Effects of polymorphic variation on the thermostability of heterogenous populations of CYP3A4 and CYP2C9 enzymes in solution.

ABSTRACT: The effect of non-synonymous single nucleotide polymorphisms (SNPs) on cytochrome P450 (CYP450) drug metabolism is currently poorly understood due to the large number of polymorphisms, the diversity of potential substrates and the complexity of CYP450 function. Previously we carried out in silico studies to explore the effect of SNPs on CYP450 function, using in silico calculations to predict the effect of mutations on protein stability. Here we have determined the effect of eight CYP3A4 and seven CYP2C9 SNPs on the thermostability of proteins in solution to test these predictions. Thermostability assays revealed distinct CYP450 sub-populations with only 65-70% of wild-type CYP3A4 and CYP2C9 susceptible to rapid heat-induced P450 to P420 conversion. CYP3A4 mutations G56D, P218R, S222P, I22

SUBMITTER: Arendse LB 

PROVIDER: S-EPMC6082832 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature