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Chemical Compound Review

Amastatin     (2S)-2-[[(2S)-2-[[(2S)-2- [[(2S,3R)-3-amino...

Synonyms: CHEMBL28650, CHEBI:2624, FT-0622252, AC1L97I5, C01552, ...
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Disease relevance of Amastatin


High impact information on Amastatin

  • Hydrolysis of the substrates was shown to be a two-step process involving initial cleavage by endopeptidase with secondary hydrolysis of the peptide products by brush-border membrane aminopeptidase N. Hydrolysis of both substrates was maximum at a neutral pH and was strongly inhibited by metal chelating agents, phosphoramidone, and amastatin [5].
  • These results show that dipeptide hydrolysis can be selectively suppressed by either amastatin or leuhistin and dipeptide transport by arphamenine [6].
  • Bestatin and amastatin, inhibitors of aminopeptidases (but not human kidney NEP), did not inhibit the rate of fMLP degradation but prevented the production of free phenylalanine and enhanced the accumulation of Leu-Phe [7].
  • The aminopeptidase activity was not affected by MERGETPA but was potently inhibited by amastatin and bestatin (IC50 = 0.05 microM and 3.0 microM, respectively) [8].
  • Amastatin, an endopeptidase inhibitor that increases the level of endogenous OXT, also reduced the evoked EPSC [9].

Biological context of Amastatin

  • A catalytic mechanism for blLAP is proposed based on the binding modes of amastatin and bestatin and plausible binding modes of a dipeptide substrate and its putative gem-diolate transition state which were modeled into the active site of blLAP after the binding mode of amastatin [10].
  • Amastatin, an aminopeptidase inhibitor, augmented salivation caused by native peptides, but not furoylated peptides [11].
  • In order to examine metabolism in vivo, blood pressure responses to angiotensins were obtained in anesthesized rats before and during infusion of amastatin (16 nmol/min i.v.). Amastatin specifically inhibited plasma AmM and AmA activities 81 and 10%, respectively [12].
  • A second experiment indicated that i.c.v. administered BE induced considerable water consumption, while amastatin (AM, an aminopeptidase A inhibitor) did not [13].
  • The absorption of peptide drugs can be improved by using aminoboronic acid derivatives, amastatin, and other enzyme inhibitors as absorption enhancers [14].

Anatomical context of Amastatin


Associations of Amastatin with other chemical compounds

  • In contrast, amastatin and leuhistin, in concentrations as low as 20 microM, almost completely inhibited dipeptide hydrolysis [6].
  • The aminopeptidase had an apparent Km of 23 microM, a pH optimum of 7.0 and was inhibited by 1 mM-EDTA and amastatin [IC50 = 0.3 microM], but was relatively insensitive to bestatin, actinonin and puromycin [19].
  • Captopril and amastatin (inhibitors of peptidyl dipeptidase A and aminopeptidases respectively) had no significant effect [20].
  • X-ray crystallographic determination of the structure of bovine lens leucine aminopeptidase complexed with amastatin: formulation of a catalytic mechanism featuring a gem-diolate transition state [10].
  • Both alanyl-naphthylamidase and enkephalin degradation were optimal at pH 7.0 to 7.5 and were inhibited by aminopeptidase inhibitors amastatin (IC50 = 20 nM), bestatin (4-7 microM) and puromycin (30-35 microM) [21].

Gene context of Amastatin

  • APA activity was calcium-dependent and was inhibited by amastatin [22].
  • We examined actions of arginine vasopressin (AVP) and amastatin (an inhibitor of the aminopeptidase that cleaves AVP) on synaptic currents in slices of rat parabrachial nucleus using the nystatin-perforated patch recording technique [23].
  • In contrast to the intact endothelial monolayers, in homogenates additional kininase activity was found which was not affected by either ACE and NEP inhibitors nor by amastatin and MGTA [24].
  • The PAR-2 agonist SLIGRL-NH2, administered intraperitoneally (i.p.) at 1-10 micromol/kg and 1.5-15 micromol/kg, in combination with amastatin, an aminopeptidase inhibitor, facilitated in vivo secretion of pancreatic and salivary amylase in a dose-dependent manner, respectively, in the mouse [25].
  • In contrast, amastatin was not able to prevent the expression of PAI-1 mRNA induced by Ang IV [26].

