Filamentation and inhibition of prokaryotic CTP synthase with ligands

作     者：Chenjun Guo Zixuan Wang Ji‐Long Liu 

作者机构：School of Life Science and TechnologyShanghaiTech UniversityShanghaiChina Department of PhysiologyAnatomy and GeneticsUniversity of OxfordOxfordUK Shanghai Clinical Research and Trial CenterShanghaiChina 

出 版 物：《mLife》 (微生物（英文）)

年 卷 期：2024年第3卷第2期

页      面：240-250页

核心收录：

学科分类：0710[理学-生物学] 08[工学] 0822[工学-轻工技术与工程] 

基　　金：supported by the grants from the Ministry of Science and Technology of China(No.2021YFA0804700) National Natural Science Foundation of China(Grant Nos.32370744 and 32350710195) Shanghai Science and Technology Commission(No.20JC1410500) UK Medical Research Council(Grant Nos.MC_UU_12021/3 and MC_U137788471)for grants to J.L.L 

主　　题：CTP synthase Cryo-electron microscopy cytoophidium metabolic filament species specific inhibition 

摘      要：Cytidine triphosphate synthase(CTPS)plays a pivotal role in the de novo synthesis of cytidine triphosphate(CTP),a fundamental building block for RNA and DNA that is essential for *** is capable of directly binding to all four nucleotide triphosphates:adenine triphosphate,uridine triphosphate,CTP,and guanidine ***,CTPS can form cytoophidia in vivo and metabolic filaments in vitro,undergoing regulation at multiple *** is considered a potential therapeutic target for combating invasions or infections by viral or prokaryotic *** cryo-electron microscopy,we determined the structure of Escherichia coli CTPS(ecCTPS)filament in complex with CTP,nicotinamide adenine dinucleotide(NADH),and the covalent inhibitor 6-diazo-5-oxo-L-norleucine(DON),achieving a resolution of *** constructed a phylogenetic tree based on differences in filament-forming interfaces and designed a variant to validate our hypothesis,providing an evolutionary perspective on CTPS filament *** computational analysis revealed a solvent-accessible ammonia tunnel upon DON *** comparative structural analysis,we discern a distinct mode of CTP binding of ecCTPS that differs from eukaryotic *** biochemical assays and structural analysis,we determined and validated the synergistic inhibitory effects of CTP with NADH or adenine on *** results expand our comprehension of the diverse regulatory aspects of CTPS and lay a foundation for the design of specific inhibitors targeting prokaryotic CTPS.