanced liver disease has long been associated with cerebral abnormalities. These abnormalities, termed acquired hepatocerebral degeneration, are typically visualized as T1 weighted hyperintensity on MRI in the deep gray matter of the basal ganglia. Recent reports, however, have demonstrated that a subset of patients with chronic alcoholic liver disease may also develop white matter abnormalities. Thus far, the morphology of these changes is not well characterized. Previous studies have described these changes as patchy, sporadic white matter abnormalities but have not posited localization of these changes to any particular white matter tracts. This paper hypothesizes that the white matter findings associated with advanced alcoholic liver disease localize to the corticocerebellar tracts. As an initial investigation of this hypothesis, 78 patients with a diagnosis of liver cirrhosis and an MRI showing clearly abnormal T1 weighted hyperintensity in the bilateral globus pallidus, characteristic of chronic liver disease, were examined for white matter signal abnormalities in the corticocerebellar tracts using FLAIR and T2 weighted images. The corticocerebellar tracts were subdivided into two regions: periventricular white matter (consisting of the sum of the centrum-semiovale and corona radiata), and lower white matter (consisting of the corona radiata, internal capsules, middle cerebral peduncles, middle cerebellar peduncles and cerebellum). As compared to matched controls, significantly greater signal abnormalities in both the periventricular white matter and lower white matter regions of the corticocerebellar tracts were observed in patients with known liver cirrhosis and abnormal T1 W hyperintensity in the globi pallidi. This difference was most pronounced in the lower white matter region of the corticocerebellar tract, with statistical significance of p<0.0005. Furthermore, the pathophysiologic mechanism underlying these changes remains unknown. This paper hypothesizes that the etiology of white matter changes associated with advanced liver disease may resemble that of white matter findings in subacute combined degeneration secondary to vitamin B12 deficiency. Specifically, significant evidence suggests that dysfunctional methionine metabolism as well as dysregulated cytokine production secondary to B12 deficiency play a major role in the development of subacute combined degeneration. Similar dysfunction of methionine metabolism and cytokine regulation is seen in alcoholic liver disease and is hypothesized in this paper to, at least in part, lead to white matter findings associated with alcoholic liver disease.
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Affiliation(s)
| | - Jimmy Huang
- Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, United States; Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, United States
| | - Amir Zamani
- Harvard Medical School, Boston, MA, United States
| | - Craig Morioka
- Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, United States
| | - Suzie El-Saden
- Department of Radiological Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA, United States; Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, United States
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Delgado M, Garrido F, Pérez-Miguelsanz J, Pacheco M, Partearroyo T, Pérez-Sala D, Pajares MA. Acute liver injury induces nucleocytoplasmic redistribution of hepatic methionine metabolism enzymes. Antioxid Redox Signal 2014; 20:2541-2554. [PMID: 24124652 PMCID: PMC4024841 DOI: 10.1089/ars.2013.5342] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 10/11/2013] [Accepted: 10/14/2013] [Indexed: 12/12/2022]
Abstract
AIMS The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease. RESULTS Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities, and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine treatment induced hepatic nuclear accumulation of methionine adenosyltransferase (MAT) α1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear MAT activity. Acetaminophen (APAP) intoxication mimicked most galactosamine effects on hepatic MATα1, including accumulation of nuclear tetramers. H35 cells that overexpress tagged-MATα1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and APAP that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MATα1 induced by these agents correlated with decreased glutathione reduced form/glutathione oxidized form ratios and was prevented by N-acetylcysteine (NAC) and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MATα1 nuclear accumulation were only prevented by NAC in galactosamine-treated cells. INNOVATION Cytoplasmic and nuclear changes in proteins that regulate the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker. CONCLUSION Altogether these results demonstrate galactosamine- and APAP-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of redox-dependent mechanisms in the control of MATα1 subcellular distribution.
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Affiliation(s)
- Miguel Delgado
- Departamento de Metabolismo y Señalización Celular, Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid, Spain
| | - Francisco Garrido
- Departamento de Metabolismo y Señalización Celular, Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid, Spain
| | - Juliana Pérez-Miguelsanz
- Departamento de Metabolismo y Señalización Celular, Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid, Spain
- Departamento de Anatomía y Embriología Humana I, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - María Pacheco
- Departamento de Metabolismo y Señalización Celular, Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid, Spain
| | - Teresa Partearroyo
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain
| | | | - María Angeles Pajares
- Departamento de Metabolismo y Señalización Celular, Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Madrid, Spain
- Molecular Hepatology Group, IdiPAZ, Madrid, Spain
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15
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Pajares MA, Alvarez L, Pérez-Sala D. How are mammalian methionine adenosyltransferases regulated in the liver? A focus on redox stress. FEBS Lett 2013; 587:1711-1716. [PMID: 23669363 DOI: 10.1016/j.febslet.2013.04.034] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Revised: 04/24/2013] [Accepted: 04/28/2013] [Indexed: 12/20/2022]
Abstract
S-adenosylmethionine synthesis is a key process for cell function, and needs to be regulated at multiple levels. In recent years, advances in the knowledge of methionine adenosyltransferases have been significant. The discovery of nuclear localization of these enzymes suggests their transport to provide the methyl donor, S-adenosylmethionine, for DNA and histone methyltransferases in epigenetic modifications, opening new regulatory possibilities. Previous hypotheses considered only the cytoplasmic regulation of these enzymes, hence the need of an update to integrate recent findings. Here, we focus mainly on the liver and redox mechanisms, and their putative effects on localization and interactions of methionine adenosyltransferases.
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Affiliation(s)
- María A Pajares
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain.
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16
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Anstee QM, Day CP. S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. J Hepatol 2012; 57:1097-109. [PMID: 22659519 DOI: 10.1016/j.jhep.2012.04.041] [Citation(s) in RCA: 165] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Revised: 04/12/2012] [Accepted: 04/15/2012] [Indexed: 12/13/2022]
Abstract
S-adenosyl-L-methionine (SAMe; AdoMet) is an important, metabolically pleiotropic molecule that participates in multiple cellular reactions as the precursor for the synthesis of glutathione and principle methyl donor required for methylation of nucleic acids, phospholipids, histones, biogenic amines, and proteins. SAMe synthesis is depressed in chronic liver disease and so there has been considerable interest in the utility of SAMe to ameliorate disease severity. Despite encouraging pre-clinical data confirming that SAMe depletion can exacerbate liver injury and supporting a hepatoprotective role for SAMe therapy, to date no large, high-quality randomised clinical trials have been performed that establish clinical utility in specific disease states. Here, we offer an in-depth review of the published scientific literature relating to the physiological and pathophysiological roles of SAMe and its therapeutic use in liver disease, critically assessing implications for clinical practice and offering recommendations for further research.
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Affiliation(s)
- Quentin M Anstee
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Framlington Place, Newcastle-Upon-Tyne NE2 4HH, UK.
