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PtmC Catalyzes the Final Step of Thioplatensimycin, Thioplatencin, and Thioplatensilin Biosynthesis and Expands the Scope of Arylamine N-Acetyltransferases

Cite this: ACS Chem. Biol. 2021, 16, 1, 96–105
Publication Date (Web):December 14, 2020
https://doi.org/10.1021/acschembio.0c00773
Copyright © 2020 American Chemical Society

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    Abstract

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    The members of the arylamine N-acetyltransferase (NAT) family of enzymes are important for their many roles in xenobiotic detoxification in bacteria and humans. However, very little is known about their roles outside of detoxification or their specificities for acyl donors larger than acetyl-CoA. Herein, we report the detailed study of PtmC, an unusual NAT homologue encoded in the biosynthetic gene cluster for thioplatensimycin, thioplatencin, and a newly reported scaffold, thioplatensilin, thioacid-containing diterpenoids and highly potent inhibitors of bacterial and mammalian fatty acid synthases. As the final enzyme of the pathway, PtmC is responsible for the selection of a thioacid arylamine over its cognate carboxylic acid and coupling to at least three large, 17-carbon ketolide-CoA substrates. Therefore, this study uses a combined approach of enzymology and molecular modeling to reveal how PtmC has evolved from the canonical NAT scaffold into a key part of a natural combinatorial biosynthetic pathway. Additionally, genome mining has revealed the presence of other related NATs located within natural product biosynthetic gene clusters. Thus, findings from this study are expected to expand our knowledge of how enzymes evolve for expanded substrate diversity and enable additional predictions about the activities of NATs involved in natural product biosynthesis and xenobiotic detoxification.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschembio.0c00773.

    • Materials; methods; detailed experimental procedures; computational details; bioinformatic analyses; in vivo, in vitro, and structural characterizations of PtmC; and structural elucidation of 5, 6, 8, 9, 1113, and 15 (PDF)

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    Cited By

    This article is cited by 6 publications.

    1. Larissa Buedenbender, Lucía Ageitos, Marta A. Lages, Carlos Platas-Iglesias, Miguel Balado, Manuel L. Lemos, Jaime Rodríguez, Carlos Jiménez. O-versus S-Metal Coordination of the Thiocarboxylate Group: An NMR Study of the Two Tautomeric Forms of the Ga(III)-Photoxenobactin E Complex. Inorganic Chemistry 2024, 63 (9) , 4176-4184. https://doi.org/10.1021/acs.inorgchem.3c04076
    2. Shiqing Zhang, Xinyi Li, Yijing Wang, Lijuan Yan, Jingjing Wei, Yongjun Liu. Computational Study of the C5-Hydroxylation Mechanism Catalyzed by the Diiron Monooxygenase PtmU3 as Part of the Platensimycin Biosynthesis. Inorganic Chemistry 2021, 60 (23) , 17783-17796. https://doi.org/10.1021/acs.inorgchem.1c02407
    3. Lucas L Fluegel, Ming-Rong Deng, Ping Su, Edward Kalkreuter, Dong Yang, Jeffrey D Rudolf, Liao-Bin Dong, Ben Shen. Development of platensimycin, platencin, and platensilin overproducers by biosynthetic pathway engineering and fermentation medium optimization. Journal of Industrial Microbiology and Biotechnology 2024, 51 https://doi.org/10.1093/jimb/kuae003
    4. Hayley L. Knox, Karen N. Allen. Expanding the viewpoint: Leveraging sequence information in enzymology. Current Opinion in Chemical Biology 2023, 72 , 102246. https://doi.org/10.1016/j.cbpa.2022.102246
    5. Lili Yan, Yinzhe Jin, Beiyu Zhang, Yingwei Xu, Xu Peng, Si Qin, Lanming Chen. Diverse Aquatic Animal Matrices Play a Key Role in Survival and Potential Virulence of Non-O1/O139 Vibrio cholerae Isolates. Frontiers in Microbiology 2022, 13 https://doi.org/10.3389/fmicb.2022.896767
    6. Robert A. Hill, Andrew Sutherland. Hot off the Press. Natural Product Reports 2021, 38 (2) , 287-291. https://doi.org/10.1039/D1NP90005F

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