Spatially restricted substrate-binding site of cortisol-synthesizing CYP11B1 limits multiple hydroxylations and hinders aldosterone synthesis.

ABSTRACT: Human cytochromes P450_11β (CYP11B1) and P450_aldo (CYP11B2) are monooxygenases that synthesize cortisol through steroid 11β-hydroxylation and aldosterone through a three-step process comprising 11β-hydroxylation and two 18-hydroxylations, respectively. CYP11B1 also catalyzes 18-monohydroxylation and 11β,18-dihydroxylation. To study the molecular basis of such catalytic divergence of the two enzymes, we examined a CYP11B1 mutant (Mt-CYP11B1) with amino acid replacements on the distal surface by determining the catalytic activities and crystal structure in the metyrapone-bound form at 1.4-Å resolution. Mt-CY11B1 retained both 11β-hydroxylase and 18-hydroxylase activities of the wild type (Wt-CYP11B1) but lacked 11β,18-dihydroxylase activity. Comparisons of the crystal st

SUBMITTER: Mukai K 

PROVIDER: S-EPMC8408562 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature