Key Laboratory of Cluster Science of Ministry of Education, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China.
J Phys Chem Lett. 2020 Aug 20;11(16):6812-6818. doi: 10.1021/acs.jpclett.0c01725. Epub 2020 Aug 7.
A unique member of the family of cobalamin (Cbl)-dependent radical -adenosylmethionine (SAM) enzymes, OxsB, catalyzes the ring constriction of deoxyadenosine triphosphate (dATP) to the base oxetane aldehyde phosphate, a crucial precursor for oxetanocin A (OXT-A), which is an antitumor, antiviral, and antibacterial compound. This enzyme reveals a new catalytic function for this big family that is different from the common methylation. On the basis of density functional theory calculations, a mechanism has been proposed to mainly include that the generation of 5'-deoxyadenosine radical, a hydrogen transfer forming 2'-dATP radical, and a Cbl-catalyzed ring contraction of the deoxyribose in 2'-dATP radical. The ring contraction is a concerted rearrangement step accompanied by an electron transfer from the deoxyribose hydroxyl oxygen to Co without any ring-opening intermediate. CoCbl has been ruled out as an active state. Other mechanistic characteristics are also revealed. This unprecedented non-methylation mechanism provides a new catalytic repertoire for the family of radical SAM enzymes, representing a new class of ring-contraction enzymes.
OxsB 是钴胺素（Cbl）依赖性自由基 - 腺苷甲硫氨酸（SAM）酶家族中的一个独特成员，它催化脱氧腺苷三磷酸（dATP）的环缩合反应，生成 base oxetane aldehyde phosphate，这是 oxetanocin A（OXT-A）的关键前体，OXT-A 是一种具有抗肿瘤、抗病毒和抗菌作用的化合物。该酶揭示了这个大家族的一个新的催化功能，与常见的甲基化不同。基于密度泛函理论计算，提出了一种主要包括 5'-脱氧腺苷自由基生成、氢转移形成 2'-dATP 自由基以及 Cbl 催化的 2'-dATP 自由基中脱氧核糖环收缩的机制。环收缩是一个协同重排步骤，伴随着脱氧核糖羟基氧向 Co 的电子转移，没有任何开环中间体。CoCbl 已被排除在活性状态之外。还揭示了其他的机制特征。这种前所未有的非甲基化机制为自由基 SAM 酶家族提供了一个新的催化库，代表了一类新的环收缩酶。
