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

Inorganic Chemistry
Xiya WangYongjun Liu

Abstract

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-1 si from 1, the syn-1,2-migration of the 2 si methyl group, and the antarafacial loss of H-3 re. The abstraction of H-1 si 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....Continue Reading

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Citations

Oct 28, 2019·Natural Product Reports·Jeffrey D Rudolf, Chin-Yuan Chang

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