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Molecular Architecture of a C-3′-Methyltransferase Involved in the Biosynthesis of d-Tetronitrose

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§ Department of Biochemistry, University of Wisconsin, Madison, Wisconsin 53706
Edgewood Campus Middle School, Madison, Wisconsin 53711
*To whom correspondence should be addressed. E-mail: [email protected]. Fax: (608) 262-1319. Phone: (608) 262-4988.
Cite this: Biochemistry 2010, 49, 28, 5891–5898
Publication Date (Web):June 8, 2010
https://doi.org/10.1021/bi100782b
Copyright © 2010 American Chemical Society

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    Abstract

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    S-Adenosylmethionine (SAM)-dependent methyltransferases are involved in a myriad of biological processes, including signal transduction, chromatin repair, metabolism, and biosyntheses, among others. Here we report the high-resolution structure of a novel C-3′-methyltransferase involved in the production of d-tetronitrose, an unusual sugar found attached to the antitumor agent tetrocarcin A or the antibiotic kijanimicin. Specifically, this enzyme, referred to as TcaB9 and cloned from Micromonospora chalcea, catalyzes the conversion of dTDP-3-amino-2,3,6-trideoxy-4-keto-d-glucose to dTDP-3-amino-2,3,6-trideoxy-4-keto-3-methyl-d-glucose. For this analysis, two structures were determined to 1.5 Å resolution: one in which the enzyme was crystallized in the presence of SAM and dTMP and the other with the protein complexed to S-adenosylhomocysteine and its dTDP-linked sugar product. The overall fold of the monomeric enzyme can be described in terms of three domains. The N-terminal domain harbors the binding site for a zinc ion that is ligated by four cysteines. The middle domain adopts the canonical “SAM-binding” fold with a seven-stranded mixed β-sheet flanked on either side by three α-helices. This domain is responsible for anchoring the SAM cofactor to the protein. Strikingly, the C-terminal domain also contains a seven-stranded β-sheet, and it appears to be related to the middle domain by an approximate 2-fold rotational axis, thus suggesting TcaB9 arose via gene duplication. Key residues involved in sugar binding include His 181, Glu 224, His 225, and Tyr 222. Their possible roles in catalysis are discussed.

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    An amino acid sequence alignment of putative C-3′-methyltransferases. This material is available free of charge via the Internet at http://pubs.acs.org.

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    2. Zhongyue Yang, Fang Liu, Adam H. Steeves, Heather J. Kulik. Quantum Mechanical Description of Electrostatics Provides a Unified Picture of Catalytic Action Across Methyltransferases. The Journal of Physical Chemistry Letters 2019, 10 (13) , 3779-3787. https://doi.org/10.1021/acs.jpclett.9b01555
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    10. Zi Li, Thiya Mukherjee, Kyle Bowler, Sholeh Namdari, Zachary Snow, Sarah Prestridge, Alexandra Carlton, Maor Bar-Peled. A four-gene operon in Bacillus cereus produces two rare spore-decorating sugars. Journal of Biological Chemistry 2017, 292 (18) , 7636-7650. https://doi.org/10.1074/jbc.M117.777417
    11. Garrett T. Dow, James B. Thoden, Hazel M. Holden. Structural studies on KijD1, a sugar C ‐3′‐methyltransferase. Protein Science 2016, 25 (12) , 2282-2289. https://doi.org/10.1002/pro.3034
    12. Nathan A. Bruender, Hazel M. Holden. Probing the catalytic mechanism of a C ‐3′‐methyltransferase involved in the biosynthesis of D ‐tetronitrose. Protein Science 2012, 21 (6) , 876-886. https://doi.org/10.1002/pro.2074
    13. David K. Liscombe, Gordon V. Louie, Joseph P. Noel. Architectures, mechanisms and molecular evolution of natural product methyltransferases. Natural Product Reports 2012, 29 (10) , 1238. https://doi.org/10.1039/c2np20029e
    14. Shanteri Singh, George N. Phillips Jr., Jon S. Thorson. The structural biology of enzymes involved in natural product glycosylation. Natural Product Reports 2012, 29 (10) , 1201. https://doi.org/10.1039/c2np20039b

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