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Publication Abstract from PubMed

P450 peroxidase activities are valued for their ability to catalyze complex chemical transformations using economical H(2)O(2); however, they have been largely underexplored compared to their monooxygenase and peroxygenase activities. In this study, we identified an unconventional P450 enzyme, PtmB, which catalyzes the dimerization of purine nucleobases and tryptophan-containing diketopiperazines (TDKPs), yielding C3-nucleobase pyrroloindolines and nucleobase-TDKP dimers. Unlike typical TDKP P450 enzymes reliant on NAD(P)H cofactors and electron transfer systems, PtmB, and its analogs exhibit remarkable peroxidase activity in synthesizing adenine and other modified 6-aminopurine nucleobase-TDKP dimers. Structural analysis of the PtmB-substrate complex, mutation assays, and computational investigations reveal adenine's dual role as both substrate and acid-base catalyst in activating H(2)O(2) to generate Compound I (Cpd I). This initiates a specific radical cascade reaction, facilitating the formation of precise C horizontal line C and C horizontal line N bonds. Biochemical assays and molecular dynamics simulations demonstrate that adenine's 6-NH(2) hydrogen-bonding networks induce necessary conformational changes for H(2)O(2) activation, thereby driving peroxidase activity. This study unveils an unusual catalytic mechanism for the P450 peroxidase system and underscores the pivotal role of nucleobases in enzyme-mediated reactions, which offers different prospects for developing P450 peroxidases and nucleobase-based biocatalysts.

A nucleobase-driven P450 peroxidase system enables regio- and stereo-specific formation of C horizontal line C and C horizontal line N bonds.,Wei G, Duan B, Zhou TP, Tian W, Sun C, Lin Z, Deng Z, Wang B, Zhang Z, Qu X Proc Natl Acad Sci U S A. 2024 Nov 12;121(46):e2412890121. doi: , 10.1073/pnas.2412890121. Epub 2024 Nov 7. PMID:39508763^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.