Nguyen Tu-Quynh, Nicolet Yvain
Metalloproteins Unit, Univ. Grenoble Alpes, CEA, CNRS, IBS, F-38000 Grenoble, France.
Life (Basel). 2022 Oct 28;12(11):1732. doi: 10.3390/life12111732.
Methyl transfer is essential in myriad biological pathways found across all domains of life. Unlike conventional methyltransferases that catalyze this reaction through nucleophilic substitution, many members of the radical -adenosyl-L-methionine (SAM) enzyme superfamily use radical-based chemistry to methylate unreactive carbon centers. These radical SAM methylases reductively cleave SAM to generate a highly reactive 5'-deoxyadenosyl radical, which initiates a broad range of transformations. Recently, crystal structures of several radical SAM methylases have been determined, shedding light on the unprecedented catalytic mechanisms used by these enzymes to overcome the substantial activation energy barrier of weakly nucleophilic substrates. Here, we review some of the discoveries on this topic over the last decade, focusing on enzymes for which three-dimensional structures are available to identify the key players in the mechanisms, highlighting the dual function of SAM as a methyl donor and a 5'-deoxyadenosyl radical or deprotonating base source. We also describe the role of the protein matrix in orchestrating the reaction through different strategies to catalyze such challenging methylations.
甲基转移在生命所有领域中发现的众多生物途径中至关重要。与通过亲核取代催化该反应的传统甲基转移酶不同，自由基 - 腺苷 - L - 甲硫氨酸（SAM）酶超家族的许多成员利用基于自由基的化学方法对无反应性的碳中心进行甲基化。这些自由基SAM甲基化酶通过还原裂解SAM生成高反应性的5'-脱氧腺苷自由基，从而引发广泛的转化反应。最近，已经确定了几种自由基SAM甲基化酶的晶体结构，揭示了这些酶用于克服弱亲核底物的巨大活化能障碍的前所未有的催化机制。在这里，我们回顾了过去十年中关于这个主题的一些发现，重点关注那些具有三维结构的酶，以确定机制中的关键因素，突出SAM作为甲基供体和5'-脱氧腺苷自由基或去质子化碱源的双重功能。我们还描述了蛋白质基质通过不同策略协调反应以催化这种具有挑战性的甲基化反应的作用。