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17
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S-Adenosyl-L-Methionine Prevents Intracellular Glutathione Depletion by GSH-Depleting Drugs in Rat and Human Hepatocytes. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03258363] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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18
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Manzillo G, Piccinino F, Surrenti C, Frezza M, Giudici GA, Grazie C. Multicentre Double-Blind Placebo-Controlled Study of Intravenous and Oral S-Adenosyl-L-Methionine (SAMe) in Cholestatic Patients with Liver Disease. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/bf03258369] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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19
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Abstract
S-adenosylmethionine (AdoMet, also known as SAM and SAMe) is the principal biological methyl donor synthesized in all mammalian cells but most abundantly in the liver. Biosynthesis of AdoMet requires the enzyme methionine adenosyltransferase (MAT). In mammals, two genes, MAT1A that is largely expressed by normal liver and MAT2A that is expressed by all extrahepatic tissues, encode MAT. Patients with chronic liver disease have reduced MAT activity and AdoMet levels. Mice lacking Mat1a have reduced hepatic AdoMet levels and develop oxidative stress, steatohepatitis, and hepatocellular carcinoma (HCC). In these mice, several signaling pathways are abnormal that can contribute to HCC formation. However, injury and HCC also occur if hepatic AdoMet level is excessive chronically. This can result from inactive mutation of the enzyme glycine N-methyltransferase (GNMT). Children with GNMT mutation have elevated liver transaminases, and Gnmt knockout mice develop liver injury, fibrosis, and HCC. Thus a normal hepatic AdoMet level is necessary to maintain liver health and prevent injury and HCC. AdoMet is effective in cholestasis of pregnancy, and its role in other human liver diseases remains to be better defined. In experimental models, it is effective as a chemopreventive agent in HCC and perhaps other forms of cancer as well.
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Affiliation(s)
- Shelly C Lu
- Division of Gastroenterology and Liver Diseases, USC Research Center for Liver Diseases, Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine, Los Angeles, California 90033, USA.
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20
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Fungal S-adenosylmethionine synthetase and the control of development and secondary metabolism in Aspergillus nidulans. Fungal Genet Biol 2012; 49:443-54. [DOI: 10.1016/j.fgb.2012.04.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Revised: 04/11/2012] [Accepted: 04/12/2012] [Indexed: 12/15/2022]
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21
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Mudd SH, Wagner C, Luka Z, Stabler SP, Allen RH, Schroer R, Wood T, Wang J, Wong LJ. Two patients with hepatic mtDNA depletion syndromes and marked elevations of S-adenosylmethionine and methionine. Mol Genet Metab 2012; 105:228-36. [PMID: 22137549 PMCID: PMC3264801 DOI: 10.1016/j.ymgme.2011.11.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 11/07/2011] [Accepted: 11/07/2011] [Indexed: 02/07/2023]
Abstract
This paper reports studies of two patients proven by a variety of studies to have mitochondrial depletion syndromes due to mutations in either their MPV17 or DGUOK genes. Each was initially investigated metabolically because of plasma methionine concentrations as high as 15-21-fold above the upper limit of the reference range, then found also to have plasma levels of S-adenosylmethionine (AdoMet) 4.4-8.6-fold above the upper limit of the reference range. Assays of S-adenosylhomocysteine, total homocysteine, cystathionine, sarcosine, and other relevant metabolites and studies of their gene encoding glycine N-methyltransferase produced evidence suggesting they had none of the known causes of elevated methionine with or without elevated AdoMet. Patient 1 grew slowly and intermittently, but was cognitively normal. At age 7 years he was found to have hepatocellular carcinoma, underwent a liver transplant and died of progressive liver and renal failure at age almost 9 years. Patient 2 had a clinical course typical of DGUOK deficiency and died at age 8 ½ months. Although each patient had liver abnormalities, evidence is presented that such abnormalities are very unlikely to explain their elevations of AdoMet or the extent of their hypermethioninemias. A working hypothesis is presented suggesting that with mitochondrial depletion the normal usage of AdoMet by mitochondria is impaired, AdoMet accumulates in the cytoplasm of affected cells poor in glycine N-methyltransferase activity, the accumulated AdoMet causes methionine to accumulate by inhibiting activity of methionine adenosyltransferase II, and that both AdoMet and methionine consequently leak abnormally into the plasma.
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Affiliation(s)
- S Harvey Mudd
- Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD 20892, USA.
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22
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Cano A, Buqué X, Martínez-Uña M, Aurrekoetxea I, Menor A, García-Rodriguez JL, Lu SC, Martínez-Chantar ML, Mato JM, Ochoa B, Aspichueta P. Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice. Hepatology 2011; 54:1975-86. [PMID: 21837751 PMCID: PMC3222787 DOI: 10.1002/hep.24607] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
UNLABELLED Very low-density lipoprotein (VLDL) secretion provides a mechanism to export triglycerides (TG) from the liver to peripheral tissues, maintaining lipid homeostasis. In nonalcoholic fatty liver disease (NAFLD), VLDL secretion disturbances are unclear. Methionine adenosyltransferase (MAT) is responsible for S-adenosylmethionine (SAMe) synthesis and MAT I and III are the products of the MAT1A gene. Deficient MAT I and III activities and SAMe content in the liver have been associated with NAFLD, but whether MAT1A is required for normal VLDL assembly remains unknown. We investigated the role of MAT1A on VLDL assembly in two metabolic contexts: in 3-month-old MAT1A-knockout mice (3-KO), with no signs of liver injury, and in 8-month-old MAT1A-knockout mice (8-KO), harboring nonalcoholic steatohepatitis. In 3-KO mouse liver, there is a potent effect of MAT1A deletion on lipid handling, decreasing mobilization of TG stores, TG secretion in VLDL and phosphatidylcholine synthesis via phosphatidylethanolamine N-methyltransferase. MAT1A deletion also increased VLDL-apolipoprotein B secretion, leading to small, lipid-poor VLDL particles. Administration of SAMe to 3-KO mice for 7 days recovered crucial altered processes in VLDL assembly and features of the secreted lipoproteins. The unfolded protein response was activated in 8-KO mouse liver, in which TG accumulated and the phosphatidylcholine-to-phosphatidylethanolamine ratio was reduced in the endoplasmic reticulum, whereas secretion of TG and apolipoprotein B in VLDL was increased and the VLDL physical characteristics resembled that in 3-KO mice. MAT1A deletion also altered plasma lipid homeostasis, with an increase in lipid transport in low-density lipoprotein subclasses and decrease in high-density lipoprotein subclasses. CONCLUSION MAT1A is required for normal VLDL assembly and plasma lipid homeostasis in mice. Impaired VLDL synthesis, mainly due to SAMe deficiency, contributes to NAFLD development in MAT1A-KO mice.
