Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dipeptidylpeptidase IV (EC 3.4.14.5), an enzyme which metabolizes substance P, is present in crude homogenates of hog mesenteric artery and aorta. Its subcellular localization is closely correlated with the plasma membrane marker enzyme 5'-nucleotidase (EC 3.1.3.5) in addition to the kinin and angiotensin metabolizing enzymes angiotensin I converting enzyme (EC 3.4.15.1) and aminopeptidase M (EC 3.4.11.2). The highest level of dipeptidylpeptidase IV is found on the surface membrane-enriched fraction and is immunologically identical to the kidney brush border-bound enzyme. Vascular dipeptidylpeptidase IV sequentially removes the N-terminal Arg1-Pro2 and Lys3-Pro4 dipeptides of substance P and exposes the biologically active C-terminal heptapeptide product to rapid degradation by vascular aminopeptidases.
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PMID:Mesentery vascular metabolism of substance P. 618 94

Distribution patterns of brush-border membrane dipeptidylpeptidase IV (DPP IV), endopeptidase-24.11, and angiotensin converting enzyme (ACE) activities along the intestine of the rat and rabbit were examined. ACE and endopeptidase-24.11 had a similar distribution profile in the intestine of the rat and rabbit, jejunum > duodenum approximately jejunoileal junction > ileum > caecum (rat) or ileocaecal junction (rabbit). DPP IV had a more uniform distribution pattern than ACE and endopeptidase-24.11. Its longitudinal distribution patterns in the intestine of the rat and rabbit were slightly different. In the rat intestine, DPP IV activity had the following rank order: ileum approximately jejunum > jejunoileal junction > duodenum > caecum. In the rabbit, DPP IV had similar activities from the jejunum to the ileocaecal junction whereas its duodenal activity was much lower. The results suggest that the distribution profiles of DPP IV, ACE, and endopeptidase-24.11 are similar in both species.
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PMID:Distribution of brush-border membrane peptidases along the intestine of rabbits and rats: implication for site-specific delivery of peptide drugs. 806 64

The cell-surface expression of endopeptidase-24.11 (EC 3.4.24.11) on Caco-2 cells cultured to confluency is markedly heterogeneous unlike that of dipeptidylpeptidase IV (EC 3.4.14.5). Here we have investigated the cell-surface expression of three other ectopeptidases: angiotensin converting enzyme (EC 3.4.15.1), aminopeptidase N (EC 3.4.11.2) and aminopeptidase W (EC 3.4.11.16). We show by indirect immunofluorescent staining that these three enzymes are present on the surface of some cells but not on others. However, these enzymes were detected in the majority of detergent-permeabilised Caco-2 cells indicating the presence of intracellular pools of these enzymes. This suggests that there may either be differential regulation of apical transport for these peptidases or that they recycle at different rates.
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PMID:Mosaic expression of membrane peptidases by confluent cultures of Caco-2 cells. 809 58

A cultured human intestinal epithelial (Caco-2) cell monolayer was used to study the transport and metabolism of delta sleep-inducing peptide [DSIP (Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu)]. DSIP is of interest because it has been reported to be capable of permeating biological barriers (e.g. blood-brain barrier), and this property has been related to its solution conformation. When applied to the apical (AP) side of Caco-2 cell monolayers, DSIP was rapidly metabolized (8.2 +/- 1.1% remaining after a 2-hr incubation), affording Trp as the major metabolite and Trp-Ala as a minor metabolite. When DSIP was added to the basolateral (BL) side of the monolayer, the same metabolites were detected, but the peptide was more stable (70.6 +/- 3.0% remaining after a 2-hr incubation). Inclusion of bestatin, an inhibitor of aminopeptidases, at concentrations up to 0.29 mM with DSIP on the AP side of the Caco-2 cell monolayer increased the stability of the peptide only slightly but dramatically altered the distribution of the metabolites (Trp-Ala became the major metabolite, and Trp became the minor metabolite). Inclusion of other aminopeptidase inhibitors (e.g. amastatin, puromycin) alone, dipeptidylpeptidase IV inhibitors (e.g. diprotin A, Gly-Pro) alone, inhibitors of proteases that require heavy metals for proper activity (e.g. EDTA, 1,10-phenanthroline) alone, or cysteine protease inhibitors (e.g. leupeptin) alone did not lead to significant stabilization of the peptide. However, inclusion of a combination of 0.29 mM bestatin and 1 mM diprotin A with DSIP on the AP side of the monolayers resulted in a substantial increase in the stability of the peptide (83.2 +/- 3.7% remaining after a 2-hr incubation). However, under these conditions, a new metabolite (Trp-Ala-Gly-Gly-Asp-Ala-Ser) was observed with a formation that could be inhibited by inclusion of 1 mM captopril, an inhibitor of peptidyl dipeptidase A. Therefore, the stability of DSIP could be further increased (95.1 +/- 1.6% remaining after a 2-hr incubation) by incubating the peptide with 0.29 mM bestatin, 1 mM diprotin A, and 1 mM captopril. However, even when the major metabolic pathways were inhibited on the AP side of the cell monolayer, no DSIP was detected on the BL side of a Caco-2 cell monolayer. These results suggest that a yet unidentified metabolic pathway is preventing the AP-to-BL flux of DSIP or that DSIP has lower "intrinsic" ability to permeate across cultured intestinal epithelial cells than across cultured brain endothelial cells, a cell culture model of the blood-brain barrier.
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PMID:Transport and metabolism of delta sleep-inducing peptide in cultured human intestinal epithelial cell monolayers. 868 46

