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Kotrulev M, Gomez-Touriño I, Cordero OJ. Soluble CD26: From Suggested Biomarker for Cancer Diagnosis to Plausible Marker for Dynamic Monitoring of Immunotherapy. Cancers (Basel) 2024; 16:2427. [PMID: 39001488 PMCID: PMC11240764 DOI: 10.3390/cancers16132427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
Soluble CD26 (sCD26), a glycoprotein with dipeptidyl peptidase (DPP4) enzymatic activity, can contribute to early diagnosis of colorectal cancer and advanced adenomas and has been studied, including for prognostic purposes, across various other types of cancer and disease. The latest research in this field has confirmed that most, though not all, serum/plasma sCD26 is related to inflammation. The shedding and/or secretion of sCD26 from different immune cells are being investigated, and blood DPP4 activity levels do not correlate very strongly with protein titers. Some of the main substrates of this enzyme are key chemokines involved in immune cell migration, and both soluble and cell-surface CD26 can bind adenosine deaminase (ADA), an enzyme involved in the metabolism of immunosuppressor extracellular adenosine. Of note, there are T cells enriched in CD26 expression and, in mice tumor models, tumor infiltrating lymphocytes exhibited heightened percentages of CD26+ correlating with tumor regression. We employed sCD26 as a biomarker in the follow-up after curative resection of colorectal cancer for the early detection of tumor recurrence. Changes after treatment with different biological disease-modifying antirheumatic drugs, including Ig-CTLA4, were also observed in rheumatoid arthritis. Serum soluble CD26/DPP4 titer variation has recently been proposed as a potential prognostic biomarker after a phase I trial in cancer immunotherapy with a humanized anti-CD26 antibody. We propose that dynamic monitoring of sCD26/DPP4 changes, in addition to well-known inflammatory biomarkers such as CRP already in use as informative for immune checkpoint immunotherapy, may indicate resistance or response during the successive steps of the treatment. As tumor cells expressing CD26 can also produce sCD26, the possibility of sorting immune- from non-immune-system-originated sCD26 is discussed.
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Affiliation(s)
- Martin Kotrulev
- Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (M.K.); (I.G.-T.)
- Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
| | - Iria Gomez-Touriño
- Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain; (M.K.); (I.G.-T.)
- Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Oscar J. Cordero
- Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain
- Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
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Barchetta I, Cimini FA, Dule S, Cavallo MG. Dipeptidyl Peptidase 4 (DPP4) as A Novel Adipokine: Role in Metabolism and Fat Homeostasis. Biomedicines 2022; 10:biomedicines10092306. [PMID: 36140405 PMCID: PMC9496088 DOI: 10.3390/biomedicines10092306] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Dipeptidyl peptidase 4 (DPP4) is a molecule implicated in the regulation of metabolic homeostasis and inflammatory processes, and it exerts its main action through its enzymatic activity. DPP4 represents the enzyme most involved in the catabolism of incretin hormones; thus, its activity impacts appetite, energy balance, and the fine regulation of glucose homeostasis. Indeed, DPP4 inhibitors represent a class of antidiabetic agents widely used for the treatment of Type 2 diabetes mellitus (T2DM). DPP4 also acts as an adipokine and is mainly secreted by the adipose tissue, mostly from mature adipocytes of the visceral compartment, where it exerts autocrine and paracrine activities. DPP4 can disrupt insulin signaling within the adipocyte and in other target cells and tissues, where it also favors the development of a proinflammatory environment. This is likely at the basis of the presence of elevated circulating DPP4 levels in several metabolic diseases. In this review, we summarize the most recent evidence of the role of the DPP4 as an adipokine-regulating glucose/insulin metabolism and fat homeostasis, with a particular focus on clinical outcomes associated with its increased secretion in the presence of adipose tissue accumulation and dysfunction.
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Ayoub BM, Michel HE, Mowaka S, Hendy MS, Tadros MM. Repurposing of Omarigliptin as a Neuroprotective Agent Based on Docking with A 2A Adenosine and AChE Receptors, Brain GLP-1 Response and Its Brain/Plasma Concentration Ratio after 28 Days Multiple Doses in Rats Using LC-MS/MS. Molecules 2021; 26:molecules26040889. [PMID: 33567615 PMCID: PMC7915074 DOI: 10.3390/molecules26040889] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/02/2021] [Accepted: 02/05/2021] [Indexed: 12/26/2022] Open
Abstract
The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases.
