Human Acetyl-CoA Carboxylase 1 is an Isomerase: Carboxyl Transfer is Activated by Catalytic Effect of Isomerization.

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.