Analytical, diagnostic and therapeutic context of Amastatin


  1. Biochemical and functional characterization of aminopeptidase N expressed by human melanoma cells. Menrad, A., Speicher, D., Wacker, J., Herlyn, M. Cancer Res. (1993) [Pubmed]
  2. The slow, tight binding of bestatin and amastatin to aminopeptidases. Wilkes, S.H., Prescott, J.M. J. Biol. Chem. (1985) [Pubmed]
  3. Amastatin, an inhibitor of aminopeptidase A, produced by actinomycetes. Aoyagi, T., Tobe, H., Kojima, F., Hamada, M., Takeuchi, T., Umezawa, H. J. Antibiot. (1978) [Pubmed]
  4. Effect of various compounds on enkephalin hydrolysis by an aminopeptidase from the thermophiles Thermomonospora fusca ATCC 27730 and Thermus thermophilus ATCC 27634. Weiss, B., Hui, M., Lajtha, A. Res. Commun. Chem. Pathol. Pharmacol. (1983) [Pubmed]
  5. Identification and characterization of brush-border membrane-bound neutral metalloendopeptidases from rat small intestine. Song, I.S., Yoshioka, M., Erickson, R.H., Miura, S., Guan, D., Kim, Y.S. Gastroenterology (1986) [Pubmed]
  6. Functional separation of dipeptide transport and hydrolysis in kidney brush border membrane vesicles. Daniel, H., Adibi, S.A. FASEB J. (1994) [Pubmed]
  7. Function of neutral endopeptidase on the cell membrane of human neutrophils. Painter, R.G., Dukes, R., Sullivan, J., Carter, R., Erdös, E.G., Johnson, A.R. J. Biol. Chem. (1988) [Pubmed]
  8. Kinin metabolism in human nasal secretions during experimentally induced allergic rhinitis. Proud, D., Baumgarten, C.R., Naclerio, R.M., Ward, P.E. J. Immunol. (1987) [Pubmed]
  9. Oxytocin retrogradely inhibits evoked, but not miniature, EPSCs in the rat supraoptic nucleus: role of N- and P/Q-type calcium channels. Hirasawa, M., Kombian, S.B., Pittman, Q.J. J. Physiol. (Lond.) (2001) [Pubmed]
  10. X-ray crystallographic determination of the structure of bovine lens leucine aminopeptidase complexed with amastatin: formulation of a catalytic mechanism featuring a gem-diolate transition state. Kim, H., Lipscomb, W.N. Biochemistry (1993) [Pubmed]
  11. Potent and metabolically stable agonists for protease-activated receptor-2: evaluation of activity in multiple assay systems in vitro and in vivo. Kawabata, A., Kanke, T., Yonezawa, D., Ishiki, T., Saka, M., Kabeya, M., Sekiguchi, F., Kubo, S., Kuroda, R., Iwaki, M., Katsura, K., Plevin, R. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  12. Role of aminopeptidase activity in the regulation of the pressor activity of circulating angiotensins. Ahmad, S., Ward, P.E. J. Pharmacol. Exp. Ther. (1990) [Pubmed]
  13. Influence of aminopeptidase inhibitors on brain angiotensin metabolism and drinking in rats. Wright, J.W., Quirk, W.S., Hanesworth, J.M., Harding, J.W. Brain Res. (1988) [Pubmed]
  14. Drug metabolism in the nasal mucosa. Sarkar, M.A. Pharm. Res. (1992) [Pubmed]
  15. The aminopeptidase activity in the human T-cell lymphoma line (Jurkat) is not at the cell surface and is not aminopeptidase N (CD-13). Murray, H., Turner, A.J., Kenny, A.J. Biochem. J. (1994) [Pubmed]
