Document Detail

Structure-function analysis of human l-prostaglandin D synthase bound with fatty acid molecules.
MedLine Citation:
PMID:  20667974     Owner:  NLM     Status:  MEDLINE    
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.
Yangyan Zhou; Neil Shaw; Yang Li; Yu Zhao; Rongguang Zhang; Zhi-Jie Liu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-28
Journal Detail:
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:
Created Date:  2010-12-02     Completed Date:  2011-01-04     Revised Date:  2012-02-15    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4668-77     Citation Subset:  IM    
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
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MeSH Terms
Crystallography, X-Ray
Fatty Acids / chemistry*,  metabolism*
Fatty Acids, Monounsaturated / chemistry,  metabolism
Intramolecular Oxidoreductases / chemistry*,  genetics,  metabolism*
Lipocalins / chemistry*,  genetics,  metabolism*
Mutagenesis, Site-Directed
Oleic Acid / chemistry,  metabolism
Protein Binding
Structure-Activity Relationship
Reg. No./Substance:
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 R2 D-isomerase

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