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Recently, Prof. Shen Yuemao and Prof. Li Yaoyao's team from the School of Pharmaceutical Sciences published a research article entitled “Discovery and Biosynthesis of Pseudoamides Reveal Enzymatic Cyclization of the Polyene Precursor to 5-5 Bicyclic Tetramate Macrolactams” in ACS Catalysis. Prof. Li Yaoyao is the corresponding author of the paper, PhD student Li Xue and MS student Liu Qingqing are co-first authors, and Shandong University is the first and corresponding affiliate.
Polycyclic tetramate macrolactams (PoTeMs) comprise a family of pharmacologically promising macrolactams that possess a tetramic acid moiety and various polycyclic systems. The polycyclic system of PoTeMs have been found to be critical for their bioactivities. Despite the progress in elucidating the biosynthetic pathways of representative PoTeMs, the mechanism by which the 5-5 bicyclic system is formed remains unclear.
This study elucidated the biosynthetic mechanism of the 5/5 bicyclic system formation of pseudoamides, which are novel PoTeMs discovered from Pseudoalteromonas elyakovii ATCC 700519. Through combinatorial biosynthesis, in vitro biochemical assays and isotope labeling experiments, the authors demonstrated that redox partners are required for the activation of Pel1 and Pel3 to generate the 5-5 bicyclic system. Pel1 catalyzes a reductive [2+3] cycloaddition to form the outer 5-membered ring, which involves the incorporation of the hydride of FMNH2 and one proton from water. Pel3 catalyzes inner 5-membered ring formation coupled with C12 hydroxylation, and is proposed to use the nucleophilic FMN-C4a-hydroxyperoxide to attack and ultimately incorporate oxygen into the substrate. Thus, this work has set the foundation for further mechanistic studies of this distinct set of cyclases in PoTeM biosynthesis, and ultimately facilitates the engineering approach to generate PoTeMs bearing novel polycyclic systems.
This work was supported by the National Natural Science Foundation of China.
Link to this paper:https://pubs.acs.org/doi/10.1021/acscatal.2c05784