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Affiliation(s)
- Ainara Cano
- Department of Physiology, University of the Basque Country Medical School, Bilbao, Spain
| | - Xabier Buqué
- Department of Physiology, University of the Basque Country Medical School, Bilbao, Spain
| | - Maite Martínez-Uña
- Department of Physiology, University of the Basque Country Medical School, Bilbao, Spain
| | - Igor Aurrekoetxea
- Department of Physiology, University of the Basque Country Medical School, Bilbao, Spain
| | - Ariane Menor
- Department of Physiology, University of the Basque Country Medical School, Bilbao, Spain
| | - Juan L García-Rodriguez
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Spain
| | - Shelly C Lu
- Division of Gastroenterology and Liver Diseases, University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - M. Luz Martínez-Chantar
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Spain
| | - José M. Mato
- CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Technology Park of Bizkaia, Spain
| | - Begoña Ochoa
- Department of Physiology, University of the Basque Country Medical School, Bilbao, Spain
| | - Patricia Aspichueta
- Department of Physiology, University of the Basque Country Medical School, Bilbao, Spain,Corresponding author: Patricia Aspichueta, Department of Physiology, University of the Basque Country Medical School, Sarriena s/n, 48940 Leioa, Spain. Phone: +34 946012896; Fax: +34 946015662;
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23
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Pajares MA, Markham GD. Methionine adenosyltransferase (s-adenosylmethionine synthetase). ADVANCES IN ENZYMOLOGY AND RELATED AREAS OF MOLECULAR BIOLOGY 2011; 78:449-521. [PMID: 22220481 DOI: 10.1002/9781118105771.ch11] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- María A Pajares
- Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid Spain
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24
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Halsted CH, Medici V. Vitamin-dependent methionine metabolism and alcoholic liver disease. Adv Nutr 2011; 2:421-7. [PMID: 22332083 PMCID: PMC3183592 DOI: 10.3945/an.111.000661] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Emerging evidence indicates that ethanol-induced alterations in hepatic methionine metabolism play a central role in the pathogenesis of alcoholic liver disease (ALD). Because malnutrition is a universal clinical finding in this disease and hepatic methionine metabolism is dependent upon dietary folate and vitamins B-6 and B-12, ALD can be considered an induced nutritional disorder that is conditioned by alcohol abuse. The present review describes the etiologies of these 3 vitamin deficiencies in ALD and how they interact with chronic ethanol exposure to alter hepatic methionine metabolism. Subsequent sections focus on molecular mechanisms for the interactions of aberrant methionine metabolism with ethanol in the pathogenesis of ALD, in particular the role of S-adenosylmethionine (SAM) in regulating the epigenetic expressions of genes relevant to pathways of liver injury. The review will conclude with descriptions of studies on the efficacy of SAM in the treatment of ALD and with discussion of potentially fruitful future avenues of research.
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25
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Gonzalez E, van Liempd S, Conde-Vancells J, Gutierrez-de Juan V, Perez-Cormenzana M, Mayo R, Berisa A, Alonso C, Marquez CA, Barr J, Lu SC, Mato JM, Falcon-Perez JM. Serum UPLC-MS/MS metabolic profiling in an experimental model for acute-liver injury reveals potential biomarkers for hepatotoxicity. Metabolomics 2011; 8:997-1011. [PMID: 23139648 PMCID: PMC3490499 DOI: 10.1007/s11306-011-0329-9] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
A key interest in clinical diagnosis and pharmaceutical industry is to have a repertoire of noninvasive biomarkers to-individually or in combination-be able to infer or predict the degree of liver injury caused by pathological conditions or drugs. Metabolomics-a comprehensive study of global metabolites-has become a highly sensitive and powerful tool for biomarker discovery thanks to recent technological advances. An ultra-performance liquid chromatography/time-of-flight tandem mass spectrometry (UPLC/TOF MS/MS)-based metabolomics approach was employed to investigate sera from galactosamine-treated rats to find potential biomarkers for acute liver injury. Hepatic damage was quantified by determining serum transaminase activity and in situ liver histological lesions. Principal component analysis in combination with coefficient of correlation analysis was used for biomarker selection and identification. According to the data, serum levels of several metabolites including glucose, amino acids, and membrane lipids were significantly modified, some of them showing a high correlation with the degree of liver damage determined by histological examination of the livers. In conclusion, this study supports that UPLC-MS/MS based serum metabolomics in experimental animal models could be a powerful approach to search for biomarkers for drug- or disease-induced liver injury.
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Affiliation(s)
- Esperanza Gonzalez
- Metabolomics Unit, CIC bioGUNE, CIBERehd, Bizkaia Technology Park, 48160 Derio, Bizkaia, Spain
| | - Sebastiaan van Liempd
- Metabolomics Platform, CIC bioGUNE, CIBERehd, Bizkaia Technology Park, 48160 Derio, Bizkaia, Spain
| | - Javier Conde-Vancells
- Metabolomics Unit, CIC bioGUNE, CIBERehd, Bizkaia Technology Park, 48160 Derio, Bizkaia, Spain
| | | | | | - Rebeca Mayo
- OWL Genomics, Bizkaia Technology Park, 48160 Derio, Bizkaia, Spain
| | - Agustin Berisa
- R&D and Innovation Department, FAES FARMA S.A., 48940 Leioa, Bizkaia, Spain
| | - Cristina Alonso
- OWL Genomics, Bizkaia Technology Park, 48160 Derio, Bizkaia, Spain
| | | | - Jonathan Barr
- OWL Genomics, Bizkaia Technology Park, 48160 Derio, Bizkaia, Spain
| | - Shelly C. Lu
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University Southern California, Los Angeles, CA 90033, USA
| | - Jose M. Mato
- Metabolomics Unit, CIC bioGUNE, CIBERehd, Bizkaia Technology Park, 48160 Derio, Bizkaia, Spain
| | - Juan M. Falcon-Perez
- Metabolomics Unit, CIC bioGUNE, CIBERehd, Bizkaia Technology Park, 48160 Derio, Bizkaia, Spain, IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
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Moghe A, Joshi-Barve S, Ghare S, Gobejishvili L, Kirpich I, McClain CJ, Barve S. Histone modifications and alcohol-induced liver disease: Are altered nutrients the missing link? World J Gastroenterol 2011; 17:2465-72. [PMID: 21633651 PMCID: PMC3103804 DOI: 10.3748/wjg.v17.i20.2465] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Revised: 02/12/2011] [Accepted: 02/19/2011] [Indexed: 02/06/2023] Open
Abstract
Alcoholism is a major health problem in the United States and worldwide, and alcohol remains the single most significant cause of liver-related diseases and deaths. Alcohol is known to influence nutritional status at many levels including nutrient intake, absorption, utilization, and excretion, and can lead to many nutritional disturbances and deficiencies. Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease (ALD). There is growing interest regarding epigenetic changes, including histone modifications that regulate gene expression during disease pathogenesis. Notably, modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation, and control gene transcription. This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD. The review is focused on four critical metabolites, namely, acetate, S-adenosylmethionine, nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD.
