Characterization and Crystal Structure of a Nonheme Diiron Monooxygenase Involved in Platensimycin and Platencin Biosynthesis

Dong, Liao-Bin; Liu, Yu-Chen; Cepeda, Alexis J.; Kalkreuter, Edward; Deng, Ming-Rong; Rudolf, Jeffrey D.; Chang, Changsoo; Joachimiak, Andrzej; Phillips, George N.; Shen, Ben

doi:10.1021/jacs.9b06183

Title: Characterization and Crystal Structure of a Nonheme Diiron Monooxygenase Involved in Platensimycin and Platencin Biosynthesis

Journal Article · Wed Jul 10 00:00:00 EDT 2019 · Journal of the American Chemical Society

DOI:https://doi.org/10.1021/jacs.9b06183· OSTI ID:1556088

Dong, Liao-Bin ^[1]; Liu, Yu-Chen ^[1]; Cepeda, Alexis J. ^[1]; Kalkreuter, Edward ^[1]; Deng, Ming-Rong ^[1];

^[1]; Chang, Changsoo ^[2]; Joachimiak, Andrzej ^[2]; Phillips, George N. ^[3];

^[1]

The Scripps Research Institute, Jupiter, FL (United States)
Argonne National Lab. (ANL), Argonne, IL (United States)
Rice Univ., Houston, TX (United States)

Nonheme diiron monooxygenases make up a rapidly growing family of oxygenases that are rarely identified in secondary metabolism. In this paper, we report the in vivo, in vitro, and structural characterizations of a nonheme diiron monooxygenase, PtmU₃, that installs a C-5 β-hydroxyl group in the unified biosynthesis of platensimycin and platencin, two highly functionalized diterpenoids that act as potent and selective inhibitors of bacterial and mammalian fatty acid synthases. This hydroxylation sets the stage for the subsequent A-ring cleavage step key to the unique diterpene-derived scaffolds of platensimycin and platencin. PtmU3 adopts an unprecedented triosephosphate isomerase (TIM) barrel structural fold for this class of enzymes and possesses a noncanonical diiron active site architecture with a saturated six-coordinate iron center lacking a μ-oxo bridge. In conclusion, this study reveals the first member of a previously unidentified superfamily of TIM-barrel-fold enzymes for metal-dependent dioxygen activation, with the majority predicted to act on CoA-linked substrates, thus expanding our knowledge of nature’s repertoire of nonheme diiron monooxygenases and TIM-barrel-fold enzymes.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); Arnold and Mabel Beckman Foundation - Arnold O. Beckman Postdoctoral Fellowship; National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1556088

Journal Information:: Journal of the American Chemical Society, Vol. 141, Issue 31; ISSN 0002-7863

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 11 works

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