Key Laboratory of Cluster Science of Ministry of Education, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China.
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden.
Inorg Chem. 2020 Oct 19;59(20):15167-15179. doi: 10.1021/acs.inorgchem.0c02139. Epub 2020 Oct 5.
The biological synthesis of acetyl-coenzyme A (acetyl-CoA), catalyzed by acetyl-CoA synthase (ACS), is of biological significance and chemical interest acting as a source of energy and carbon. The catalyst contains an unusual hexa-metal cluster with two nickel ions and a [FeS] cluster. DFT calculations have been performed to investigate the ACS reaction mechanism starting from three different oxidation states (+2, +1, and 0) of Ni, the nickel proximal to [FeS]. The results indicate that the ACS reaction proceeds first through a methyl radical transfer from cobalamin (Cbl) to Ni randomly accompanying with the CO binding. After that, C-C bond formation occurs between the Ni-bound methyl and CO, forming Ni-acetyl. The substrate CoA-S then binds to Ni, allowing C-S bond formation between the Ni-bound acetyl and CoA-S. Methyl transfer is rate-limiting with a barrier of ∼14 kcal/mol, which does not depend on the presence or absence of CO. Both the Ni and Ni states are chemically capable of catalyzing the ACS reaction independent of the state (+2 or +1) of the [FeS] cluster. The [FeS] cluster is not found to affect the steps of methyl transfer and C-C bond formation but may be involved in the C-S bond formation depending on the detailed mechanism chosen. An ACS active site containing a Ni(0) state could not be obtained. Optimizations always led to a Ni state coupled with [FeS]. The calculations show a comparable activity for Ni/[FeS], Ni/[FeS], and Ni/[FeS]. The results here give significant insights into the chemistry of the important ACS reaction.
乙酰辅酶 A（acetyl-CoA）的生物合成由乙酰辅酶 A 合酶（ACS）催化，作为能量和碳的来源，具有生物学意义和化学意义。该催化剂含有一个不寻常的六金属簇，其中包含两个镍离子和一个 [FeS] 簇。我们进行了密度泛函理论（DFT）计算，以研究 ACS 反应机制，从镍的三种不同氧化态（+2、+1 和 0）开始，靠近 [FeS] 的镍。结果表明，ACS 反应首先通过钴胺素（Cbl）随机向 Ni 转移甲基自由基，同时伴随着 CO 的结合。之后，Ni 结合的甲基和 CO 之间发生 C-C 键形成，形成 Ni-乙酰基。然后，辅酶 A-S 结合到 Ni 上，允许 Ni 结合的乙酰基和辅酶 A-S 之间形成 C-S 键。甲基转移是速率限制步骤，其势垒约为 14 kcal/mol，与 CO 的存在与否无关。Ni 和 Ni 态都具有独立于 [FeS] 簇的状态（+2 或+1）催化 ACS 反应的化学能力。[FeS] 簇未发现影响甲基转移和 C-C 键形成的步骤，但根据所选的详细机制，可能参与 C-S 键形成。不能获得含有 Ni(0) 态的 ACS 活性中心。优化总是导致与 [FeS] 耦合的 Ni 态。计算表明 Ni/[FeS]、Ni/[FeS] 和 Ni/[FeS] 的活性相当。这些结果为重要的 ACS 反应的化学性质提供了重要的见解。