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27
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Mudd SH. Hypermethioninemias of genetic and non-genetic origin: A review. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2011; 157C:3-32. [PMID: 21308989 DOI: 10.1002/ajmg.c.30293] [Citation(s) in RCA: 147] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
This review covers briefly the major conditions, genetic and non-genetic, sometimes leading to abnormally elevated methionine, with emphasis on recent developments. A major aim is to assist in the differential diagnosis of hypermethioninemia. The genetic conditions are: (1) Homocystinuria due to cystathionine β-synthase (CBS) deficiency. At least 150 different mutations in the CBS gene have been identified since this deficiency was established in 1964. Hypermethioninemia is due chiefly to remethylation of the accumulated homocysteine. (2) Deficient activity of methionine adenosyltransferases I and III (MAT I/III), the isoenzymes the catalytic subunit of which are encoded by MAT1A. Methionine accumulates because its conversion to S-adenosylmethionine (AdoMet) is impaired. (3) Glycine N-methyltrasferase (GNMT) deficiency. Disruption of a quantitatively major pathway for AdoMet disposal leads to AdoMet accumulation with secondary down-regulation of methionine flux into AdoMet. (4) S-adenosylhomocysteine (AdoHcy) hydrolase (AHCY) deficiency. Not being catabolized normally, AdoHcy accumulates and inhibits many AdoMet-dependent methyltransferases, producing accumulation of AdoMet and, thereby, hypermethioninemia. (5) Citrin deficiency, found chiefly in Asian countries. Lack of this mitochondrial aspartate-glutamate transporter may produce (usually transient) hypermethioninemia, the immediate cause of which remains uncertain. (6) Fumarylacetoacetate hydrolase (FAH) deficiency (tyrosinemia type I) may lead to hypermethioninemia secondary either to liver damage and/or to accumulation of fumarylacetoacetate, an inhibitor of the high K(m) MAT. Additional possible genetic causes of hypermethioninemia accompanied by elevations of plasma AdoMet include mitochondrial disorders (the specificity and frequency of which remain to be elucidated). Non-genetic conditions include: (a) Liver disease, which may cause hypermethioninemia, mild, or severe. (b) Low-birth-weight and/or prematurity which may cause transient hypermethioninemia. (c) Ingestion of relatively large amounts of methionine which, even in full-term, normal-birth-weight babies may cause hypermethioninemia.
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Affiliation(s)
- S Harvey Mudd
- Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, MD, USA.
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28
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Cederbaum AI. Hepatoprotective effects of S-adenosyl-L-methionine against alcohol- and cytochrome P450 2E1-induced liver injury. World J Gastroenterol 2010; 16:1366-76. [PMID: 20238404 PMCID: PMC2842529 DOI: 10.3748/wjg.v16.i11.1366] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
S-adenosyl-L-methionine (SAM) acts as a methyl donor for methylation reactions and participates in the synthesis of glutathione. SAM is also a key metabolite that regulates hepatocyte growth, differentiation and death. Hepatic SAM levels are decreased in animal models of alcohol liver injury and in patients with alcohol liver disease or viral cirrhosis. This review describes the protection by SAM against alcohol and cytochrome P450 2E1-dependent cytotoxicity both in vitro and in vivo and evaluates mechanisms for this protection.
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29
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Cederbaum AI, Lu Y, Wu D. Role of oxidative stress in alcohol-induced liver injury. Arch Toxicol 2009; 83:519-48. [PMID: 19448996 DOI: 10.1007/s00204-009-0432-0] [Citation(s) in RCA: 441] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2009] [Accepted: 04/28/2009] [Indexed: 02/06/2023]
Abstract
Reactive oxygen species (ROS) are highly reactive molecules that are naturally generated in small amounts during the body's metabolic reactions and can react with and damage complex cellular molecules such as lipids, proteins, or DNA. Acute and chronic ethanol treatments increase the production of ROS, lower cellular antioxidant levels, and enhance oxidative stress in many tissues, especially the liver. Ethanol-induced oxidative stress plays a major role in the mechanisms by which ethanol produces liver injury. Many pathways play a key role in how ethanol induces oxidative stress. This review summarizes some of the leading pathways and discusses the evidence for their contribution to alcohol-induced liver injury. Special emphasis is placed on CYP2E1, which is induced by alcohol and is reactive in metabolizing and activating many hepatotoxins, including ethanol, to reactive products, and in generating ROS.
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Affiliation(s)
- Arthur I Cederbaum
- Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, Box 1603, One Gustave L Levy Place, New York, NY 10029, USA.
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Fernández A, Colell A, Caballero F, Matías N, García-Ruiz C, Fernández-Checa JC. Mitochondrial S-adenosyl-L-methionine transport is insensitive to alcohol-mediated changes in membrane dynamics. Alcohol Clin Exp Res 2009; 33:1169-80. [PMID: 19389197 DOI: 10.1111/j.1530-0277.2009.00940.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Alcohol-induced liver injury is associated with decreased S-adenosyl-l-methionine (SAM)/S-adenosyl-l-homocysteine (SAH) ratio and mitochondrial glutathione (mGSH) depletion, which has been shown to sensitize hepatocytes to tumor necrosis factor (TNF). AIMS As the effect of alcohol on mitochondrial SAM (mSAM) has been poorly characterized, our aim was to examine the status and transport of mSAM in relation to that of mGSH during alcohol intake. METHODS Sprague-Dawley rats were pair fed Lieber-DeCarli diets containing alcohol for 1 to 4 weeks and liver fractionated into cytosol and mitochondria to examine the mSAM transport and its sensitivity to membrane dynamics. RESULTS We found that cytosol SAM was depleted from the first week of alcohol feeding, with mSAM levels paralleling these changes. Cytosol SAH, however, increased during the first 3 weeks of alcohol intake, whereas its mitochondrial levels remained unchanged. mGSH depletion occurred by 3 to 4 weeks of alcohol intake due to cholesterol-mediated impaired transport from the cytosol. In contrast to this outcome, the transport of SAM into hepatic mitochondria was unaffected by alcohol intake and resistant to cholesterol-mediated perturbations in membrane dynamics; furthermore cytosolic SAH accumulation in primary hepatocytes by SAH hydrolase inhibition reproduced the mSAM depletion by alcohol due to the competition of SAH with SAM for mitochondrial transport. However, alcohol feeding did not potentiate the sensitivity to inhibition by SAH accumulation. CONCLUSIONS Alcohol-induced mSAM depletion precedes that of mGSH and occurs independently of alcohol-mediated perturbations in membrane dynamics, disproving an inherent defect in the mSAM transport by alcohol. These findings suggest that the early mSAM depletion may contribute to the alterations of mitochondrial membrane dynamics and the subsequent mGSH down-regulation induced by alcohol feeding.
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Affiliation(s)
- Anna Fernández
- Liver Unit and Centro de Investigaciones Biomédicas Esther Koplowitz, Instituto Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain
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Abstract
Methionine adenosyltransferases (MATs) are the family of enzymes that synthesize the main biological methyl donor, S-adenosylmethionine. The high sequence conservation among catalytic subunits from bacteria and eukarya preserves key residues that control activity and oligomerization, which is reflected in the protein structure. However, structural differences among complexes with substrates and products have led to proposals of several reaction mechanisms. In parallel, folding studies begin to explain how the three intertwined domains of the catalytic subunit are produced, and to highlight the importance of certain intermediates in attaining the active final conformation. This review analyzes the available structural data and proposes a consensus interpretation that facilitates an understanding of the pathological problems derived from impairment of MAT function. In addition, new research opportunities directed toward clarification of aspects that remain obscure are also identified.
