Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
J Am Chem Soc. 2022 Apr 6;144(13):5673-5684. doi: 10.1021/jacs.1c12064. Epub 2022 Mar 28.
Cobalamin (Cbl)-dependent -adenosyl-l-methionine (AdoMet) radical methylases are known for their use of a dual cofactor system to perform challenging radical methylation reactions at unactivated carbon and phosphorus centers. These enzymes are part of a larger subgroup of Cbl-dependent AdoMet radical enzymes that also perform difficult ring contractions and radical rearrangements. This subgroup is a largely untapped reservoir of diverse chemistry that requires steady efforts in biochemical and structural characterization to reveal its complexity. In this Perspective, we highlight the significant efforts over many years to elucidate the function, mechanism, and structure of TsrM, an unexpected nonradical methylase in this subgroup. We also discuss recent achievements in characterizing radical methylase subgroup members that exemplify how key tools in mechanistic enzymology are valuable time and again. Finally, we identify recent enzyme activity studies that have made use of bioinformatic analyses to expand our definition of the subgroup. Additional breakthroughs in radical (and nonradical) enzymatic chemistry and challenging transformations from the unexplored space of this subgroup are undoubtedly on the horizon.
钴胺素 (Cbl)-依赖性 -腺苷基-l-甲硫氨酸 (AdoMet) 自由基甲基转移酶以其使用双重辅因子系统在未活化的碳和磷中心进行具有挑战性的自由基甲基化反应而闻名。这些酶是 Cbl 依赖性 AdoMet 自由基酶的一个更大亚组的一部分，该亚组还执行困难的环收缩和自由基重排。这个亚组是一个多样化化学物质的未被充分利用的宝库，需要在生化和结构表征方面进行持续努力，以揭示其复杂性。在本观点中，我们重点介绍了多年来阐明 TsrM 功能、机制和结构的重要努力，TsrM 是该亚组中一种出乎意料的非自由基甲基转移酶。我们还讨论了最近在表征自由基甲基转移酶亚组成员方面的成就，这些成就体现了在机制酶学中关键工具的价值。最后，我们确定了最近利用生物信息学分析来扩展亚组定义的酶活性研究。毫无疑问，这个亚组中未探索空间的自由基（和非自由基）酶促化学和挑战性转化的新突破即将出现。
