| GABA production by glutamic acid decarboxylase is regulated by a dynamic catalytic loop. | |
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MedLine Citation:
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PMID: 17384644 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Gamma-aminobutyric acid (GABA) is synthesized by two isoforms of the pyridoxal 5'-phosphate-dependent enzyme glutamic acid decarboxylase (GAD65 and GAD67). GAD67 is constitutively active and is responsible for basal GABA production. In contrast, GAD65, an autoantigen in type I diabetes, is transiently activated in response to the demand for extra GABA in neurotransmission, and cycles between an active holo form and an inactive apo form. We have determined the crystal structures of N-terminal truncations of both GAD isoforms. The structure of GAD67 shows a tethered loop covering the active site, providing a catalytic environment that sustains GABA production. In contrast, the same catalytic loop is inherently mobile in GAD65. Kinetic studies suggest that mobility in the catalytic loop promotes a side reaction that results in cofactor release and GAD65 autoinactivation. These data reveal the molecular basis for regulation of GABA homeostasis. |
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Authors:
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Gustavo Fenalti; Ruby H P Law; Ashley M Buckle; Christopher Langendorf; Kellie Tuck; Carlos J Rosado; Noel G Faux; Khalid Mahmood; Christiane S Hampe; J Paul Banga; Matthew Wilce; Jason Schmidberger; Jamie Rossjohn; Ossama El-Kabbani; Robert N Pike; A Ian Smith; Ian R Mackay; Merrill J Rowley; James C Whisstock |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-03-25 |
Journal Detail:
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Title: Nature structural & molecular biology Volume: 14 ISSN: 1545-9993 ISO Abbreviation: Nat. Struct. Mol. Biol. Publication Date: 2007 Apr |
Date Detail:
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Created Date: 2007-04-05 Completed Date: 2007-05-30 Revised Date: 2007-10-24 |
Medline Journal Info:
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Nlm Unique ID: 101186374 Medline TA: Nat Struct Mol Biol Country: United States |
Other Details:
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Languages: eng Pagination: 280-6 Citation Subset: IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, VIC 3800, Australia. |
| Data Bank Information | |
Bank Name/Acc. No.:
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PDB/2OKJ; 2OKK |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Autoantigens / immunology Binding Sites / drug effects Catalysis / drug effects Crystallography, X-Ray Dimerization Enzyme Activation / drug effects Glutamate Decarboxylase / chemistry, immunology, metabolism* Glutamic Acid / pharmacology Humans Isoenzymes / chemistry, immunology, metabolism* Models, Molecular Molecular Sequence Data Protein Structure, Secondary / drug effects gamma-Aminobutyric Acid / biosynthesis* |
| Chemical | |
Reg. No./Substance:
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0/Autoantigens; 0/Isoenzymes; 56-12-2/gamma-Aminobutyric Acid; 56-86-0/Glutamic Acid; EC 4.1.1.15/Glutamate Decarboxylase; EC 4.1.1.15/glutamate decarboxylase 1; EC 4.1.1.15/glutamate decarboxylase 2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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