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Affiliation(s)
- G. D. Markham
- Institute for Cancer Research, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111 USA
| | - M. A. Pajares
- Instituto de Investigaciones Biomédicas “Alberto Sols” (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain
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Wang X, Cederbaum AI. S-adenosyl-L-methionine decreases the elevated hepatotoxicity induced by Fas agonistic antibody plus acute ethanol pretreatment in mice. Arch Biochem Biophys 2008; 477:1-11. [PMID: 18482574 DOI: 10.1016/j.abb.2008.04.033] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2007] [Revised: 04/19/2008] [Accepted: 04/23/2008] [Indexed: 12/29/2022]
Abstract
The current study was designed to investigate the effect and potential mechanism of exogenous administration of S-adenosyl-l-methionine (SAM) on the enhanced hepatotoxicity induced by the Fas agonistic Jo2 antibody plus acute ethanol pretreatment in C57BL/6 mice. Acute ethanol plus Jo2 treatment produces liver toxicity under conditions in which ethanol alone or Jo2 alone do not. SAM significantly attenuated this elevated hepatotoxicity in mice as manifested by a decrease of serum aminotransferases and morphological amelioration. Levels of SAM and activity of methionine adenosyltransferase were lowered by the ethanol plus Jo2 treatment but restored by administration of SAM. The ethanol plus Jo2 treatment increased activity and content of CYP2E1, iNOS content and TNF-alpha levels; these increases were blunted by SAM. SAM also protected against the elevated oxidative and nitrosative stress found after ethanol plus Jo2, likely due to the decreases in CYP2E1, iNOS and TNF-alpha. Calcium-induced swelling of mitochondria was enhanced by the ethanol plus Jo2 treatment and this was prevented by SAM. JNK and P38 MAPK were activated by the ethanol plus Jo2 treatment; JNK activation was partially prevented by SAM. It is suggested that SAM protects against the ethanol plus Jo2 toxicity by restoring hepatic SAM levels, preventing the increase in iNOS, CYP2E1 and TNF-alpha and there by lowering the elevated oxidative/nitrosative stress and activation of the JNK signal pathway, ultimately preventing mitochondrial damage.
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Affiliation(s)
- Xiaodong Wang
- Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, One Gustave L. Levy Place, 1468 Madison Avenue, New York, NY 10029, USA.
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Ingenbleek Y, Young VR. The essentiality of sulfur is closely related to nitrogen metabolism: a clue to hyperhomocysteinaemia. Nutr Res Rev 2007; 17:135-51. [DOI: 10.1079/nrr200489] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
AbstractN and S metabolisms are closely interwoven throughout both the plant and animal kingdoms. The essentiality of S relates to its participation in the structure of S-containing amino acids (SAA), to its inclusion in many sulfonated molecules, and to a myriad of metabolic and catalytic reactions of vital importance. Methionine (Met) is the indispensable SAA supplied by food proteins and its plasma homeostasis is achieved via a number of highly efficient regulatory mechanisms. In all conditions characterised by a negative body protein balance such as in dietary restriction or cytokine-induced hypercatabolic losses, N and S endogenous pools manifest parallel tissue depletion rates. Adaptive conservation of N and S body stores is reached by a functional restraint of the trans-sulfuration cascade, through the depression of cystathionine β-synthase activity. As a result, upstream accumulation of homocysteine favours its re-methylation conversion to Met which helps maintain metabolic pathways of survival value. In addition to the measurement of vitamin indices, that of plasma transthyretin, a sensitive marker of protein nutritional status, is proposed to identify the fluctuations of the total body N component accountable for the alterations of homocysteine concentrations in body fluids.
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Kharbanda KK. Role of transmethylation reactions in alcoholic liver disease. World J Gastroenterol 2007; 13:4947-4954. [PMID: 17854136 PMCID: PMC4434617 DOI: 10.3748/wjg.v13.i37.4947] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2007] [Revised: 07/18/2007] [Accepted: 07/26/2007] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease is a major health care problem worldwide. Findings from many laboratories, including ours, have demonstrated that ethanol feeding impairs several of the many steps involved in methionine metabolism. Ethanol consumption predominantly results in a decrease in the hepatocyte level of S-adenosylmethionine and the increases in two toxic metabolites, homocysteine and S-adenosylhomocysteine. These changes, in turn, result in serious functional consequences which include decreases in essential methylation reactions via inhibition of various methyltransferases. Of particular interest to our laboratory is the inhibition of three important enzymes, phosphatidylethanolamine methyltransferase, isoprenylcysteine carboxyl methyltransferase and protein L-isoaspartate methyltransferase. Decreased activity of these enzymes results in increased fat deposition, increased apoptosis and increased accumulation of damaged proteins-all of which are hallmark features of alcoholic liver injury. Of all the therapeutic modalities available, betaine has been shown to be the safest, least expensive and most effective in attenuating ethanol-induced liver injury. Betaine, by virtue of aiding in the remethylation of homocysteine, removes both toxic metabolites (homocysteine and S-adenosylhomocysteine), restores S-adenosylmethionine level, and reverses steatosis, apoptosis and damaged proteins accumulation. In conclusion, betaine appears to be a promising therapeutic agent in relieving the methylation and other defects associated with alcoholic abuse.
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Affiliation(s)
- Kusum K Kharbanda
- Department of Veterans Affairs Medical Center, Research Service 151, 4101 Woolworth Avenue, Omaha, Nebraska 68105, USA.
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Hote PT, Sahoo R, Jani TS, Ghare SS, Chen T, Joshi-Barve S, McClain CJ, Barve SS. Ethanol inhibits methionine adenosyltransferase II activity and S-adenosylmethionine biosynthesis and enhances caspase-3-dependent cell death in T lymphocytes: relevance to alcohol-induced immunosuppression. J Nutr Biochem 2007; 19:384-91. [PMID: 17869084 PMCID: PMC4867115 DOI: 10.1016/j.jnutbio.2007.05.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2007] [Revised: 05/18/2007] [Accepted: 05/23/2007] [Indexed: 02/02/2023]
Abstract
An important aspect in alcohol abuse-associated immune suppression is the loss of T helper CD4(+) lymphocytes, leading to impairment of multiple immune functions. Our work has shown that ethanol can sensitize CD4(+) T lymphocytes to caspase-3-dependent activation-induced cell death (AICD). It has been demonstrated that the formation of S-adenosylmethionine (SAMe) catalyzed by methionine adenosyltransferase (MAT) II is essential for CD4(+) T-cell activation and proliferation. Since ethanol is known to affect SAMe metabolism in hepatocytes, we investigated the effect of ethanol on MAT II activity/expression, SAMe biosynthesis and cell survival in CD4(+) T lymphocytes. We demonstrate for the first time that ethanol at a physiologically relevant concentration (25 mM) substantially decreased the enzymatic activity of MAT II in T lymphocytes. Ethanol was observed to decrease the transcription of MAT2A, which encodes the catalytic subunit of MAT II and is vital for MAT II activity and SAMe biosynthesis. Furthermore, correspondent to its effect on MAT II, ethanol decreased intracellular SAMe levels and enhanced caspase-3-dependent AICD. Importantly, restoration of intracellular SAMe levels by exogenous SAMe supplementation considerably decreased both caspase-3 activity and apoptotic death in T lymphocytes. In conclusion, our data show that MAT II and SAMe are critical molecular components essential for CD4(+) T-cell survival that are affected by ethanol, leading to enhanced AICD. Furthermore, these studies provide a clinical paradigm for the development of much needed therapy using SAMe supplementation in the treatment of immune dysfunction induced by alcohol abuse.
