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|Title:||Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity|
Couch, Robin D
Hydroxymethylglutaryl-coenzyme A reductase
|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 <i>HMGCR</i> 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 <i>K</i><sub>i</sub> for lovastatin. Thus, alterations in HMGCR could contribute towards the synergistic effects of multiple loci in the statin response.|
|ISSN:||0975-0959 (Online); 0301-1208 (Print)|
|Appears in Collections:||IJBB Vol.47(6) [December 2010]|
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