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)

1. We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15. 2. In conscious rabbits, cFP (5 mg kg-1, i.v.) markedly slowed the degradation of [3H]-bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10-1000 ng kg-1), and inhibited the pressor response to right atrial angiotensin I (10-100 ng kg-1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg-1h-1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone. 3. In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg-1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 micrograms kg-1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg-1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril. 4. CFP displaced the binding of [125I]-351A (the p-hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 microM respectively), and inhibited rat plasma ACE activity (KI = 2.4 microM). Addition of phosphoramidon (10 microM), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems. 5. Taken together these findings suggest that the actions of cFP in vivo are attributable to inhibition of ACE rather than EP 24.15. Given that cFP is a poor inhibitor of ACE in the presence of phosphoramidon in vitro, it is likely that cFP is cleaved by a phosphoramidon-sensitive metallopeptidase in vivo to liberate N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala, a potent ACE inhibitor.
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PMID:Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor. 762 Jul 8

The capillary endothelial cells of the median eminence represent a potential site for the degradation/modification of both circulating and hypothalamic peptides passing through the hypophysial portal system toward the pituitary. This study examines endothelial cell peptidase expression in vitro by monitoring the metabolism of gonadotropin-releasing hormone (GnRH) by cultured endothelial cells from sheep median eminence. Cleavage of GnRH by median eminence endothelial cell membranes generated GnRH1-5 as the primary stable product, which was then degraded to GnRH1-3 and free amino acids. Degradation of GnRH was completely inhibited by TPCK, ZnCl2 and N-ethylmaleimide, and partially inhibited by EDTA and by a specific inhibitor of the metalloendopeptidase EC 3.4.24.15, CFP-AAY-pAB. Interestingly, an increase in GnRH1-9 production was seen with the latter inhibitors, suggesting a two-step mechanism of GnRH degradation involving a primary cleavage at the Pro9-Gly10-NH2 bond, inhibitable by TPCK, ZnCl2, and NEM, followed by cleavage by EC 3.4.24.15 to generate GnRH1-5. Phosphoramidon and angiotensin converting enzyme inhibitors (as well as other non-specific inhibitors) were without effect, indicating that endopeptidase EC 3.4.24.11 and angiotensin converting enzyme are not involved. Neither bovine aortic endothelial cell nor AtT-20 cell membranes exhibited this pattern of peptidase activity. Degradation of GnRH by intact median eminence endothelial cells in culture was also observed, suggesting an extracellular orientation for these enzymes; the potential role of such peptidases in the fine regulation of both pituitary function and local blood flow is currently under investigation.
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PMID:Characterization of membrane-associated peptidase activities expressed by endothelial cells of the ovine median eminence. 804 22

Endopeptidase EC 3.4.24.15 (EP 24.15) is a thermolysin-like metalloendopeptidase which is expressed widely throughout the body, with the highest concentrations in the brain, pituitary and testis. While the precise role of EP 24.15 remains unknown, it is thought to participate in the regulated metabolism of a number of specific neuropeptides. Of the limited number of inhibitors described for EP 24.15, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-amino benzoate (CFP) is the most widely studied. CFP is a potent and specific inhibitor, but is unstable in vivo due to its cleavage between the alanine and tyrosine residues by the enzyme neprilysin (EP 24.11). The cpp-Ala-Ala N-terminal product of this cleavage is a potent inhibitor of angiotensin converting enzyme, which further limits the use of CFP in vivo. To generate specific inhibitors of EP 24.15 that are resistant to in vivo proteolysis by EP 24.11, beta-amino acids have been incorporated into the structure of CFP. We have prepared racemic mixtures of beta-amino acids containing proteogenic side chains, which are 9-fluorenylmethoxycarbonyl (Fmoc)-protected, and several analogues of CFP containing beta-amino acids have been synthesized by solid phase peptide synthesis. The results of stability and inhibitory studies of these new analogues show that the incorporation of beta-amino acids adjacent to the scissile bond can indeed stabilize the peptides against cleavage by EP 24.11 and still inhibit EP 24.15. The results obtained in these studies demonstrate the potential of these amino acids in the synthesis of peptidomimetics and in the design of new stable and specific therapeutics.
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PMID:Design and synthesis of inhibitors incorporating beta -amino acids of metalloendopeptidase EC 3.4.24.15. 1101 84

The enzyme EC 3.4.24.15 (EP 24.15) is a zinc metalloendopeptidase whose precise function in vivo remains unknown but is thought to participate in the regulated metabolism of a number of specific neuropeptides. The lack of stable and selective inhibitors has hindered the determination of the exact function of EP 24.15. Of the limited number of EP 24.15 inhibitors that have been developed, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (CFP) is the most widely studied. CFP is a potent and specific inhibitor, but it is unstable in vivo due to cleavage between the alanine and tyrosine residues by the enzyme neprilysin (EP 24.11). This cleavage by EP 24.11 generates a potent inhibitor of angiotensin converting enzyme, thereby limiting the use of CFP for in vivo studies. To develop specific inhibitors of EP 24.15 that are resistant to in vitro and potentially in vivo proteolysis by EP 24.11, this study incorporated beta-amino acids replacing the Ala-Tyr scissile alpha-amino acids of CFP. Both C2 and C3 substituted beta-amino acids were synthesized and substituted at the EP 24.11 scissile Ala-Tyr bond. Significant EP 24.15 inhibitory activity was observed with some of the beta-amino acid containing analogues. Moreover, binding to EP 24.11 was eliminated, thus rendering all analogues containing beta-amino acids resistant to degradation by EP 24.11. Selective inhibition of either EP 24.15 or EP 24.16 was also observed with some analogues. The results demonstrated the use of beta-amino acids in the design of inhibitors of EP 24.15 and EP 24.16 with K(i)'s in the low micromolar range. At the same time, these analogues were resistant to cleavage by the related metalloendopeptidase EP 24.11, in contrast to the alpha-amino acid based parent peptide. This study has therefore clearly shown the potential of beta-amino acids in the design of stable enzyme inhibitors and their use in generating molecules with selectivity between closely related enzymes.
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PMID:Inhibitors of metalloendopeptidase EC 3.4.24.15 and EC 3.4.24.16 stabilized against proteolysis by the incorporation of beta-amino acids. 1219 21