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Indian Journal of Biochemistry and Biophysics (IJBB) >
IJBB Vol.47 [2010] >
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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