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Affiliation(s)
- Bassam M. Ayoub
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt; (S.M.); (M.S.H.)
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt
- Correspondence: ; Tel.: +20-226-890-000; Fax: +20-226-300-010
| | - Haidy E. Michel
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abassia, Cairo 11566, Egypt;
| | - Shereen Mowaka
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt; (S.M.); (M.S.H.)
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt
- Analytical Chemistry Department, Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo 11795, Egypt
| | - Moataz S. Hendy
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt; (S.M.); (M.S.H.)
- The Center for Drug Research and Development (CDRD), Faculty of Pharmacy, The British University in Egypt, El-Sherouk City, Cairo 11837, Egypt
| | - Mariam M. Tadros
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abassia, Cairo 11566, Egypt;
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Nargis T, Chakrabarti P. Significance of circulatory DPP4 activity in metabolic diseases. IUBMB Life 2018; 70:112-119. [DOI: 10.1002/iub.1709] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 12/18/2017] [Indexed: 01/12/2023]
Affiliation(s)
- Titli Nargis
- Division of Cell Biology and Physiology; CSIR-Indian Institute of Chemical Biology; Kolkata India
| | - Partha Chakrabarti
- Division of Cell Biology and Physiology; CSIR-Indian Institute of Chemical Biology; Kolkata India
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Abstract
Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.
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Affiliation(s)
- Erin E Mulvihill
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada
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Leicht S, Shipkova M, Klett C, Gert H, Altrock E, Wilhelm J, Bolley R, Wollmeyer J, Ender A, Luz B, Olbricht C, Wieland E. CD26/dipeptidyl peptidase IV: A comparative study of healthy persons and kidney transplant recipients before and early after transplantation. Clin Biochem 2013; 46:1383-8. [DOI: 10.1016/j.clinbiochem.2013.04.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Revised: 04/02/2013] [Accepted: 04/03/2013] [Indexed: 12/12/2022]
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Cordero OJ, Imbernon M, Chiara LD, Martinez-Zorzano VS, Ayude D, de la Cadena MP, Rodriguez-Berrocal FJ. Potential of soluble CD26 as a serum marker for colorectal cancer detection. World J Clin Oncol 2011; 2:245-61. [PMID: 21773075 PMCID: PMC3139035 DOI: 10.5306/wjco.v2.i6.245] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 03/28/2011] [Accepted: 04/05/2011] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is characterized by a low survival rate even though the basis for colon cancer development, which involves the evolution of adenomas to carcinoma, is known. Moreover, the mortality rates continue to rise in economically transitioning countries although there is the opportunity to intervene in the natural history of the adenoma–cancer sequence through risk factors, screening, and treatment. Screening in particular accounted for most of the decline in colorectal cancer mortality achieved in the USA during the period 1975-2000. Patients show a better prognosis when the neoplasm is diagnosed early. Among the variety of screening strategies, the methods range from invasive and costly procedures such as colonoscopy to more low-cost and non-invasive tests such as the fecal occult blood test (guaiac and immunochemical). As a non-invasive biological serum marker would be of great benefit because of the performance of the test, several biomarkers, including cytologic assays, DNA and mRNA, and soluble proteins, have been studied. We found that the soluble CD26 (sCD26) concentration is diminished in serum of colorectal cancer patients compared to healthy donors, suggesting the potential utility of a sCD26 immunochemical detection test for early diagnosis. sCD26 originates from plasma membrane CD26 lacking its transmembrane and cytoplasmic domains. Some 90%–95% of sCD26 has been associated with serum dipeptidyl peptidase IV (DPP-IV) activity. DPP-IV, assigned to the CD26 cluster, is a pleiotropic enzyme expressed mainly on epithelial cells and lymphocytes. Our studies intended to validate this test for population screening to detect colorectal cancer and advanced adenomas are reviewed here.