  16. The metabolism of neuropeptides. Phase separation of synaptic membrane preparations with Triton X-114 reveals the presence of aminopeptidase N. Matsas, R., Stephenson, S.L., Hryszko, J., Kenny, A.J., Turner, A.J. Biochem. J. (1985) [Pubmed]
  17. Characterization of somatostatin receptors in guinea-pig isolated ileum, vas deferens and right atrium. Feniuk, W., Dimech, J., Humphrey, P.P. Br. J. Pharmacol. (1993) [Pubmed]
  18. Somatostatin sst2 receptor-mediated inhibition of parietal cell function in rat isolated gastric mucosa. Wyatt, M.A., Jarvie, E., Feniuk, W., Humphrey, P.P. Br. J. Pharmacol. (1996) [Pubmed]
  19. Proctolin degradation by membrane peptidases from nervous tissues of the desert locust (Schistocerca gregaria). Isaac, R.E. Biochem. J. (1987) [Pubmed]
  20. The hydrolysis of alpha-human atrial natriuretic peptide by pig kidney microvillar membranes is initiated by endopeptidase-24.11. Stephenson, S.L., Kenny, A.J. Biochem. J. (1987) [Pubmed]
  21. N-terminal degradation of low molecular weight opioid peptides in human cerebrospinal fluid. Benter, I.F., Hirsh, E.M., Tuchman, A.J., Ward, P.E. Biochem. Pharmacol. (1990) [Pubmed]
  22. Receptor-mediated induction of aminopeptidase A (APA) of human glomerular epithelial cells (HGEC) by glucocorticoids. Stefanovic, V., Vlahovic, P., Ardaillou, N., Ardaillou, R. FEBS Lett. (1991) [Pubmed]
  23. Vasopressin and amastatin induce V(1)-receptor-mediated suppression of excitatory transmission in the rat parabrachial nucleus. Chen, X., Pittman, Q.J. J. Neurophysiol. (1999) [Pubmed]
  24. Bradykinin degrading activity in cultured human endothelial cells. Graf, K., Gräfe, M., Auch-Schwelk, W., Baumgarten, C.R., Bossaller, C., Fleck, E. J. Cardiovasc. Pharmacol. (1992) [Pubmed]
  25. Protease-activated receptor-2 (PAR-2) in the pancreas and parotid gland: Immunolocalization and involvement of nitric oxide in the evoked amylase secretion. Kawabata, A., Kuroda, R., Nishida, M., Nagata, N., Sakaguchi, Y., Kawao, N., Nishikawa, H., Arizono, N., Kawai, K. Life Sci. (2002) [Pubmed]
  26. Angiotensin IV stimulates plasminogen activator inhibitor-1 expression in proximal tubular epithelial cells. Gesualdo, L., Ranieri, E., Monno, R., Rossiello, M.R., Colucci, M., Semeraro, N., Grandaliano, G., Schena, F.P., Ursi, M., Cerullo, G. Kidney Int. (1999) [Pubmed]
  27. In vivo evidence that protease-activated receptors 1 and 2 modulate gastrointestinal transit in the mouse. Kawabata, A., Kuroda, R., Nagata, N., Kawao, N., Masuko, T., Nishikawa, H., Kawai, K. Br. J. Pharmacol. (2001) [Pubmed]
  28. Aerosolized neutral endopeptidase reverses ozone-induced airway hyperreactivity to substance P. Murlas, C.G., Lang, Z., Williams, G.J., Chodimella, V. J. Appl. Physiol. (1992) [Pubmed]
  29. Intracisternal neutral endopeptidase-24.11 inhibitors produce inhibition in gastric acid output: independence from opiate, bombesin, or neurotensin-mediated mechanisms. Stephens, R.L., LePard, K.J., Mohammed, J.R., Ward, P.E. Regul. Pept. (1993) [Pubmed]
  30. Amastatin potentiates drinking elicited by osmotic stimuli: evidence for peptidergic mediation of intracellular dehydration-induced thirst. Sullivan, M.J., Johnson, A.K. Brain Res. (1992) [Pubmed]
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