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Affiliation(s)
- Prachi T Hote
- Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY 40292, USA
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Achón M, Alonso-Aperte E, Ubeda N, Varela-Moreiras G. Supranormal dietary folic acid supplementation: effects on methionine metabolism in weanling rats. Br J Nutr 2007; 98:490-6. [PMID: 17419891 DOI: 10.1017/s0007114507721499] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
There are nationwide folic acid (FA) fortification programmes of staple foods established or under consideration in order to prevent neural tube defects. Universal FA fortification still remains controversial because of the concern that additional FA in the diets of population groups (e.g. children and elderly) not initially targeted for fortification may suffer adverse effects. However, dietary surveys regarding folate generally deal with adults and little is known about the consumption and long-term effects of fortified food and supplements in growing individuals. Recent reports from our laboratory show several effects of high-dose folate supplementation in rats. In the present work, we studied the effect of FA on the methionine cycle in weanling (3-week-old) male rats after 4 weeks of supplementation with 40 mg FA/kg dietv.control (1 mg FA/kg diet). FA supplementation resulted in a reduction of homocysteine and creatinine concentrationsv.control group. FA supplementation did not alterS-adenosylmethionine/S-adenosylhomocysteine ratio, DNA methylation, enzymatic activities or concentrations of vitamins involved in the nutritional regulation of the methionine cycle, except for folate. FA supplementation of 40 mg/kg did not lead to hepatic or renal damage. In conclusion, there were no apparent adverse effects on one-carbon metabolism after FA supplementation in the studied conditions.
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Affiliation(s)
- M Achón
- Departamento de Nutrición, Bromatología y Tecnología de los Alimentos, Facultad de Farmacia, Universidad San Pablo-CEU, 28668 Boadilla del Monte, Madrid, Spain
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Purohit V, Abdelmalek MF, Barve S, Benevenga NJ, Halsted CH, Kaplowitz N, Kharbanda KK, Liu QY, Lu SC, McClain CJ, Swanson C, Zakhari S. Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr 2007; 86:14-24. [PMID: 17616758 DOI: 10.1093/ajcn/86.1.14] [Citation(s) in RCA: 132] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and folate in the treatment of alcoholic liver disease (ALD), which was organized by the National Institute on Alcohol Abuse and Alcoholism in collaboration with the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine of the National Institutes of Health (Bethesda, MD) and held on 3 October 2005. SAM supplementation may attenuate ALD by decreasing oxidative stress through the up-regulation of glutathione synthesis, reducing inflammation via the down-regulation of tumor necrosis factor-alpha and the up-regulation of interleukin-10 synthesis, increasing the ratio of SAM to S-adenosylhomocysteine (SAH), and inhibiting the apoptosis of normal hepatocytes and stimulating the apoptosis of liver cancer cells. Folate deficiency may accelerate or promote ALD by increasing hepatic homocysteine and SAH concentrations; decreasing hepatic SAM and glutathione concentrations and the SAM-SAH ratio; increasing cytochrome P4502E1 activation and lipid peroxidation; up-regulating endoplasmic reticulum stress markers, including sterol regulatory element-binding protein-1, and proapoptotic gene caspase-12; and decreasing global DNA methylation. Betaine may attenuate ALD by increasing the synthesis of SAM and, eventually, glutathione, decreasing the hepatic concentrations of homocysteine and SAH, and increasing the SAM-SAH ratio, which can trigger a cascade of events that lead to the activation of phosphatidylethanolamine methyltransferase, increased phosphatidylcholine synthesis, and formation of VLDL for the export of triacylglycerol from the liver to the circulation. Additionally, decreased concentrations of homocysteine can down-regulate endoplasmic reticulum stress, which leads to the attenuation of apoptosis and fatty acid synthesis.
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Affiliation(s)
- Vishnudutt Purohit
- Division of Metabolism and Health Effects, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
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Santamaría E, Muñoz J, Fernández-Irigoyen J, Prìeto J, Corrales FJ. Toward the discovery of new biomarkers of hepatocellular carcinoma by proteomics. Liver Int 2007; 27:163-173. [PMID: 17311610 DOI: 10.1111/j.1478-3231.2007.01447.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Primary liver cancer is the fifth most frequent neoplasm and the third most common cause of cancer-related death, with more than 500,000 new cases diagnosed yearly. The outcome for hepatocellular carcinoma (HCC) patients still remains dismal, partly because of our limited knowledge of its molecular pathogenesis and the difficulty in detecting the disease at its early stages. Therefore, studies aimed at the definition of the mechanisms associated with HCC progression and the identification of new biomarkers leading to early diagnosis and more effective therapeutic interventions are urgently needed. Proteomics is a rapidly expanding discipline that is expected to change the way in which diseases will be diagnosed, treated, and monitored in the near future. In the last few years, HCC has been extensively investigated using different proteomic approaches on HCC cell lines, animal models, and human tumor tissues. In this review, state-of-the-art technology on proteomics is overviewed, and recent advances in liver cancer proteomics and their clinical projections are discussed.
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Affiliation(s)
- Enrique Santamaría
- Division of Hepatology and Gene Therapy, Laboratory of Proteomics, CIMA, University of Navarra, Pamplona, Spain
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Hanje AJ, Fortune B, Song M, Hill D, McClain C. The use of selected nutrition supplements and complementary and alternative medicine in liver disease. Nutr Clin Pract 2006; 21:255-72. [PMID: 16772543 PMCID: PMC4239999 DOI: 10.1177/0115426506021003255] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Almost all patients with liver disease, especially advanced liver disease, have some evidence of malnutrition, including mineral/vitamin deficiency. A major health trend in the United States has been the significant growth in the use of complementary and alternative medicine (CAM), including nutrition supplements and herbal agents. In the 1990s, the United States government created the National Center for Complementary and Alternative Medicine (NCCAM), as well as the Office on Dietary Supplements, to extend our knowledge in these areas. CAM users are often highly educated and frequently use CAM therapy for chronic diseases, including chronic liver disease. Indeed, most studies suggest that patients with chronic liver disease frequently use nutrition supplements and CAM agents in addition to their traditional medicines. The purpose of this review is to provide an update on the role of nutrition supplements and herbals in liver disease. This article will focus mainly on 7 selected agents (vitamin E, zinc, magnesium, S-adenosylmethionine, betaine, silymarin, and glycyrrhizin), for which there have been not only in vitro and animal studies but also human clinical trials, and we will review both potential efficacy and safety issues.
