细菌c-di-AMP特异性磷酸二酯酶的研究进展

Advances in bacterial c-di-AMP-specific phosphodiesterase

c-di-AMP特异性磷酸二酯酶(c-di-AMP-specific phosphodiesterase,PDE)是一类能够将c-di-AMP水解为线性pApA或AMP的酶,对维持细菌体内c-di-AMP的代谢平衡至关重要.在不同的细菌中存在着不同结构类型的PDE,其功能既具有一定的保守性,又存在特异性.c-di-AMP作为第二信使分子在包括古菌、革兰氏阳性菌及支原体、衣原体、蓝细菌等部分革兰氏阴性菌等在内的原核生物中发挥多种功能.近年来研究显示,PDE通过调节细菌中cdi-AMP水平,进而调控细菌生长、生物被膜形成、细菌耐药性、细菌毒力和宿主细胞的免疫应答等生物学过程,是预防和治疗病原菌感染的重要潜在靶点,在疫苗研发及小分子药物筛选开发领域中具有极大的潜力.本文对近年来PDE分类、结构及生物学功能等方面进行综述,旨在为相关研究人员提供参考.

Cyclic dimeric adenosine 3′,5′-monophosphate(c-di-AMP)is an emerging second messenger with multiple functions in Archaea,Gram-positive bacteria,Mycoplasma,Chlamydia,Cyanobacteria,and some other Gram-negative bacteria.C-diAMP-specific phosphodiesterase(PDE)maintains the balance of c-di-AMP metabolism in bacteria.PDEs in bacteria have a vibrant structure and can be classified into three categories based on their functional domains.The first characterized PDE includes Gdp P and Dhh P homologs.Gdp P has two transmembrane helices,a PAS(Per-Arnt-Sim)domain,a degenerate GGDEF domain,and the catalytic domains DHH and DHHA1.Dhh P is a stand-alone DHH-DHHA1 domain protein compared with Gdp P.Both Dhh P and Gdp P homologs degrade c-di-AMP via DHH/DHHA1(Asp-His-His)domain.The second involves Pgp H homologs,HD(Asp-His)is the main functional domain of hydrolyzing c-di-AMP.The HD domain structure remains conserved,although the amino acid sequence identity is low in certain bacteria.The newly discovered bacterial extracellular nucleosidases contain Cdn P and Ata C and are sensitive to p H and metal ions.However,their catalytic domain for enzymatic activity and specific hydrolysis mechanism needs improvement.C-di-AMP-specific PDE could degrade c-di-AMP to one p Ap A molecule or two AMP molecules.Some PDEs hydrolyze in two steps,while others only hydrolyze in one,which could be due to conserved metal ion centers and unique substrate binding sites found in different PDEs.However,some c-di-AMP-specific PDEs,such as Dhh P,can hydrolyze not only c-di-AMP and p Ap A but also c-di-GMP and p Gp G.Most c-di-AMP-containing bacteria encode two or more PDEs simultaneously,which sense different signals or display distinct substrate preferences to perform diverse cellular functions individually or cooperatively.PDEs are important for maintaining the physiological function of bacteria and eliciting the immune response of host cells by regulating the bacterial c-di-AMP level.Recent studies suggest that PDE deletion or mutation affects multiple physiological functions including bacterial growth,virulence,and sensitivity to the external environment.Gdp P leads to a dramatic increase of c-di-AMP in Staphylococcus aureus,thus reducing bacterial metabolic activity and growth.PDE absence in Lactococcus lactis improves bacterial heat tolerance and increases susceptibility to osmotic stress.PDE deletion could inhibit the overall virulence of particle pathogenic bacteria such as Streptococcus.Thus,PDE can be concluded as a potential virulence factor of pathogenic bacteria.Meanwhile,PDE also mediates bacterial biofilm formation via modulating c-di-AMP,which may be a key element in microbial drug resistance.Furthermore,c-di-AMP can effectively activate key molecules of the host cell immune response during pathogen infection;however,its levels are strictly regulated by PDE.This indicates the PDE’s importance in bacterial physiological function and host immune response.Therefore,cdi-AMP-specific PDEs have great significance in the field of antibacterial drugs as a target for preventing and treating pathogenic infections.This paper reviews the types,structures,and biological functions of PDE,aiming to provide references for related research.