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Publication Abstract from PubMed

FtmOx1 is a nonheme iron (NHFe) endoperoxidase, catalyzing three disparate reactions, endoperoxidation, alcohol dehydrogenation, and dealkylation, under in vitro conditions; the diversity complicates its mechanistic studies. In this study, we use two substrate analogues to simplify the FtmOx1-catalyzed reaction to either a dealkylation or an alcohol dehydrogenation reaction for structure-function relationship analysis to address two key FtmOx1 mechanistic questions: (1) Y224 flipping in the proposed COX-like model vs alpha-ketoglutarate (alphaKG) rotation proposed in the CarC-like mechanistic model and (2) the involvement of a Y224 radical (COX-like model) or a Y68 radical (CarC-like model) in FtmOx1-catalysis. When 13-oxo-fumitremorgin B (7) is used as the substrate, FtmOx1-catalysis changes from the endoperoxidation to a hydroxylation reaction and leads to dealkylation. In addition, consistent with the dealkylation side-reaction in the COX-like model prediction, the X-ray structure of the FtmOx1*Co(II)*alphaKG*7 ternary complex reveals a flip of Y224 to an alternative conformation relative to the FtmOx1*Fe(II)*alphaKG binary complex. Verruculogen (2) was used as a second substrate analogue to study the alcohol dehydrogenation reaction to examine the involvement of the Y224 radical or Y68 radical in FtmOx1-catalysis, and again, the results from the verruculogen reaction are more consistent with the COX-like model.

Dissecting the Mechanism of the Nonheme Iron Endoperoxidase FtmOx1 Using Substrate Analogues.,Zhu G, Yan W, Wang X, Cheng R, Naowarojna N, Wang K, Wang J, Song H, Wang Y, Liu H, Xia X, Costello CE, Liu X, Zhang L, Liu P JACS Au. 2022 Jun 10;2(7):1686-1698. doi: 10.1021/jacsau.2c00248. eCollection, 2022 Jul 25. PMID:35911443^[2]

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