Facile Chemoenzymatic Strategies for the Synthesis and Utilization of S-Adenosyl-L-Methionine Analogues

Authors

  • Dr. Shanteri Singh,

    Corresponding author
    1. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536 (USA)
    2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536 (USA)
    • Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536 (USA)===

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  • Dr. Jianjun Zhang,

    1. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536 (USA)
    2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536 (USA)
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  • Tyler D. Huber,

    1. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536 (USA)
    2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536 (USA)
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  • Manjula Sunkara,

    1. Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY 40536 (USA)
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  • Katherine Hurley,

    1. Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53705 (USA)
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  • Dr. Randal D. Goff,

    1. Western Wyoming Community College, 2500 College Dr., Rock Springs, WY 82902-0428 (USA)
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  • Dr. Guojun Wang,

    1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536 (USA)
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  • Wen Zhang,

    1. Molecular and Cellular Biochemistry, University of Kentucky, College of Medicine, University of Kentucky, Lexington, KY 40536 (USA)
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  • Prof. Chunming Liu,

    1. Molecular and Cellular Biochemistry, University of Kentucky, College of Medicine, University of Kentucky, Lexington, KY 40536 (USA)
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  • Prof. Jürgen Rohr,

    1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536 (USA)
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  • Prof. Steven G. Van Lanen,

    1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536 (USA)
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  • Prof. Andrew J. Morris,

    1. Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY 40536 (USA)
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  • Prof. Jon S. Thorson

    Corresponding author
    1. Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536 (USA)
    2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536 (USA)
    • Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, KY 40536 (USA)===

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  • This work was supported by NIH RO1 CA84374 (JST), U01 GM098248and the National Center for Advancing Translational Sciences (UL1TR000117).

Abstract

A chemoenzymatic platform for the synthesis of S-adenosyl-L-methionine (SAM) analogues compatible with downstream SAM-utilizing enzymes is reported. Forty-four non-native S/Se-alkylated Met analogues were synthesized and applied to probing the substrate specificity of five diverse methionine adenosyltransferases (MATs). Human MAT II was among the most permissive of the MATs analyzed and enabled the chemoenzymatic synthesis of 29 non-native SAM analogues. As a proof of concept for the feasibility of natural product “alkylrandomization”, a small set of differentially-alkylated indolocarbazole analogues was generated by using a coupled hMAT2–RebM system (RebM is the sugar C4′-O-methyltransferase that is involved in rebeccamycin biosynthesis). The ability to couple SAM synthesis and utilization in a single vessel circumvents issues associated with the rapid decomposition of SAM analogues and thereby opens the door for the further interrogation of a wide range of SAM utilizing enzymes.

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