Deep mutational scanning of CYP2C19 in human cells reveals a substrate specificity-abundance tradeoff.

ABSTRACT: The cytochrome P450s enzyme family metabolizes ∼80% of small molecule drugs. Variants in cytochrome P450s can substantially alter drug metabolism, leading to improper dosing and severe adverse drug reactions. Due to low sequence conservation, predicting variant effects across cytochrome P450s is challenging. Even closely related cytochrome P450s like CYP2C9 and CYP2C19, which share 92% amino acid sequence identity, display distinct phenotypic properties. Using variant abundance by massively parallel sequencing, we measured the steady-state protein abundance of 7,660 single amino acid variants in CYP2C19 expressed in cultured human cells. Our findings confirmed critical positions and structural features essential for cytochrome P450 function, and revealed how variants at conserved positions

SUBMITTER: Boyle GE 

PROVIDER: S-EPMC11538415 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature