尿苷肽类抗生素生物合成研究进展

摘要

尿苷肽类抗生素是一类具有相同母核结构的化合物,其化学结构独特、作用机制新颖、抗菌谱窄,是寻找新型低毒、窄谱抗菌药物的先导化合物或候选药物的最佳选择之一.本文介绍了尿苷肽类抗生素的化学结构特征以及构效关系,着重介绍了其生物合成机制的最新研究进展.尿苷肽类抗生素肽链的合成由非核糖体肽合成酶(nonribosomal peptide synthetase,NRPS)以非线性机制催化完成,肽链的组装始于中心模块2,3-二氨基丁酸(2,3-diaminobutyric acid,DABA),其后的延伸包括N端氨基酸或二肽与DABA β-氨基间的缩合,以及C端的脲二肽与DABAα-氨基间的缩合.3'-脱氧-4',5'-烯酰胺尿苷由尿苷经过3步反应转化而来,并在NRPS的催化下与四肽或五肽缩合形成尿苷肽类抗生素.尿苷肽类抗生素生物合成机制的阐明为利用组合生物合成技术获得新结构的尿苷肽类化合物奠定了基础.%Uridyl peptide antibiotics are a family of structure closely related compounds. The novel structure features and the clinically unexploited mode of action make them one of the best choices to discover lead compounds of narrow-spectrum new antibiotics. Their structure characteristics and structure-activity relationship were introduced, and the latest advances in the biosynthetic mechanism were mainly reviewed. The peptidyl chain is assembled by a nonlinear non-ribosomal peptide synthetase (NRPS) -like mechanism. Its assembly starts at the central building block 23-diaminobutyric acid (DABA); then the elongation of the peptide framework includes attachment of theNterminal amino acid or dipeptide to the (3-group of DABA, and attachment of the C-terminal ureido dipeptide to α-group of DABA. 3'-Deoxy-4' ,5'-enamino-uridine proceeds through three steps from uridine. NRPS catalyzes the condensation between the modified nucleoside and tetra/pentapeptidyl chain to yield uridyl peptide antibiotics. The explanation of the biosynthetic mechanism of uridyl peptide antibiotics provides the basis for applying combinatorial biosynthesis in their future structural modification.