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Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity

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Title Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity
 
Creator Jawaid, Safdar
Gertz, Monica
Corsino, Carlin
Cheung, Jamie
Seidle, Heather
Couch, Robin D
 
Subject HMGCR
Hydroxymethylglutaryl-coenzyme A reductase
Lovastatin
Hypercholesterolemia
 
Description 331-339
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.
 
Date 2011-01-07T09:39:18Z
2011-01-07T09:39:18Z
2010-12
 
Type Article
 
Identifier 0975-0959 (Online); 0301-1208 (Print)
http://hdl.handle.net/123456789/10855
 
Language en_US
 
Rights CC Attribution-Noncommercial-No Derivative Works 2.5 India
 
Publisher NISCAIR-CSIR, India
 
Source IJBB Vol.47(6) [December 2010]