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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
6
|
| pubmed:dateCreated |
1990-6-28
|
| pubmed:abstractText |
A series of O'-(epoxyalkyl)tyrosines and a carboxy terminal (epoxyalkyl)tyrosine and -phenylalanine were synthesized as potential serine protease inhibitors. N-Acetyl derivatives showed irreversible inactivation vis-a-vis subtilisin, while the N-benzoyl ones were specific toward chymotrypsin. The most potent inactivation of chymotrypsin was achieved by a O'-(3,4-epoxybutyl)-L-tyrosine derivative. The inactivation was shown to be stereospecific since a D derivative led to no irreversible inactivation. Placement of the epoxyalkyl group at the carboxy terminus led to potent rapid inactivation. Under these conditions some of the activity was later recovered. The two classes of inactivators (O'-epoxyalkyl and carboxy-epoxyalkyl) appear to operate by different mechanisms. Most importantly, it was found that irreversible inactivation by O'-(epoxyalkyl)-L-tyrosine only resulted if the carboxy terminus was a substrate (i.e. a compound with free carboxy terminus did not lead to inactivation). The ultimate activity kinetic assay (Daniels, S. B.; et al. J. Biol. Chem. 1983, 258, 15046-15053.) indicated that the epoxyalkyl group on the phenolic oxygen had an optimal length of four carbons with respect to the turnover ratio (the ratio of molecules undergoing turnover compared to those that inactivate the enzyme) for chymotrypsin. A different kinetic assay (Ashani, Y.; Wins, P.; Wilson, I. B. Biochim. Biophys. Acta 1972, 284, 427-434.) demonstrated that substratelike turnover was proceeding at considerably slower rates than for the corresponding true substrates and with rate-limiting deacylation of the acyl-enzyme. Amino acid analysis subsequent to acid hydrolysis demonstrated that Met had been selectively alkylated by the O'-(epoxyalkyl)tyrosine derivative. By contrast, alpha-chymotrypsin inactivated with N-benzoyl-L-Phe-2,3-epoxypropyl ester then subjected to amino acid analysis showed no change in the content of any amino acid that would serve as a potential nucleophile to the inhibitor. Yet, the L-Phe content increased, indicating that a covalent bond had been formed between the inhibitor and the enzyme. Either the bond between the inhibitor and the enzyme did not withstand the hydrolytic conditions and/or there was less than 10% decrease in the amino acids with nucleophilic side chains upon inactivation. Finally, two tripeptides containing O'-(epoxyalkyl)-L-tryosines were synthesized [N-(tert-butoxycarbonyl)-L-alanyl-L-alanyl-O'-(2,3-epoxypropyl)-L-tyrosi ne ethyl ester and N-(trifluoroacetyl)-L-valyl-O'-(2,3-epoxypropyl)-L-tyrosyl-L-valine methyl ester] as potential elastase inhibitors and were found to reversibly and competitively inhibit porcine pancreatic elastase.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jun
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:volume |
33
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1620-34
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading | |
| pubmed:year |
1990
|
| pubmed:articleTitle |
O'-(epoxyalkyl)tyrosines and (epoxyalkyl)phenylalanine as irreversible inactivators of serine proteases: synthesis and inhibition mechanism.
|
| pubmed:affiliation |
Department of Chemistry, Rutgers, State University, Newark, New Jersey 07102.
|
| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
|