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Affiliation(s)
- Oscar J Cordero
- Oscar J Cordero, Monica Imbernon, Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, School of Biology, CIBUS Building, Campus Vida, 15782 Santiago de Compostela, Spain
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8
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Cordero OJ, Salgado FJ, Nogueira M. On the origin of serum CD26 and its altered concentration in cancer patients. Cancer Immunol Immunother 2009; 58:1723-47. [PMID: 19557413 PMCID: PMC11031058 DOI: 10.1007/s00262-009-0728-1] [Citation(s) in RCA: 156] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2009] [Accepted: 06/02/2009] [Indexed: 12/23/2022]
Abstract
Dipeptidyl peptidase IV (DPP-IV), assigned to the CD26 cluster, is expressed on epithelial cells and lymphocytes and is a multifunctional or pleiotropic protein. Its peptidase activity causes degradation of many biologically active peptides, e.g. some incretins secreted by the enteroendocrine system. DPP-IV has, therefore, become a novel therapeutic target for inhibitors that extend endogenously produced insulin half-life in diabetics, and several reviews have appeared in recent months concerning the clinical significance of CD26/DPP-IV. Biological fluids contain relatively high levels of soluble CD26 (sCD26). The physiological role of sCD26 and its relation, if any, to CD26 functions, remain poorly understood because whether the process for CD26 secretion and/or shedding from cell membranes is regulated or not is not known. Liver epithelium and lymphocytes are often cited as the most likely source of sCD26. It is important to establish which tissue or organ is the protein source as well as the circumstances that can provoke an abnormal presence/absence or altered levels in many diseases including cancer, so that sCD26 can be validated as a clinical marker or a therapeutic target. For example, we have previously reported low levels of sCD26 in the blood of colorectal cancer patients, which indicated the potential usefulness of the protein as a biomarker for this cancer in early diagnosis, monitoring and prognosis. Through this review, we envisage a role for sCD26 and the alteration of normal peptidase capacity (in clipping enteroendocrine or other peptides) in the complex crosstalk between the lymphoid lineage and, at least, some malignant tumours.
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Affiliation(s)
- Oscar J Cordero
- Department of Biochemistry and Molecular Biology, CIBUS, University of Santiago de Compostela, r/Lopez de Marzoa s/n, Campus Sur, 15782 Santiago de Compostela, Spain.
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9
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Kim H, Lipscomb WN. Structure and mechanism of bovine lens leucine aminopeptidase. ADVANCES IN ENZYMOLOGY AND RELATED AREAS OF MOLECULAR BIOLOGY 2006; 68:153-213. [PMID: 8154324 DOI: 10.1002/9780470123140.ch4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Affiliation(s)
- H Kim
- Gibbs Chemical Laboratory, Harvard University, Cambridge, MA
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Lambeir AM, Durinx C, Scharpé S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci 2003; 40:209-94. [PMID: 12892317 DOI: 10.1080/713609354] [Citation(s) in RCA: 729] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Dipeptidyl-peptidase IV/CD26 (DPP IV) is a cell-surface protease belonging to the prolyloligopeptidase family. It selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. Apart from its catalytic activity, it interacts with several proteins, for instance, adenosine deaminase, the HIV gp120 protein, fibronectin, collagen, the chemokine receptor CXCR4, and the tyrosine phosphatase CD45. DPP IV is expressed on a specific set of T lymphocytes, where it is up-regulated after activation. It is also expressed in a variety of tissues, primarily on endothelial and epithelial cells. A soluble form is present in plasma and other body fluids. DPP IV has been proposed as a diagnostic or prognostic marker for various tumors, hematological malignancies, immunological, inflammatory, psychoneuroendocrine disorders, and viral infections. DPP IV truncates many bioactive peptides of medical importance. It plays a role in glucose homeostasis through proteolytic inactivation of the incretins. DPP IV inhibitors improve glucose tolerance and pancreatic islet cell function in animal models of type 2 diabetes and in diabetic patients. The role of DPP IV/ CD26 within the immune system is a combination of its exopeptidase activity and its interactions with different molecules. This enables DPP IV/CD26 to serve as a co-stimulatory molecule to influence T cell activity and to modulate chemotaxis. DPP IV is also implicated in HIV-1 entry, malignant transformation, and tumor invasion.
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Affiliation(s)
- Anne-Marie Lambeir
- Department of Pharmaceutical Sciences, Laboratory of Medical Biochemistry, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium.
