TY - JOUR
T1 - Facile chemoenzymatic strategies for the synthesis and utilization of S-adenosyl-L-methionine analogues
AU - Singh, Shanteri
AU - Zhang, Jianjun
AU - Huber, Tyler D.
AU - Sunkara, Manjula
AU - Hurley, Katherine
AU - Goff, Randal D.
AU - Wang, Guojun
AU - Zhang, Wen
AU - Liu, Chunming
AU - Rohr, Jürgen
AU - Van Lanen, Steven G.
AU - Morris, Andrew J.
AU - Thorson, Jon S.
PY - 2014/4/7
Y1 - 2014/4/7
N2 - 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. Mix and MATch: Methionine adenosyltransferase (MAT) was used to synthesize S-adenosylmethionine (SAM) analogues in a method directly compatible with downstream SAM-utilizing enzymes. As a proof of concept for the feasibility of natural product "alkylrandomization" by using this method, a coupled strategy in which MAT was applied in conjunction with the methyltransferase RebM was used to generate a small set of indolocarbazole analogues.
AB - 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. Mix and MATch: Methionine adenosyltransferase (MAT) was used to synthesize S-adenosylmethionine (SAM) analogues in a method directly compatible with downstream SAM-utilizing enzymes. As a proof of concept for the feasibility of natural product "alkylrandomization" by using this method, a coupled strategy in which MAT was applied in conjunction with the methyltransferase RebM was used to generate a small set of indolocarbazole analogues.
KW - S-adenosylmethionine
KW - alkylrandomization
KW - biocatalysis
KW - enzymes
KW - methionine adenosyltransferase
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U2 - 10.1002/anie.201308272
DO - 10.1002/anie.201308272
M3 - Article
C2 - 24616228
AN - SCOPUS:84898068070
SN - 1433-7851
VL - 53
SP - 3965
EP - 3969
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 15
ER -