Enzyme redesign guided by cancer-derived IDH1 mutations

Abstract

Mutations in an enzyme can result in a neomorphic catalytic activity in cancers. We applied cancer-associated mutations from isocitrate dehydrogenases (IDHs) to homologous residues in the active sites of homoisocitrate dehydrogenases (HIDHs) to derive enzymes that catalyze the conversion of 2-oxoadipate to (R)-2-hydroxyadipate, a critical step for adipic acid production. Thus, we provide a prototypic example of how insights from cancer genome sequencing and functional studies can aid in enzyme redesign.