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IJBB Vol.47(6) [December 2010] >


Title: Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity
Authors: Jawaid, Safdar
Gertz, Monica
Corsino, Carlin
Cheung, Jamie
Seidle, Heather
Couch, Robin D
Keywords: HMGCR
Hydroxymethylglutaryl-coenzyme A reductase
Lovastatin
Hypercholesterolemia
Issue Date: Dec-2010
Publisher: NISCAIR-CSIR, India
Abstract: While statins, hydroxymethylglutaryl-coenzyme A reductase (HMGCR) inhibitors, are clinically proven to reduce plasma cholesterol levels, a wide variation in inter-individual response to statin therapy has been observed. Pharmacogenetic studies have identified multiple loci that potentially contribute towards the statin response, including the HMGCR gene. To examine, if a statin-resistant, catalytically-active isoform of the human HMGCR could be generated, we have rationally altered the protein to include additional residues in the flap domain, which has a role in statin binding. Comparative enzyme assays with purified wild-type and mutant isoforms reveal the alteration imposes a slight (38%) decrease in the for the substrate, a near 2-fold increase in turnover number, and a 480% increase in the Ki for lovastatin. Thus, alterations in HMGCR could contribute towards the synergistic effects of multiple loci in the statin response.
Page(s): 331-339
CC License:  CC Attribution-Noncommercial-No Derivative Works 2.5 India
ISSN: 0975-0959 (Online); 0301-1208 (Print)
Source:IJBB Vol.47(6) [December 2010]

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