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Lambeir AM, Durinx C, Scharpé S, De Meester I. Dipeptidyl-Peptidase IV from Bench to Bedside: An Update on Structural Properties, Functions, and Clinical Aspects of the Enzyme DPP IV. Crit Rev Clin Lab Sci 2003. [DOI: 10.1080/713609354/?{alert(1)}] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/30/2022]
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12
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Shibuya-Saruta H, Sugiyama M, Kasahara Y. Colorimetrical rate assay for urinary dipeptidyl peptidase IV (DPPIV) activity using a new substrate. J Clin Lab Anal 1995; 9:113-8. [PMID: 7714663 DOI: 10.1002/jcla.1860090207] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
We synthesized a new substrate glycyl-L-proline 3,5-dibromo-4-hydroxyanilide (Gly-Pro-DBAP), for dipeptidyl peptidase IV (DPPIV). Its hydrolysis by DPPIV resulted in the formation of a chromophore, 2,6-dibromophenol-indo-p-xylenol, and its maximal absorption wavelength (600 nm) was longer than that of p-nitroaniline (415 nm) released from conventional substrate, glycyl-L-proline p-nitroanilide (Gly-Pro-pNA). We also established the rate assay for urinary DPPIV activity using Gly-Pro-DBAP. The optimum pH was between 8.5 and 9.0. The apparent Km was 1.1 mmol/1. The detectable range was 2.5-350 U/l. No changes in blank values occurred throughout the enzyme reaction in the optimum pH. Its value was also much lower than Gly-Pro-pNA. CVs for within-run and between-run were 1.1% (n = 10) and 3.0% (n = 10), respectively. Among tested peptidases, only DPPIV could hydrolyze Gly-Pro-DBAP. Among the protease inhibitors, only two, diprotin-A and phenylmethylsulfonyl fluoride (PMSA), could inhibit DPPIV activity. The present method did not interfere with urinary ingredients such as hemoglobin. The correlation between the present (y) and conventional (x) methods is presented by the equation y = 1.121x + 0.096 (r = 0.993). Thus the present method provides practical advantages over the conventional method for routine laboratory use.
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Avasarala JR, Naoi M, Sasaki S, Ueda M, Saga S, Suzuki T, Yanagita N, Nagatsu T. Distribution of peptidases in cultured cells from middle ear mucosa: prolyl endopeptidase is localized in fibroblasts and dipeptidyl peptidase IV and II in epithelial cells. BIOCHEMICAL MEDICINE AND METABOLIC BIOLOGY 1991; 45:355-8. [PMID: 1675574 DOI: 10.1016/0885-4505(91)90041-i] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
To examine the distribution of prolyl endopeptidase (PEP), dipeptidyl peptidase IV (DPP IV), and dipeptidyl peptidase II (DPP II) in specific cell types, fibroblasts and epithelial cells were selectively cultured from middle ear mucosal tissues of guinea pigs. In fibroblasts, PEP had the highest activity, 12.28 +/- 4.00 nmole/min/mg protein (mean +/- SD), 45-fold higher than corresponding DPP II levels. In epithelial cells, DPP IV activity was the highest, 6.48 +/- 0.90 nmole/min/mg protein. This communication describes, for the first time, the distribution of the enzyme activities of PEP, DPP IV, and DPP II in fibroblasts and epithelial cells, and the occurrence of PEP in fibroblasts.
