| (+/-)-(1S,2R,5S)-5-Amino-2-fluorocyclohex-3-enecarboxylic acid. A potent GABA aminotransferase inactivator that irreversibly inhibits via an elimination-aromatization pathway. | |
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MedLine Citation:
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PMID: 17128990 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Inhibition of gamma-aminobutyric acid aminotransferase (GABA-AT) increases the concentration of GABA, an inhibitory neurotransmitter in human brain, which could have therapeutic applications for a variety of neurological diseases, including epilepsy. On the basis of studies of several previously synthesized conformationally restricted GABA-AT inhibitors, (+/-)-(1S,2R,5S)-5-amino-2-fluorocyclohex-3-enecarboxylic acid (12) was designed as a mechanism-based inactivator. This compound was shown to irreversibly inhibit GABA-AT; substrate protects the enzyme from inactivation. Mechanistic experiments demonstrated the loss of one fluoride ion per active site during inactivation and the formation of N-m-carboxyphenylpyridoxamine 5'-phosphate (26), the same product generated by inactivation of GABA-AT by gabaculine (8). An elimination-aromatization mechanism is proposed to account for these results. |
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Authors:
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Zhiyong Wang; Hai Yuan; Dejan Nikolic; Richard B Van Breemen; Richard B Silverman |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural |
Journal Detail:
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Title: Biochemistry Volume: 45 ISSN: 0006-2960 ISO Abbreviation: Biochemistry Publication Date: 2006 Dec |
Date Detail:
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Created Date: 2006-11-28 Completed Date: 2007-01-18 Revised Date: 2010-09-20 |
Medline Journal Info:
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Nlm Unique ID: 0370623 Medline TA: Biochemistry Country: United States |
Other Details:
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Languages: eng Pagination: 14513-22 Citation Subset: IM |
Affiliation:
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Department of Chemistry, Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, Illinois 60208-3113, USA. |
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*,
metabolism* Amino Acids, Cyclic / chemical synthesis*, chemistry, pharmacology* Chromatography, High Pressure Liquid Cyclohexanecarboxylic Acids / chemical synthesis*, chemistry, pharmacology* Enzyme Activation / drug effects Enzyme Inhibitors / chemical synthesis*, chemistry, pharmacology* Fluorine / chemistry, metabolism Molecular Structure gamma-Aminobutyric Acid / analogs & derivatives, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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GM66132/GM/NIGMS NIH HHS; R01 GM066132-01A2/GM/NIGMS NIH HHS; R01 GM066132-02/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/5-amino-2-fluorocyclohex-3-enecarboxylic acid; 0/Amino Acids, Cyclic; 0/Cyclohexanecarboxylic Acids; 0/Enzyme Inhibitors; 56-12-2/gamma-Aminobutyric Acid; 7782-41-4/Fluorine; EC 2.6.1.19/4-Aminobutyrate Transaminase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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