放线菌环二肽类活性天然产物生物合成研究进展

Advances in the biosynthesis of cyclodipeptide type natural products derived from actinomycetes

摘要:

环二肽(cyclodipeptide, CDP)是一类由2个α-氨基酸缩合而成的最小环肽分子，也可称为二酮哌嗪类化合物(diketopiperazines, DKPs)。CDP具有稳定的DKP环状骨架结构，活性广泛而显著，药用前景良好，发掘意义重大。放线菌是重要的CDP生产菌，同时具有非核糖体肽合成酶(nonribosomal peptide synthetase, NRPS)与环二肽合酶(cyclodipeptide synthase, CDPS)两种DKP骨架合成催化酶，并从中发现多种骨架结构修饰酶，研究开发价值巨大。本文系统介绍了放线菌CDP类活性化合物的DKP骨架合成途径及其结构修饰机制两方面的研究工作，以期为新型CDP类天然产物的发掘、新颖CDP分子生物合成机制的阐明及合成生物学设计与应用等领域的研究与实践提供参考。

Abstract:

Cyclodipeptide (CDP) composed of two amino acids is the simplest cyclic peptide. These two amino acids form a typical diketopiperazine (DKP) ring by linking each other with peptide bonds. This characteristic stable ring skeleton is the foundation of CDP to display extensive and excellent bioactivities, which is beneficial for CDPs’ pharmaceutical research and development. The natural CDP products are well isolated from actinomycetes. These bacteria can synthesize DKP backbones with nonribosomal peptide synthetase (NRPS) or cyclodipeptide synthase (CDPS). Moreover, actinomycetes could produce a variety of CDPs through different enzymatic modification. The presence of these abundant and diversified catalysis indicates that actinomycetes are promising microbial resource for exploring CDPs. This review summarized the pathways for DKP backbones biosynthesis and their post-modification mechanism in actinomycetes. The aim of this review was to accelerate the genome mining of CDPs and their isolation, purification and structure identification, and to facilitate revealing the biosynthesis mechanism of novel CDPs as well as their synthetic biology design.