Pre-reaction state may determine thioesterase-catalyzed macrocyclization, based on the QM/MM calculation by Zhao’s group

     Recently, ACS Catalysis published an article by Zhao’s group at Shanghai Jiao Tong University, titled "Theoretical Studies on the Mechanism of Thioesterase-Catalyzed Macrocyclization in Erythromycin Biosynthesis" (DOI: 10.1021 / acscatal.6b01154), where Dr. Ting Shi and Mr. Xiongping Chen (graduate student) were the two joint first authors. Through collaboration with Professor Linquan Bai of Deng’s group, the DEBS thioesterase-catalytic mechanism of erythromycin PKS biosynthesis has been in-depth investigated computationally. The study used two highly similar substrates as probe molecules to analyze the bifurcating pathways of cyclization and hydrolysis. According to the dynamic structures of the covalent enzyme-substrate complex, it was found that molecular recognition of the distal C7 carbonyl position led to a cyclic pre-reaction state towards cyclization, while hydrolysis occurs in the case of the C7 hydroxyl substrate for lack of such structural arrangement. This work indicates that pre-reaction state theory may be widespread in biosynthesis, as a key condition for a cascade of desired reactions; thus it could be a new strategy for molecular design of biosynthetic parts.