Document Detail

Inactivation of gamma-aminobutyric acid aminotransferase by (S,E)-4-amino-5-fluoropent-2-enoic acid and effect on the enzyme of (E)-3-(1-aminocyclopropyl)-2-propenoic acid.
MedLine Citation:
PMID:  3761305     Owner:  NLM     Status:  MEDLINE    
(S,E)-4-Amino-5-fluoropent-2-enoic acid (6) is synthesized in six steps starting from the known gamma-aminobutyric acid aminotransferase (gamma-Abu-T) inactivator, (S)-4-amino-5-fluoropentanoic acid (1). Compound 6 is a mechanism-based inactivator of gamma-Abu-T: time-dependent inactivation is saturatable and protected by substrate; thiols do not protect the enzyme from inactivation; no enzyme activity returns upon dialysis. This compound (6) binds 50 times more tightly to gamma-Abu-T than does the saturated analogue (1). No transamination of 6 occurs prior to inactivation. However, five molecules of 6 are required to inactivate the enzyme with concomitant release of five fluoride ions. Therefore, four molecules are being converted to product for each inactivation event. (E)-3-(1-Aminocyclopropyl)-2-propenoic acid is synthesized in seven steps from 1-aminocyclopropanecarboxylic acid. It is prepared as a cyclopropyl derivative of the proposed intermediate in the inactivation of gamma-Abu-T by 6. The cyclopropyl derivative, however, is a noncompetitive inhibitor and does not inactivate the enzyme. This study shows the usefulness and hazards of incorporation of a trans double bond into potential gamma-Abu-T inactivators.
R B Silverman; B J Invergo; J Mathew
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  29     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1986 Oct 
Date Detail:
Created Date:  1986-11-19     Completed Date:  1986-11-19     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1840-6     Citation Subset:  IM    
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MeSH Terms
4-Aminobutyrate Transaminase / antagonists & inhibitors*
Amino Acids / chemical synthesis*,  pharmacology
Amino Acids, Cyclic*
Structure-Activity Relationship
Grant Support
Reg. No./Substance:
0/Amino Acids; 0/Amino Acids, Cyclic; 103500-27-2/3-(1-aminocyclopropyl)-2-propenoic acid; 98212-93-2/4-amino-5-fluoropent-2-enoic acid; EC Transaminase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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