title: Human hydroxymethylglutaryl-coenzyme A reductase (HMGCR) and statin sensitivity.
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 K(app)(M) 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.
authors.affiliation: Chemistry and Biochemistry Department, George Mason University, Manassas, VA 20110, USA.
authors.forename: Safdar
authors.initials: S
authors.lastname: Jawaid
authors.forename: Monica
authors.initials: M
authors.lastname: Gertz
authors.forename: Carlin
authors.initials: C
authors.lastname: Corsino
authors.forename: Jamie
authors.initials: J
authors.lastname: Cheung
authors.forename: Heather
authors.initials: H
authors.lastname: Seidle
authors.forename: Robin D
authors.initials: RD
authors.lastname: Couch
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010597:Pharmacogenetics; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011994:Recombinant Proteins; D006903:Hydroxymethylglutaryl CoA Reductases