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Affiliation(s)
- J R Avasarala
- Department of Otorhinolaryngology, Nagoya University School of Medicine, Japan
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14
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Rao AJ, Hagihara M, Nagatsu T, Yanagita N. Presence of dipeptidyl peptidase II, dipeptidyl peptidase IV, and prolyl endopeptidase in effusion from patients with serous otitis media. BIOCHEMICAL MEDICINE AND METABOLIC BIOLOGY 1990; 43:276-82. [PMID: 1974452 DOI: 10.1016/0885-4505(90)90035-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
We have measured for the first time, using specific substrates and specific fluorometric analyses, activities of three pathophysiologically important peptidases, i.e., dipeptidyl peptidase II, dipeptidyl peptidase IV, and prolyl endopeptidase in effusions from 45 patients with chronic otitis media with effusion. In 20 patients, DPP II and DPP IV were assayed simultaneously in effusions and sera. Activity of PEP was also estimated in effusions and sera from 25 patients. The mean values (+/- SD) of DPP II and DPP IV (n = 45) and PEP (n = 25) in effusion from patients with OME were 0.020 +/- 0.007, 0.66 +/- 0.04, and 0.040 +/- 0.006 nmole/min/mg protein, and 0.21 +/- 0.01, 16.2 +/- 1.87, and 1.90 +/- 0.23 nmole/min/ml of effusion, respectively. The mean values (+/- SD) for DPP II, DPP IV, and PEP in sera were 2.82 +/- 0.18, 54.8 +/- 1.23, and 3.73 +/- 0.33 nmole/min/ml of serum, respectively, which were similar to our previously reported values. Activities of DPP II, DPP IV, and PEP of serous effusions were comparable to those in serum. However, there was no significant correlation between their activities in serum and effusion. This may suggest that the major source of these enzymes in effusions may not be serum but the cells in the middle ear.
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Affiliation(s)
- A J Rao
- Department of Otorhinolaryngology, Nagoya University School of Medicine, Japan
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15
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Kasahara Y, Leroux-Roels G, Nakamura R, Chisari F. Glycylprolyl-diaminopeptidase in human leukocytes: selective occurrence in T lymphocytes and influence on the total serum enzyme activity. Clin Chim Acta 1984; 139:295-302. [PMID: 6146412 DOI: 10.1016/0009-8981(84)90275-4] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Using biochemical methods glycylprolyl-diaminopeptidase (GP-DAP, EC 3.4.14.5) was measured in purified leukocyte subpopulations and found selectively in T lymphocytes. In 129 subjects with normal hepatic function a significant correlation was observed between the serum GP-DAP activity and the peripheral blood lymphocyte count. In four patients suffering from rheumatoid arthritis, four weeks of thoracic duct drainage resulted in a reduction of the peripheral blood lymphocyte count and a concomitant decrease of the serum GP-DAP activity. These observations suggest that lymphocytic GP-DAP may contribute to the total serum GP-DAP activity.
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16
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Fukasawa KM, Fukasawa K, Hiraoka BY, Harada M. Comparison of dipeptidyl peptidase IV prepared from pig liver and kidney. BIOCHIMICA ET BIOPHYSICA ACTA 1981; 657:179-89. [PMID: 6783094 DOI: 10.1016/0005-2744(81)90141-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Dipeptidyl peptidase IV (dipeptidylpeptide hydrolase, EC 3.4.14.-) has been purified from the microsomal fraction of pig liver, using an immunoaffinity chromatography, and its properties compared with those of the enzyme purified from pig kidney. The amino acid compositions of both enzymes were similar. The same kinds of carbohydrates were found in both enzymes, but there were differences in the molar concentrations of individual sugars. The liver enzyme had greater concentrations of mannose, fucose and sialic acid than the kidney enzyme, while the concentrations of galactose and glucosamine were greater in the kidney enzyme. The carbohydrates accounted for approx. 18.3 and 22.7% of the weight of the kidney and liver enzymes, respectively. The pH optima, molecular weights, substrate specificities and Km values of the two enzymes and the effects of diisopropylfluorophosphate on their activities were nearly identical. The liver enzyme was heat- and pH-sensitive, but not attacked by proteinases.
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17
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Tobe H, Kojima F, Aoyagi T, Umezawa H. Purification by affinity chromatography using amastatin and properties of aminopeptidase A from pig kidney. BIOCHIMICA ET BIOPHYSICA ACTA 1980; 613:459-68. [PMID: 7448199 DOI: 10.1016/0005-2744(80)90100-x] [Citation(s) in RCA: 72] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
1. Amastatin, a specific inhibitor of aminopeptidase A (L-alpha-aspartyl(L-alpha-glutamyl)-peptide hydrolase, EC 3.4.11.7), was linked to an agarose matrix and by this affinity chromatography aminopeptidase A of pig kidneys was purified as a single protein shown by acrylamide gel electrophoresis. 2. Aminopeptidase A which was purified 710-fold, hydrolyzed only acidic amino acid beta-naphthylamide. The optimum pH and the optimum temperature was 7.5 and 45-50 degrees C, respectively. 3. The molecular weight was approx. 300 000 as determined by Sephadex G-200 gel filtration. 4. The activity of aminopeptidase A was not affected by sulfhydryl agents, S-S dissociating agents and serine proteinase inhibitor, but was inhibited strongly by metal chelating agents, and enhanced by alkaline earth metals. 5. Amastatin inhibited aminopeptidase A in a competitive manner with L-glutamic acid beta-naphthylamide, and the Ki value was calculated to be 2.5 x 10(-7) M. The inhibitory effect of amastatin on aminopeptidase A was not reversed by addition of Ca2+.
