Oxidative Rearrangement Mechanism of Pentalenolactone F Catalyzed by Cytochrome P450 CYP161C2 (PntM)

The CYP161C2 (PntM) from Streptomyces arenae is a member of the cytochrome P450 enzymes, which catalyzes the unusual oxidative rearrangement of pentalenolactone F (1) to the sesquiterpenoid antibiotic pentalenolactone (3). On the basis of the crystal structure of PntM bound with substrate, quantum m...

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Published in:Inorganic chemistry 2018-08, Vol.57 (15), p.8933-8941
Main Authors: Wang, Xiya, Shi, Junyou, Liu, Yongjun
Format: Article
Language:English
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Summary:The CYP161C2 (PntM) from Streptomyces arenae is a member of the cytochrome P450 enzymes, which catalyzes the unusual oxidative rearrangement of pentalenolactone F (1) to the sesquiterpenoid antibiotic pentalenolactone (3). On the basis of the crystal structure of PntM bound with substrate, quantum mechanical/molecular mechanics (QM/MM) calculations have been performed to explore the detailed mechanism of PntM-catalyzed oxidative rearrangement. The conversion from pentalenolactone F (1) to pentalenolactone (3) involves the stereospecific removal of the H-1si from 1, the syn-1,2-migration of the 2si methyl group, and the antarafacial loss of H-3re. The abstraction of H-1si by Cpd I is calculated to be rate limiting with an energy barrier of 20.3 kcal/mol, which basically agrees with the estimated free energy barrier from experiments (18.6 kcal/mol). It is the unfavorable geometry of Fe–OH–C1 that blocks the oxygen rebound reaction, and the subsequent intramolecular syn-1,2-methyl migration is accompanied by an electron transfer from the substrate to the porphyrin ring via an Fe–OH group, generating the carbocation intermediate. Owing to the positive charge, the intermediate can easily lose a proton to form the final products. Our calculation results indicate that both the carboxyl group of porphyrin and Fe–OH can act as bases to accept the proton of the substrate. The target product pentalenolactone and the three isomeric byproducts correspond to four different modes of deprotonation.
ISSN:0020-1669
1520-510X
DOI:10.1021/acs.inorgchem.8b00860