双嵌入家族抗肿瘤非核糖体肽的生物合成研究进展  

Research advances in the biosynthesis of nonribosomal peptides within the bisintercalator family as anticancer drugs

作　　者：施鑫杰 杜艺岭[1] SHI Xinjie;DU Yiling(Institute of Pharmaceutical Biotechnology,Department of Microbiology,School of Basic Medical Science,Zhejiang University,Hangzhou 310058,Zhejiang,China)

机构地区：[1]浙江大学基础医学院微生物系,药物生物技术研究所,浙江杭州310058

出　　处：《合成生物学》2024年第3期593-611,共19页Synthetic Biology Journal

基　　金：国家自然科学基金(32122005,32370051)。

摘　　要：双嵌入家族(bisintercalator)非核糖体肽是一类由放线菌产生的C2中心对称的环状肽类化合物,能够通过其结构中两个独特的发色基团插入到DNA分子中,因此具有良好的抗菌和抗肿瘤等生物活性。这些家族化合物的结构多样性主要源于芳香杂环、氨基酸种类和数量以及修饰基团的不同。这些结构差异不仅导致其抗菌和抗肿瘤活性的强度和选择性的不同,还赋予了它们抗真菌、抗疟、抗病毒等其他活性。本文总结了双嵌入家族非核糖体肽的结构与活性和生物合成途径,展望了其未来发展方向以及面对的挑战。双嵌入家族非核糖体肽的分子结构复杂,化学合成非常具有挑战性,微生物发酵是生产此家族化合物的主要方法。近年来,双嵌入非核糖体肽类家族的生物合成途径得到了较为系统的研究,该家族主要代表性分子的肽链骨架组装、起始单元的生物合成以及后修饰过程已被基本阐明。这些研究成果不仅揭示了一系列微生物次级代谢中新颖的生物合成酶家族和酶催化机理,也为通过合成生物技术对该家族分子进行分子结构创新提供了珍贵的生物催化组件。这些生物合成的理论知识将进一步推动这一具有前景的天然产物家族的精准发现与后续的药物开发研究。Natural products with the bisintercalator family are a group of C2-symmetric cyclic non-ribosomal peptides produced by actinobacteria,possessing potent antimicrobe,antitumor and other bioactivities.Bisintercalators can be divided into two groups based on the size of their macrocycles:the minor and major scaffold types with eight and ten amino acid residues,respectively.Structure diversity with bisintercalators arises from variations in aromatic heterocycles,amino acid residue identities and quantities,and post-assembly line modifications.The major scaffold type bisintercalators harbor two structurally rigid six-membered nitrogen heterocycle-containing amino acids,which can further undergo oxidative and acylation tailorings.The minor scaffold type bisintercalators seemingly derive their rigidity from disulfide or thioacetal bridges formed by sulfydryls of two cysteines,and the thioacetal bridges allow variable S-alkyl elongation and conversion of S-alkyl sulfur into sulfoxide moiety.In addition,bisintercalators also exhibit differences in other amino acid identities,which further contribute to their diverse activities,including antimicrobial,antitumor,antifungal,anti-malarial,or antiviral effects.The chemical synthesis of these nonribosomal peptides is complex due to their intricate architectures,making microbial fermentation a more efficient production method.On the other hand,structural optimization can be achieved for bisintercalators through combinatorial and precursor-guided biosynthesis.Therefore,understanding the biosynthetic pathways of bisintercalators is crucial for yield enhancement via the pathway-specific regulation and also offering biocatalytic parts for structural modifications.This knowledge will facilitate future discovery and drug development for this promising natural product family.

关 键 词：非核糖体肽 双嵌入家族 天然产物 抗肿瘤化合物 生物合成 

分 类 号：Q936[生物学—微生物学]