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Affiliation(s)
- A James Hanje
- Department of Medicine, The Ohio State University, Columbus, Ohio, USA
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Kareta MS, Botello ZM, Ennis JJ, Chou C, Chédin F. Reconstitution and mechanism of the stimulation of de novo methylation by human DNMT3L. J Biol Chem 2006; 281:25893-902. [PMID: 16829525 DOI: 10.1074/jbc.m603140200] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The DNMT3-like protein, DNMT3L, is required for germ line DNA methylation, although it is inactive as a DNA methyltransferase per se. Previous studies have shown that DNMT3L physically associates with the active de novo DNA methyltransferases, DNMT3A and DNMT3B, and stimulates their catalytic activities in a cell culture system. However, the mechanism by which DNMT3L stimulates de novo methylation remains unclear. Here, we have purified the full-length human DNMT3A2 and DNMT3L proteins and determined unique conditions that allow for the proper reconstitution of the stimulation of DNMT3A2 de novo methyltransferase activity by DNMT3L. These conditions include the use of buffers resembling physiological conditions and the preincubation of the two proteins. Under these conditions, maximal stimulation is reached at equimolar amounts of DNMT3L and DNMT3A2 proteins, and the catalytic efficiency of DNMT3A2 is increased up to 20-fold. Biochemical analysis revealed that whereas DNMT3L on its own does not significantly bind to the methyl group donor, S-adenosyl-L-methionine (SAM), it strongly increases the binding of SAM to DNMT3A2. DNA binding, on the contrary, was not appreciably improved. Analysis of DNA methyltransferase complexes in solution using size exclusion chromatography revealed that DNMT3A2 forms large structures of heterogeneous sizes, whereas DNMT3L appears as a monomer. Binding of DNMT3L to DNMT3A2 promotes a dramatic reorganization of DNMT3A2 subunits and leads to the formation of specific complexes with enhanced DNA methyltransferase activity and increased SAM binding.
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Affiliation(s)
- Michael S Kareta
- Section of Molecular and Cellular Biology and Center for Genetics and Development, University of California, Davis, California 95616, USA
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Abstract
BACKGROUND Alcohol is a major cause of liver disease and disrupts methionine and oxidative balances. S-adenosyl-L-methionine (SAMe) acts as a methyl donor for methylation reactions and participates in the synthesis of glutathione, the main cellular antioxidant. Randomised clinical trials have addressed the question whether SAMe may benefit patients with alcoholic liver diseases. OBJECTIVES To evaluate the beneficial and harmful effects of SAMe for patients with alcoholic liver diseases. SEARCH STRATEGY We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (May 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1950 to May 2005), EMBASE (1980 to May 2005), and Science Citation Index Expanded (searched May 2005). SELECTION CRITERIA We included randomised clinical trials studying patients with alcoholic liver diseases. Interventions encompassed per oral or parenteral administration of SAMe at any dose versus placebo or no intervention. DATA COLLECTION AND ANALYSIS We performed all analyses according to the intention-to-treat method using RevMan Analyses provided by the Cochrane Collaboration. We evaluated the methodological quality of the randomised clinical trials by quality components. MAIN RESULTS We identified nine randomised clinical trials including a heterogeneous sample of 434 patients with alcoholic liver diseases. The methodological quality regarding randomisation was generally low, but 8 out of 9 trials were placebo controlled. Only one trial including 123 patients with alcoholic cirrhosis used adequate methodology and reported clearly on all-cause mortality and liver transplantation. We found no significant effects of SAMe on all-cause mortality (relative risks (RR) 0.62, 95% confidence interval (CI) 0.30 to 1.26), liver-related mortality (RR 0.68, 95% CI 0.31 to 1.48), all-cause mortality or liver transplantation (RR 0.55; 95% CI 0.27 to 1.09), or complications (RR 1.35, 95% CI 0.84 to 2.16), but the analysis is based mostly on one trial only. SAMe was not significantly associated with non-serious adverse events (RR 4.92; 95% CI 0.59 to 40.89) and no serious adverse events were reported. AUTHORS' CONCLUSIONS We could not find evidence supporting or refuting the use of SAMe for patients with alcoholic liver diseases. We need more long-term, high-quality randomised trials on SAMe for these patients before SAMe may be recommended for clinical practice.
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Affiliation(s)
- A Rambaldi
- Ospedale San Paolo, Divisione di Medicina Generale, Via Terracina, Napoli, Campania, Italy, 80100.
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Santamaría E, Muñoz J, Fernandez-Irigoyen J, Sesma L, Mora MI, Berasain C, Lu SC, Mato JM, Prieto J, Avila MA, Corrales FJ. Molecular profiling of hepatocellular carcinoma in mice with a chronic deficiency of hepatic s-adenosylmethionine: relevance in human liver diseases. J Proteome Res 2006; 5:944-953. [PMID: 16602702 DOI: 10.1021/pr050429v] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
S-adenosylmethionine arises as a central molecule in the preservation of liver homeostasis as a chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. In the present work, we have attempted a comprehensive analysis of proteins associated with hepatocarcinogenesis in MAT1A knock out mice using a combination of two-dimensional electrophoresis and mass spectrometry, to then apply the resulting information to identify hallmarks of human HCC. Our results suggest the existence of individual-specific factors that might condition the development of preneoplastic lesions. Proteomic analysis allowed the identification of 151 differential proteins in MAT1A-/- mice tumors. Among all differential proteins, 27 changed in at least 50% of the analyzed tumors, and some of these alterations were already detected months before the development of HCC in the KO liver. The expression level of genes coding for 13 of these proteins was markedly decreased in human HCC. Interestingly, seven of these genes were also found to be down-regulated in a pretumoral condition such as cirrhosis, while depletion of only one marker was assessed in less severe liver disorders.
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Affiliation(s)
- Enrique Santamaría
- Division of Hepatology and Gene Therapy, CIMA, University of Navarra, 31008 Pamplona, Spain
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McClain C, Barve S, Joshi-Barve S, Song Z, Deaciuc I, Chen T, Hill D. Dysregulated cytokine metabolism, altered hepatic methionine metabolism and proteasome dysfunction in alcoholic liver disease. Alcohol Clin Exp Res 2006; 29:180S-8S. [PMID: 16344606 DOI: 10.1097/01.alc.0000189276.34230.f5] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Alcoholic liver disease (ALD) remains an important complication and cause of morbidity and mortality from alcohol abuse. Major developments in our understanding of the mechanisms of ALD over the past decade are now being translated into new forms of therapy for this disease process which currently has no FDA approved treatment. Cytokines are low molecular weight mediators of cellular communication, and the pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to play a pivotal role in the development of experimental ALD. Similarly, TNF levels are elevated in the serum of alcoholic hepatitis patients. Abnormal methionine metabolism is well documented in patients with ALD, with patients having elevated serum methionine levels, but low S-adenosylmethionine levels in the liver. On the other hand, S-adenosylhomocysteine and homocysteine levels are elevated in ALD. Recent studies have documented potential interactions between homocysteine and S-adenosylhomocysteine with TNF in the development of ALD. Altered proteasome function also is now well documented in ALD, and decreased proteasome function can cause hepatocyte apoptosis. Recently it has been shown that decreased proteasome function can also act synergistically to enhance TNF hepatotoxicity. Hepatocytes dying of proteasome dysfunction release pro-inflammatory cytokines such as Interleukin-8 to cause sustained inflammation. This article reviews the interactions of cytokines, altered methionine metabolism, and proteasome dysfunction in the development of ALD.
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Affiliation(s)
- Craig McClain
- Department of Internal Medicine, Department of Pharmacology and Toxicology, University of Louisville Medical Center, Louisville, KY 40202, USA.
