QM/MM study of the C-C coupling reaction mechanism of CYP121, an essential cytochrome p450 of Mycobacterium tuberculosis

Proteins
Victoria G DumasMarcelo A Marti

Abstract

Among 20 p450s of Mycobacterium tuberculosis (Mt), CYP121 has received an outstanding interest, not only due to its essentiality for bacterial viability but also because it catalyzes an unusual carbon-carbon coupling reaction. Based on the structure of the substrate bound enzyme, several reaction mechanisms were proposed involving first Tyr radical formation, second Tyr radical formation, and C-C coupling. Key and unknown features, being the nature of the species that generate the first and second radicals, and the role played by the protein scaffold each step. In the present work we have used classical and quantum based computer simulation methods to study in detail its reaction mechanism. Our results show that substrate binding promotes formation of the initial oxy complex, Compound I is the responsible for first Tyr radical formation, and that the second Tyr radical is formed subsequently, through a PCET reaction, promoted by the presence of key residue Arg386. The final C-C coupling reaction possibly occurs in bulk solution, thus yielding the product in one oxygen reduction cycle. Our results thus contribute to a better comprehension of MtCYP121 reaction mechanism, with direct implications for inhibitor design, and also con...Continue Reading

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Citations

Oct 4, 2016·Journal of the American Chemical Society·Xia YuYi Tang
Dec 13, 2016·Chemical Reviews·Man-Cheng TangYi Tang
Feb 25, 2021·Applied Microbiology and Biotechnology·Lauritz Harken, Shu-Ming Li
Mar 7, 2021·Journal of Industrial Microbiology & Biotechnology·Yuxuan YeTodd K Hyster
Apr 28, 2018·Organic Letters·Xu ZhuCorinna S Schindler
Aug 14, 2020·Journal of the American Chemical Society·Vikram V ShendeDavid H Sherman

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