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Kato T, Hama T, Nagatsu T, Kuzuya H, Sakakibara S. Changes of X-prolyl dipeptidyl-aminopeptidase activity in developing rat brain. EXPERIENTIA 1979; 35:1329-30. [PMID: 499410 DOI: 10.1007/bf01963989] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
We found X-prolyl dipeptidyl-aminopeptidase activity in rat brain and examined the developmental changes at various ages. The total enzyme activity per brain increased until 4 weeks of age, and then decreased during maturation. Specific activity in young rat brain was higher than that in adult rat brain. The properties of the brain enzyme were different from those of pituitary and other tissues.
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Kato T, Iwase K, Nagatsu T, Sakakibara S, Fujita K. Comparison of X-prolyl dipeptidyl-aminopeptidase activity in human cerebrospinal fluid with that in serum. EXPERIENTIA 1979; 35:20-1. [PMID: 421786 DOI: 10.1007/bf01917849] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
X-Prolyl dipeptidyl-aminopeptidase activities in cerebrospinal fluid and serum from the same patients without neurological diseases, undergoing surgery under lumbar anesthesia, were assayed fluorometrically with a newly synthesized fluorogenic substrate, 7-glycylproline-4-methylcoumarinamide; the values were 129.1 +/- 19.5 nmoles/min/l and 54.17 +/- 3.11 mumoles/min/l (mean +/- SEM, n = 23), respectively, and there was no correlation between both activities (r = 0.0894).
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Fujita K, Hirano M, Ochiai J, Funabashi M, Nagatsu I, Nagatsu T, Sakakibara S. Serum glycylproline p-nitroanilidase activity in rheumatoid arthritis and systemic lupus erythematosus. Clin Chim Acta 1978; 88:15-20. [PMID: 679484 DOI: 10.1016/0009-8981(78)90142-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Glycylproline p-nitroanilidase activity in serum of patients with advanced rheumatoid arthritis or with systemic lupus erythematosus but with normal hepatic function was found to be significantly lower than that of normal adult controls. Decrease of this enzyme's serum activity was more pronounced in systemic lupus erythematosus. A significant inverse correlation was observed between the enzyme activity and the duration of rheumatoid arthritis.
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Kato T, Nagatsu T, Kimura T, Sakakibara S. Fluorescence assay of x-prolyl dipeptidyl-aminopeptidase activity with a new fluorogenic substrate. BIOCHEMICAL MEDICINE 1978; 19:351-9. [PMID: 28120 DOI: 10.1016/0006-2944(78)90035-2] [Citation(s) in RCA: 75] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Fujita K, Hirano M, Tokunaga K, Nagatsu I, Nagatsu T, Sakakibara S. Serum glycylproline p-nitroanilidase activity in blood cancers. Clin Chim Acta 1977; 81:215-7. [PMID: 579337 DOI: 10.1016/0009-8981(77)90014-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Glycylproline p-nitroanilidase activity in serum of patients with acute lymphatic leukemia, lymphosarcoma and Hodgkin's disease, and of normal neonates (umbilical blood) was significantly lower than that of normal adult controls. In contrast, the enzyme activity of patients with myelocytic leukemias did not differ significantly from that of normal controls.
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Fuyamada H, Hino M, Nagatsu T, Ogawa K, Sakakibara S. Serum glyccylproline p-nitroanilidase activity in human hypertension. Clin Chim Acta 1977; 74:177-81. [PMID: 832421 DOI: 10.1016/0009-8981(77)90220-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Glycylproline p-nitroanilidase activity in serum from patients with essential hypertension was significantly higher than that from normotensive healthy subjects. In contrast, serum leucine beta-naphthylamidase activity did not differ significantly between hypertensive patients and normotensive controls.
