Jawaid, SafdarGertz, MonicaCorsino, CarlinCheung, JamieSeidle, HeatherCouch, Robin D2011-11-152011-11-152010-12Jawaid Safdar, Gertz Monica, Corsino Carlin, Cheung Jamie, Seidle Heather, Couch Robin D. Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity. Indian Journal of Biochemistry & Biophysics. 2010 Dec; 47(6): 331-339.https://imsear.searo.who.int/handle/123456789/135284While 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.enHMGCRHydroxymethylglutaryl-coenzyme A reductaseLovastatinHypercholesterolemiaAmino Acid SequenceBase SequenceDNA Primers --geneticsHumansHydroxymethylglutaryl CoA Reductases --chemistryHydroxymethylglutaryl CoA Reductases --geneticsHydroxymethylglutaryl CoA Reductases --metabolismHydroxymethylglutaryl-CoA Reductase Inhibitors --pharmacologyKineticsModels, MolecularMolecular Sequence DataMutagenesisPharmacogeneticsProtein EngineeringRecombinant Proteins --chemistryRecombinant Proteins --geneticsRecombinant Proteins --metabolismSequence Homology, Amino AcidArticle