| 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. | |
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MedLine Citation:
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PMID: 3761305 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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(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. |
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Authors:
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R B Silverman; B J Invergo; J Mathew |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 29 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1986 Oct |
Date Detail:
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Created Date: 1986-11-19 Completed Date: 1986-11-19 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1840-6 Citation Subset: IM |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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4-Aminobutyrate Transaminase
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antagonists & inhibitors* Amino Acids / chemical synthesis*, pharmacology Amino Acids, Cyclic* Kinetics Structure-Activity Relationship |
| Grant Support | |
ID/Acronym/Agency:
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NS 15703/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 2.6.1.19/4-Aminobutyrate Transaminase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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