The cell surface aminopeptidase N (APN/CD13), overexpressed in tumor cells, plays a critical role in angiogenesis. However, potent, selective, and, particularly, noncytotoxic inhibitors ot this protein are lacking, and the present work was undertaken with the aim of developing a new generation of noncytotoxic inhibitors that bind to APN/CD13. In this context, we have synthesized a series of novel flavone-8-acetic acid derivatives. Among the herein described and evaluated compounds, the 2',3-dinitroflavone-8-acetic acid (19b) proved to be the most efficient and exhibited an IC(50) of 25 microM which is 2.5 times higher than that of bestatin (1), the natural known inhibitor of APN/CD13. However, in contrast to bestatin (1), the dinitroflavone 19b did not induce any cytotoxicity to cultured human model cells. The presence of other substituents such as NO(2) or OCH(3) groups at the 3'- or 4'-position of the B phenyl group, or the existence of steric constraints (compounds 24 and 29), did not improve selectivity and potency. The flavone 19b affinity for APN/CD13 is not recovered with other proteases such as matrix metalloproteinase-9 (MMP-9), angiotensin converting enzyme (ACE/CD143), neutral endopeptidase (NEP/CD10), gamma-glutamyl transpeptidase (CD224), or the serine proteases dipeptidyl peptidase IV (DPPIV/CD26) or cathepsin G.
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PMID:Synthesis and biological evaluation of novel flavone-8-acetic acid derivatives as reversible inhibitors of aminopeptidase N/CD13. 1293 Jan 51

Transmembrane proteases (TPs) are proteins anchored in the plasma membrane with their catalytic site exposed to the external surface of the membrane. TPs are widely expressed, and their dysregulated expression is associated with cancer, infection, inflammation, autoimmune and cardiovascular diseases, all diseases where angiogenesis is part of the pathology. TPs participate in extracellular proteolysis (degradation of extracellular matrix components, regulation of chemokine activity, release of membrane-anchored cytokines, cytokine receptors and adhesion molecules) and influence cell functions (growth, secretion of angiogenic molecules, motility). Recent attention has been focused on the ADAM-17 (a disintegrin and metalloprotease)/TACE/CD156q, the MT1-MMP (membrane-type-1 matrix metallo proteinase)/MMP-14, and the ectopeptidases aminopeptidase N (APN/CD13), dipeptidyl peptidase IV (DPPIV/CD26) and angiotensin-converting enzyme (ACE/CD143), that appear to have a critical role in angiogenesis. This article summarizes current knowledge on these TPs, and reviews recent investigations that document their participation during angiogenic-related events. Through their multiple roles, TPs may thereby provide critical links in angiogenesis.
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PMID:Transmembrane proteases in cell growth and invasion: new contributors to angiogenesis? 1472 62

Sitagliptin is a dipeptidyl peptidase-4 (DPP IV, CD26) inhibitor indicated for treatment of Type II diabetes as a second line therapy after metformin. We report fifteen sitagliptin intolerant patients who developed anterior and posterior rhinorrhea, cough, dyspnea, and fatigue. Symptoms typically developed within 1 to 8 weeks of starting, and resolved within 1 week of stopping the drug. Peak expiratory flow rates increased 34% in 8 patients who stopped sitagliptin. Similar changes were found in 4 out of 5 persons who had confirmatory readministration. Chart review identified 17 patients who tolerated sitagliptin and had no symptomatic changes. The sitagliptin intolerant group had higher rates of clinically diagnosed allergic rhinitis (15/15 vs. 6/18; p = 0.00005), Fisher's Exact test) and angiotensin converting enzyme inhibitor - induced cough (6/13 vs. 1/18; p = 0.012). Nasal and inhaled glucocorticoids may control the underlying allergic inflammation and abrogate this new sitagliptin - induced pharmacological syndrome. Potential mucosal and central nervous system mechanisms include disruption of neuropeptides and/or cytokines that rely on DPP IV for activation or inactivation, and T cell dysfunction.
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PMID:Rhinorrhea, cough and fatigue in patients taking sitagliptin. 2046 26

Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.
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PMID:Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers. 2119 57

Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.
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PMID:Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome. 2844 52

Tibetan pigs that inhabit the Tibetan Plateau exhibit striking phenotypic and physiological differences from lowland pigs, and have adapted well to extreme conditions. However, the mechanisms involved in regulating gene expression at high altitude in these animals are not fully understood. In this study, we obtained transcriptomic and proteomic data from the heart tissues of Tibetan and Yorkshire pigs raised in the highlands (TH and YH) and lowlands (TL and YL) via RNA-seq and iTRAQ (isobaric tags for relative and absolute quantitation) analyses, respectively. Comparative analyses of TH vs. YH, TH vs.TL, TL vs. YL, and YH vs. YL yielded 299, 169, 242, and 368 differentially expressed genes (DEGs), and 473, 297, 394, and 297 differentially expressed proteins (DEPs), respectively. By functional annotation of these DEGs and DEPs, genes that were enriched in the HIF-1 signaling pathway (NPPA, ERK2, ENO3, and EGLN3), VEGF signaling pathway (ERK2, A2M, FGF1, CTGF, and DPP4), and hypoxia-related processes (CRYAB, EGLN3, TGFB2, DPP4, and ACE) were identified as important candidate genes for high-altitude adaptation in the Tibetan pig. This study enhances our understanding of the molecular mechanisms involved in hypoxic adaptation in pigs, and furthers our understanding of human hypoxic diseases.
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PMID:Comparative transcriptomic and proteomic analyses provide insights into the key genes involved in high-altitude adaptation in the Tibetan pig. 2862 14


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