期刊
ACS CATALYSIS
卷 9, 期 1, 页码 565-577出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.8b03733
关键词
biocatalysis; cytochrome P450; peroxygenase; hydroxylation; desaturation; decarboxylation; density functional theory; valence bond modeling
资金
- Austrian Science Fund (FWF) within the DK Molecular Enzymology [W901]
- Federal Ministry for Digital and Economic Affairs (bmwd)
- Federal Ministry for Transport, Innovation and Technology (bmvit)
- Styrian Business Promotion Agency SFG
- Standortagentur Tirol
- Government of Lower Austria
- ZIT-Technology Agency of the City of Vienna through the COMET-Funding Program
- Conacyt Mexico
- Biotechnology and Biological Sciences Research Council (BBSRC) [BB/N006275/1]
- BBSRC [BB/N006275/1] Funding Source: UKRI
The majority of cytochrome P450 enzymes (CYPs) predominantly operate as monooxygenases, but recently a class of P450 enzymes was discovered, that can act as peroxygenases (CYP152). These enzymes convert fatty acids through oxidative decarboxylation, yielding terminal alkenes, and through alpha- and beta-hydroxylation to yield hydroxy-fatty acids. Bioderived olefins may serve as biofuels, and hence understanding the mechanism and substrate scope of this class of enzymes is important. In this work, we report on the substrate scope and catalytic promiscuity of CYP OleT(JE) and two of its orthologues from the CYP152 family, utilizing alpha-monosubstituted branched carboxylic acids. We identify alpha,beta-desaturation as an unexpected dominant pathway for CYP OleT(JE) with 2-methylbutyric acid. To rationalize product distributions arising from alpha/beta-hydroxylation, oxidative decarboxylation, and desaturation depending on the substrate's structure and binding pattern, a computational study was performed based on an active site complex of CYP OleT(JE) containing the heme cofactor in the substrate binding pocket and 2-methylbutyric acid as substrate. It is shown that substrate positioning determines the accessibility of the oxidizing species (Compound I) to the substrate and hence the regio- and chemoselectivity of the reaction. Furthermore, the results show that, for 2-methylbutyric acid, alpha,beta-desaturation is favorable because of a rate-determining alpha-hydrogen atom abstraction, which cannot proceed to decarboxylation. Moreover, substrate hydroxylation is energetically impeded due to the tight shape and size of the substrate binding pocket.
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