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Publication Abstract from PubMed

Given prominent physicochemical similarities between H(2)O(2) and water, we report a new strategy for promoting the peroxygenase activity of P450 enzymes by engineering their water tunnels to facilitate H(2)O(2) access to the heme center buried therein. Specifically, the H(2)O(2)-driven activities of two native NADH-dependent P450 enzymes (CYP199A4 and CYP153A(M.aq)) increase significantly (by >183-fold and >15-fold, respectively). Additionally, the amount of H(2)O(2) required for an artificial P450 peroxygenase facilitated by a dual-functional small molecule to obtain the desired product is reduced by 95%-97.5% (with approximately 95% coupling efficiency). Structural analysis suggests that mutating the residue at the bottleneck of the water tunnel may open a second pathway for H(2)O(2) to flow to the heme center (in addition to the natural substrate tunnel). This study highlights a promising, generalizable strategy whereby P450 monooxygenases can be modified to adopt peroxygenase activity through H(2)O(2) tunnel engineering, thus broadening the application scope of P450s in synthetic chemistry and synthetic biology.

Enabling Peroxygenase Activity in Cytochrome P450 Monooxygenases by Engineering Hydrogen Peroxide Tunnels.,Zhao P, Kong F, Jiang Y, Qin X, Tian X, Cong Z J Am Chem Soc. 2023 Mar 8;145(9):5506-5511. doi: 10.1021/jacs.3c00195. Epub 2023 , Feb 15. PMID:36790023^[1]

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