| Mechanistic crystallography. Mechanism of inactivation of gamma-aminobutyric acid aminotransferase by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid as elucidated by crystallography. | |
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MedLine Citation:
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PMID: 15518554 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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(1R,3S,4S)-3-Amino-4-fluorocyclopentane-1-carboxylic acid (7) was previously shown to be a mechanism-based inactivator of gamma-aminobutyric acid aminotransferase (GABA-AT) [Qiu, J. and Silverman, R. B. (2000) J. Med. Chem. 43, 706-720]. Two mechanisms were considered as reasonable possibilities, a Michael addition mechanism and an enamine mechanism. On the basis of a variety of chemical studies, including tedious radiolabeling experiments, it was concluded that inactivation by 7 proceeds by a Michael addition mechanism. Here, a crystal structure of 7 bound to pig liver GABA-AT is reported, which clearly demonstrates that the adduct formed is derived from an enamine mechanism. This represents another example of how crystallography is an important tool for elucidation of inactivation mechanisms. |
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Authors:
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Paola Storici; Jian Qiu; Tilman Schirmer; Richard B Silverman |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Biochemistry Volume: 43 ISSN: 0006-2960 ISO Abbreviation: Biochemistry Publication Date: 2004 Nov |
Date Detail:
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Created Date: 2004-11-02 Completed Date: 2005-01-11 Revised Date: 2007-11-14 |
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: 14057-63 Citation Subset: IM |
Affiliation:
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Division of Structural Biology, Biozentrum, University of Basel, CH-4056 Basel, Switzerland. |
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*,
chemistry*,
metabolism Amines / chemistry Amino Acids / chemistry*, metabolism Animals Binding Sites Carboxylic Acids / chemistry*, metabolism Crystallization Crystallography, X-Ray / methods Cyclopentanes / chemistry*, metabolism Enzyme Activation Enzyme Inhibitors / chemistry*, metabolism Ligands Liver / enzymology Models, Chemical Models, Molecular Protein Conformation Pyridoxal Phosphate / chemistry Substrate Specificity Swine |
| Grant Support | |
ID/Acronym/Agency:
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GM66132/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/3-amino-4-(difluoromethylidene)cyclopentanecarboxylic acid; 0/Amines; 0/Amino Acids; 0/Carboxylic Acids; 0/Cyclopentanes; 0/Enzyme Inhibitors; 0/Ligands; 54-47-7/Pyridoxal Phosphate; 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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