ω- versus (ω-1)-hydroxylation: Cytochrome P450 4B1 sterics make the call

Emily E Scott

doi:10.1074/jbc.h117.775494

Abstract

Many family 4 cytochrome P450s play key roles in fatty acid hydroxylation at the terminal, or ω, carbon, but the mechanistic basis for this energetically disfavored regiostereochemistry has been less clear. A co-crystal structure of the rabbit family 4 enzyme CYP4B1 with its substrate octane reveals that the propensity for ω-hydroxylation is orchestrated by active-site sterics, partially mediated by an unusual heme-polypeptide ester bond.

Highlights

The author declares that she has no conflicts of interest with the contents of this article
The overall features of CYP4B1 mirror those of other cytochromes P450, but the 2.7 Å complex further revealed that the octane substrate approaches the heme iron—the site of the catalytic oxygen intermediate during turnover— end on (Fig. 1)
The linear hydrocarbon is constrained to an extended conformation within a “slot-like” active site cavity that narrows near the heme so that the (␻-1)- hydrogens are more shielded from the heme than those ␻-carbons, promoting the observed regioselectivity of the hydroxylation reaction

Summary

Introduction

The author declares that she has no conflicts of interest with the contents of this article. Of Medicinal Chemistry, Pharmacology, and Biophysics, University of Michigan, 428 Church St., Ann Arbor, MI 48109. The overall features of CYP4B1 mirror those of other cytochromes P450, but the 2.7 Å complex further revealed that the octane substrate approaches the heme iron—the site of the catalytic oxygen intermediate during turnover— end on (Fig. 1).

Results

Conclusion