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Fernández-Irigoyen J, Santamaría E, Sesma L, Muñoz J, Riezu JI, Caballería J, Lu SC, Prieto J, Mato JM, Avila MA, Corrales FJ. Oxidation of specific methionine and tryptophan residues of apolipoprotein A-I in hepatocarcinogenesis. Proteomics 2005; 5:4964-4972. [PMID: 16252306 DOI: 10.1002/pmic.200500070] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common neoplasm with more than 500 000 new cases diagnosed yearly. Although major risk factors of HCC are currently known, the identification of biological targets leading to an early diagnosis of the disease is considered one of the priorities of clinical hepatology. In this work we have used a proteomic approach to identify markers of hepatocarcinogenesis in the serum of a knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)), as well as in patients with HCC. Three isoforms of apolipoprotein A-I (Apo A-I) with different pI were identified in murine serum. Isoform 1 is up-regulated in the serum of MAT1A(-/-) mice much earlier than any histological manifestation of liver disease. Further characterization of the differential isoform by electrospray MS/MS revealed specific oxidation of methionine 85 and 216 to methionine sulfoxide while the sequence of the analogous peptides on isoforms 2 and 3 showed the nonoxidized methionine residues. Enrichment of an acidic isoform of Apo A-I was also assessed in the serum of hepatitis B virus patients who developed HCC. Specific oxidation of methionine 112 to methionine sulfoxide and tryptophans 50 and 108 to formylkinurenine were identified selectively in the up-regulated isoform. Although it is not clear at present whether the occurrence of these modifications has a causal role or simply reflects secondary epiphenomena, this selectively oxidized Apo A-I isoform may be considered as a pathological hallmark that may help to the understanding of the molecular pathogenesis of HCC.
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Pérez-Pertejo Y, Reguera RM, Ordóñez D, Balaña-Fouce R. Characterization of a methionine adenosyltransferase over-expressing strain in the trypanosomatid Leishmania donovani. Biochim Biophys Acta Gen Subj 2005; 1760:10-9. [PMID: 16280200 DOI: 10.1016/j.bbagen.2005.09.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2005] [Revised: 09/02/2005] [Accepted: 09/06/2005] [Indexed: 10/25/2022]
Abstract
Methionine adenosyltransferase (MAT: EC 2.5.1.6) catalyzes the synthesis of S-adenosylmethionine (AdoMet) in two sequential steps, AdoMet formation and subsequent tripolyphosphate (PPPi) cleavage, induced by AdoMet. In pursuit of a better understanding of the biological function of the enzyme, the MAT gene was cloned into vector PX63NEO to induce episomal overexpression in leishmania parasites. Neomycin-selected clones originated a strain of such overexpressing parasites that accumulated more than 3-fold AdoMet than mock-transfected cells and showed over ten times the wild type MAT activity, concurring with a significant accumulation of the MAT protein during the early logarithmic phase and MAT transcripts throughout the growth cycle. The rate of AdoMet efflux, practically nil in the control promastigotes, was exceptionally high in the MAT-overexpressing parasites, whilst growth in this strain was comparable to development in control cells, i.e., it was not affected by deleterious hypermethylation. Moreover, the modified strain was 10-fold more resistant to sinefungin, a S-adenosylmethionine-like antibiotic, than control cells. The effects of overexpression on polyamine metabolism and transport were likewise studied.
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Affiliation(s)
- Yolanda Pérez-Pertejo
- Departamento de Farmacología y Toxicología (INTOXCAL), Universidad de León, Campus de Vegazana s/n; 24071 León, Spain
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Murillo-Fuentes ML, Artillo R, Ubeda N, Varela-Moreiras G, Murillo ML, Carreras O. Hepatic S-adenosylmethionine after maternal alcohol exposure on offspring rats. Addict Biol 2005; 10:139-44. [PMID: 16191665 DOI: 10.1080/13556210500123043] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
S-adenosylmethionine (SAM) is an universal methyl donor for biological systems in transmethylation reactions. Another metabolic pathway involving S-adenosylmethionine is initiated with the release of -CH3 from the molecule and the formation of S-adenosylhomocysteine and then homocysteine and cysteine, a precursor of the main cellular antioxidant glutathione. Chronic ethanol consumption could affect the bioavailability of amino acids such as methionine. Our purpose was to determine the effect of chronic alcohol feeding during gestation or lactation on hepatic S-adenosyl-methionine, S-adenosylhomocysteine, DNA methylation and homocysteine serum concentration at the end of the lactation period (21-day-old offspring). Wistar dam rats were fed with alcohol during periconceptional, gestation and lactation periods (alcohol-fed rats). This study was conducted with three groups of offspring with different periods of alcohol exposure: control offspring (C), no treatment; and gestation (G) and lactation (L) offspring, exposed to alcohol only during gestation or lactation, respectively. To obtain these last two groups of offspring, on parturition day control newborn rats were cross-fostered to alcohol-fed dams (L) and alcohol new-born rats were cross-fostered to control dams (G). In conclusion, these results indicate that exposure of rats to ethanol during the lactation period affects SAM values more severely than ethanol exposure only during gestation.
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Center S, Randolph J, Warner K, McCabe-McClelland J, Foureman P, Hoffmann W, Erb H. The Effects of S-Adenosylmethionine on Clinical Pathology and Redox Potential in the Red Blood Cell, Liver, and Bile of Clinically Normal Cats. J Vet Intern Med 2005. [DOI: 10.1111/j.1939-1676.2005.tb02699.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Affiliation(s)
- J D Finkelstein
- Department of Veterans Affairs Medical Center and George Washington University School of Medicine, Washington, DC, USA
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Iloro I, Chehín R, Goñi FM, Pajares MA, Arrondo JLR. Methionine adenosyltransferase alpha-helix structure unfolds at lower temperatures than beta-sheet: a 2D-IR study. Biophys J 2005; 86:3951-8. [PMID: 15189891 PMCID: PMC1304296 DOI: 10.1529/biophysj.103.028373] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Two-dimensional infrared spectroscopy has been used to characterize rat liver methionine adenosyltransferase and the events taking place during its thermal unfolding. Secondary structure data have been obtained for the native recombinant enzyme by fitting the amide I band of infrared spectra. Thermal denaturation studies allow the identification of events associated with individual secondary-structure elements during temperature-induced unfolding. They are correlated to the changes observed in enzyme activity and intrinsic fluorescence. In all cases, thermal denaturation proved to be an irreversible process, with a T(m) of 47-51 degrees C. Thermal profiles and two-dimensional infrared spectroscopy show that unfolding starts with alpha-helical segments and turns, located in the outer part of the protein, whereas extended structure, associated with subunit contacts, unfolds at higher temperatures. The data indicate a good correlation between the denaturation profiles obtained from activity measurements, fluorescence spectroscopy, and the behavior of the infrared bands. A study of the sequence of events that takes place is discussed in light of the previous knowledge on methionine adenosyltransferase structure and oligomerization pathway.
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Affiliation(s)
- Ibon Iloro
- Unidad de Biofisica (Centro Mixto CSIC-UPV) and Departamento de Bioquimica, Universidad del Pais Vasco, Bilbao, Spain
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