Human Acetyl-CoA Carboxylase 1 Is an Isomerase: Carboxyl Transfer Is Activated by Catalytic Effect of Isomerization
Human Acetyl-CoA Carboxylase 1 Is an Isomerase: Carboxyl Transfer Is Activated by Catalytic Effect of Isomerization
复制标题
人乙酰辅酶A羧化酶1是异构酶：通过异构化的催化作用激活羧基转移
DOI：
10.1021/acs.jpcb.9b05384
复制
发表时间：
2019
影响因子：
3.3
通讯作者：
Yao Jianzhuang
中科院分区：
文献类型：
--
作者：
Wang Xia;Li Yajing;Chen Xiabin;Zhou Ziyuan;Yao Jianzhuang
肥胖及其相关疾病，如癌症和糖尿病，是现代世界威胁生命的主要问题。因此，非常需要针对肥胖和肥胖引起的疾病的新药。人乙酰辅酶A羧化酶1（hACC 1）是人体脂肪酸合成的限速酶，是一个理想的药物设计靶点。hACC 1的基本反应机制和过渡态的性质仍不清楚。在这项研究中，结合量子力学和分子力学（QM/MM），分子动力学（MD）和自由能模拟进行研究的催化机制的hACC 1催化的羧基转移反应。我们的计算结果表明，羧基转移酶（CT）催化反应的三步机制，包括异构化的羧基生物素，质子转移从乙酰辅酶A到羧基生物素，和羧基化的乙酰辅酶A烯醇化。有趣的是，羧基生物素的异构化是整个反应途径的限速步骤，表明hACC 1具有异构化的催化作用，因此也可能是异构酶。计算得到hACC 1催化羧基转移反应的活化自由能垒为16.4 kcal/mol，与实验结果（16.7 kcal/mol）非常吻合。所得的反应机理和过渡态的性质不仅为将来研究其他ACC提供了有用的知识，而且也为合理设计hACC 1抑制剂，如TS类似物提供了有用的知识。讨论了hACC 1异构化的催化作用。
Obesity and its related diseases such as cancer and diabetes are leading life-threatening issues in the modern world. Thus, new drugs toward obesity and obesity-caused diseases are highly desired. Human acetyl-CoA carboxylase 1 (hACC1) in charge of the rate-limiting step of the human fatty acid synthesis was recognized as an attractive target for rational drug design. The fundamental reaction mechanism and nature of the transition state of hACC1 remain unclear. In this study, combined quantum mechanics and molecular mechanics (QM/MM), molecular dynamics (MD), and free-energy simulations were performed to investigate the catalytic mechanism of the hACC1-catalyzed carboxyl-transfer reaction. Our computational results show a three-step mechanism for carboxyl transferase (CT)-catalyzed reaction, including isomerization of carboxybiotin, proton-transfer from acetyl-CoA to carboxybiotin, and carboxylation of acetyl-CoA enolate. Interestingly, isomerization of carboxybiotin is the rate-limiting step of the entire reaction pathway, indicating hACC1 has the catalytic effect of isomerization and thus might be an isomerase also. The activation free-energy barrier of carboxyl-transfer catalyzed by hACC1 was calculated to be 16.4 kcal/mol, in excellent agreement with the experimental result (16.7 kcal/mol). The obtained reaction mechanism together with the nature of the transition state provides helpful knowledge not only for future investigation of other ACCs but also for rational design of hACC1 inhibitors, such as TS analogue. The catalytic effect of hACC1 isomerization is discussed.