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Crystal structure of the catalytic portion of human HMG‐CoA reductase: insights into regulation of activity and catalysis
Author(s) -
Istvan Eva S.,
Palnitkar Maya,
Buchanan Susan K.,
Deisenhofer Johann
Publication year - 2000
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/19.5.819
Subject(s) - reductase , biology , hmg coa reductase , enzyme , mevalonate pathway , biochemistry , coenzyme a , hydroxymethylglutaryl coa reductase , active site , biosynthesis
3‐hydroxy‐3‐methylglutaryl‐CoA reductase (HMGR) catalyzes the formation of mevalonate, the committed step in the biosynthesis of sterols and isoprenoids. The activity of HMGR is controlled through synthesis, degradation and phosphorylation to maintain the concentration of mevalonate‐derived products. In addition to the physiological regulation of HMGR, the human enzyme has been targeted successfully by drugs in the clinical treatment of high serum cholesterol levels. Three crystal structures of the catalytic portion of human HMGR in complexes with HMG‐CoA, with HMG and CoA, and with HMG, CoA and NADP + , provide a detailed view of the enzyme active site. Catalytic portions of human HMGR form tight tetramers. The crystal structure explains the influence of the enzyme's oligomeric state on the activity and suggests a mechanism for cholesterol sensing. The active site architecture of human HMGR is different from that of bacterial HMGR; this may explain why binding of HMGR inhibitors to bacterial HMGRs has not been reported.