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Nagatsu T, Hino M, Fuyamada H, Hayakawa T, Sakakibara S. New chromogenic substrates for X-prolyl dipeptidyl-aminopeptidase. Anal Biochem 1976; 74:466-76. [PMID: 962103 DOI: 10.1016/0003-2697(76)90227-x] [Citation(s) in RCA: 235] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Raina PN, Ellis S. Studies on human urinary arylamidases. ARCHIVES INTERNATIONALES DE PHYSIOLOGIE ET DE BIOCHIMIE 1975; 83:519-28. [PMID: 54131 DOI: 10.3109/13813457509071396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human urinary protein was found to contain enzymes that hydrolyze leucyl-, alanyl-, and glycyl-prolyl-beta-naphthylamides. The kinetic constants of these enzymes were determined and their chemical properties studied. The values for Km calculated for leucyl-, alanyl-, and glycyl-prolyl arylamidases were 3.7 times 10(-5) M, 7.1 times 10(-5) M, and 1 times 10(-4) M, respectively. The pH optima for the hydrolysis of Leu-beta-naphthylamide and Ala-beta-naphthylamide were between 7.4-7.8; whereas for glycyl-prolyl-beta-naphthylamide, it was around 8.8. Unlike the glycyl-prolyl-arylamidase which was inhibited by Co2+ and Mn2+, the other two arylamidases were slightly activated by Co2+. p-Chloromercuriphenyl-sulfonate and puromycin significantly inhibited leucyl-, and alanyl arylamidases. The mean values for 24-h urinary output for leucyl-, alanyl-, and glycyl-prolyl arylamidases in normal human male subjects were 4.32, 9.97, and 2.2 units, respectively.
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Hino M, Nagatsu T, Kakumu S, Okuyama S, Yoshii Y, Nagatsu I. Glycylprolyl beta-naphthylamidase activity in human serum. Clin Chim Acta 1975; 62:5-11. [PMID: 1149281 DOI: 10.1016/0009-8981(75)90273-9] [Citation(s) in RCA: 55] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Glycylprolyl beta-naphthylamidase activities in sera from 40 normal subjects (18-81 years) were: 22.6 +/- 0.9 (S.E.) (11.8-38.2) I.U./1 serum at 37 degrees C. The enzyme activities did not differ significantly with age between the younger group under 40-years-old and the older group over 40-years-old. Males, especially under 40-years-old, had slight but significantly higher activities than females. The levels were decreased in patients with gastric cancer. The levels were elevated in patients with hepatobiliary diseases, and had significant correlations with the results of the serum tests in hepatic diseases such as glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, alkaline phosphatase and total bilirubin, but had no correlation with serum lactate dehydrogenase. In cellulose acetate electrophoresis, normal sera had a single peak at the beta-globulin region, but the sera in hepatitis or liver cirrhosis showed not only an increase in the normal peak at the beta-globulin region but also the appearance of the other one or two new peaks in the alpha1 and alpha2-globulin regions.
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Hino M, Nakano G, Harada M, Nagatsu T. Distribution of PZ-peptidase and glycylprolyl beta-naphthylamidase activities in oral tissues. Arch Oral Biol 1975; 20:19-22. [PMID: 1054566 DOI: 10.1016/0003-9969(75)90147-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Oya H, Harada M, Nagatsu T. Peptidase activity of glycylprolyl beta-naphthylamidase from human submaxillary gland. Arch Oral Biol 1974; 19:489-91. [PMID: 4531301 DOI: 10.1016/0003-9969(74)90158-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Oya H, Nagatsu I, Nagatsu T. Purification and properties of glycylprolyl -naphthylamidase in human submaxillary gland. BIOCHIMICA ET BIOPHYSICA ACTA 1972; 258:591-9. [PMID: 5062248 DOI: 10.1016/0005-2744(72)90251-3] [Citation(s) in RCA: 72] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Oya H, Nagatsu T, Kobayashi Y, Takei M. Arylaminopeptidase activities in human cariogenic and non-cariogenic oral bacteria. Arch Oral Biol 1971; 16:675-80. [PMID: 4997488 DOI: 10.1016/0003-9969(71)90073-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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