Journal of the American Chemical Society p. 2877 - 2880 (2016)
Update date:2022-08-05
Topics: Substrates In situ formation S-Adenosyl-vinthionine AdoMet-dependent methyltransferases Bisubstrate Adducts
Qu, Wanlu
Catcott, Kalli C.
Zhang, Kun
Liu, Shanshan
Guo, Jason J.
Ma, Jisheng
Pablo, Michael
Glick, James
Xiu, Yuan
Kenton, Nathaniel
Ma, Xiaoyu
Duclos, Richard I.
Zhou, Zhaohui Sunny
Identifying an enzyme's substrates is essential to understand its function, yet it remains challenging. A fundamental impediment is the transient interactions between an enzyme and its substrates. In contrast, tight binding is often observed for multisubstrate-adduct inhibitors due to synergistic interactions. Extending this venerable concept to enzyme-catalyzed in situ adduct formation, unknown substrates were affinity-captured by an S-adenosyl-methionine (AdoMet, SAM)-dependent methyltransferase (MTase). Specifically, the electrophilic methyl sulfonium (alkyl donor) in AdoMet is replaced with a vinyl sulfonium (Michael acceptor) in S-adenosyl-vinthionine (AdoVin). Via an addition reaction, AdoVin and the nucleophilic substrate form a covalent bisubstrate-adduct tightly complexed with thiopurine MTase (2.1.1.67). As such, an unknown substrate was readily identified from crude cell lysates. Moreover, this approach is applicable to other systems, even if the enzyme is unknown.
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