Mechanistic Insights into CYP199A4-Catalyzed α-Hydroxyketone Formation and Hydrogen Bond-Assisted C-C Bond Cleavage Catalyzed by the CYP199A4 F182L Mutant.

ABSTRACT: CYP199A4 is a cytochrome P450 and can catalyze the hydroxylation of 4-propionylbenzoic acid (4-pIBA) to generate α-hydroxyketone with high stereoselectivity. The F182L mutant of CYP199A4 (F182L-CYP199A4) has been shown to support the cleavage of the C-C bond between the carbonyl and hydroxyl groups of α-hydroxyketone, whereas wild-type CYP199A4 cannot. To uncover how the Phe182 regulates substrate reactivity, we conducted classical molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) MD simulations on these systems. The results predicted that the formation of α-hydroxyketone preferentially led to the (S)-enantiomer. Moreover, the findings revealed that the F182L-CYP199A4 facilitated the formation of a hydrogen bond between the α-hydroxyketone and the reactive pe

SUBMITTER: Yuan C 

PROVIDER: S-EPMC11854964 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature