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Facile Chemoenzymatic Strategies for the Synthesis and Utilization of S ‐Adenosyl‐ L ‐Methionine Analogues
Author(s) -
Singh Shanteri,
Zhang Jianjun,
Huber Tyler D.,
Sunkara Manjula,
Hurley Katherine,
Goff Randal D.,
Wang Guojun,
Zhang Wen,
Liu Chunming,
Rohr Jürgen,
Van Lanen Steven G.,
Morris Andrew J.,
Thorson Jon S.
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201308272
Subject(s) - methionine , biosynthesis , stereochemistry , chemistry , enzyme , methionine adenosyltransferase , substrate (aquarium) , alkylation , biochemistry , amino acid , biology , catalysis , ecology
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.