| Structure-function analysis of human l-prostaglandin D synthase bound with fatty acid molecules. | |
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MedLine Citation:
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PMID: 20667974 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Human prostaglandin D synthase (L-PGDS) is a lipocalin-type enzyme involved in the metabolism of arachidonic acid and plays a key role in the regulation of sleep, allergy, pain sensation, and the development of male reproductive organs. Here, using a combination of crystallographic, biochemical, mutagenesis, and kinetic studies, we have gained insights into the mode of ligand binding by human L-PGDS and have identified residues involved in catalysis. Interestingly, structural evidence reveals that 2 molecules of fatty acids, one molecule each of oleic and palmitoleic acid, bind inside the β barrel. The oleic acid is buried and binds in a highly basic patch in proximity to the catalytically critical Cys65, mimicking the binding of prostaglandin H(2). The palmitoleic acid sits in a relatively neutral region with very few interactions with the protein. Mutating Met64, Leu79, Phe83, or Leu131 to alanine reduced the catalytic efficiency by almost 10-fold, while K59A and Y149A mutations enhanced the catalytic efficiency by >2-fold. Met64 seems to function as a kinetic clamp, pushing the thiol group of Cys65 close to the site of nucleophilic attack during catalysis. |
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Authors:
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Yangyan Zhou; Neil Shaw; Yang Li; Yu Zhao; Rongguang Zhang; Zhi-Jie Liu |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-28 |
Journal Detail:
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Title: FASEB journal : official publication of the Federation of American Societies for Experimental Biology Volume: 24 ISSN: 1530-6860 ISO Abbreviation: FASEB J. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-02 Completed Date: 2011-01-04 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 8804484 Medline TA: FASEB J Country: United States |
Other Details:
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Languages: eng Pagination: 4668-77 Citation Subset: IM |
Affiliation:
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National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Crystallography, X-Ray Fatty Acids / chemistry*, metabolism* Fatty Acids, Monounsaturated / chemistry, metabolism Humans Intramolecular Oxidoreductases / chemistry*, genetics, metabolism* Lipocalins / chemistry*, genetics, metabolism* Mutagenesis, Site-Directed Mutation Oleic Acid / chemistry, metabolism Protein Binding Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/Fatty Acids; 0/Fatty Acids, Monounsaturated; 0/Lipocalins; 112-80-1/Oleic Acid; 2091-29-4/palmitoleic acid; EC 5.3.-/Intramolecular Oxidoreductases; EC 5.3.99.2/prostaglandin R2 D-isomerase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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