真菌源非核糖体肽类药物生物合成及代谢工程

doi:10.12211/2096-8280.2023-080

摘要/Abstract

摘要：

真菌源非核糖体肽类（NRP）药物因其活性优异、结构多样而备受关注。至今美国食品药品监督管理局（FDA）已批准了数十种真菌NRP药物，包括环孢菌素、头孢菌素和棘白菌素等重磅药物。这些NRP药物均由非核糖体肽合成酶（NRPS）催化形成，其多样化的结构域和模块数量决定了产物骨架的多样性，从而为天然源活性NRP的开发提供了广阔的空间。此外，骨架结构上的特殊后修饰过程往往为NRP药物提供了强效的药效基团，进一步扩充了NRP结构与活性的多样性。本文综述了真菌NRP药物的研究进展，主要涵盖药物活性、生物合成途径、酶学机理和代谢工程改造等。深入了解真菌NRP药物生物合成途径不仅有助于理解相关的酶学组装机制，还有望为新型真菌NRP药物及其衍生物的深度开发提供重要的指导和参考。

关键词: 真菌非核糖体肽, 非核糖体肽合成酶, 生物合成, 酶学组装机制, 代谢工程

Abstract:

As natural products, non-ribosomal peptides (NRPs) exhibit biological activities with a broad spectrum, including anticancer, antibiotic and immunosuppression. Among U.S. Food and Drug Administration (FDA) approved drugs, fungal NRPs are a major category of pioneering pharmacological agents like immunosuppressive cyclosporine, antibacterial cephalosporin and antifungal echinocandins. Under the catalysis of complicated multimodular enzyme complexes known as non-ribosomal peptide synthetases (NRPSs), NRPs are synthesized with three core domains: adenylation (A), thiolation domain/peptidyl carrier protein (T/PCP) and condensation (C), which collectively form repetitive modules responsible for activating and incorporating specific amino acids or hydroxycarboxylic acid building blocks into the growing peptide chains. Beyond the core domains, optional domains are exemplified by epimerization (E), heterocyclization (Cy) and oxidation (Ox), facilitating the customization of the building blocks. These domains and the variability in the number of modules with NRPs significantly contribute to the structural diversity of the skeletons. Furthermore, post-modifications to the structural skeletons yield potent pharmacological groups for NRPs, contributing significantly to their structural diversity and biological activities, which not only provide opportunities for discovering naturally sourced and active NRPs, but also opens avenues for modifications to create non-natural NRPs via synthetic biological technology. To date, numerous strategies have been employed for developing NRPs, including heterologous expression, transcriptional factor activation, precursor-directed biosynthesis, mutasynthesis, combinatorial biosynthesis and enzyme engineering. This review summarizes the progress in research on fungal NRPs, encompassing their bioactivities, biosynthetic pathways, enzymatic reaction mechanisms and metabolic engineering. A comprehensive understanding of fungal NRPs biosynthesis not only benefits for deciphering the corresponding enzymatic assembly mechanism, but also serves as a guidance for advancing novel fungal NRPs and their derivatives, thereby paving the way for developing potential drug candidates from NRPs.

Key words: fungal non-ribosomal peptide, non-ribosomal peptide synthetase, biosynthesis, enzymatic reaction mechanism, metabolic engineering

中图分类号:

陈锡玮, 张华然, 邹懿. 真菌源非核糖体肽类药物生物合成及代谢工程[J]. 合成生物学, 2024, 5(3): 571-592.

Xiwei CHEN, Huaran ZHANG, Yi ZOU. Biosynthesis and metabolic engineering of fungal non-ribosomal peptides[J]. Synthetic Biology Journal, 2024, 5(3): 571-592.

图/表 8

图1 代表性非核糖体肽类药物

Fig. 1 Typical NRP drugs

图2 非核糖体肽的酶学组装机制

Fig. 2 Enzymatic assembly mechanism of NRP

图3 青霉素G和头孢菌素C生物合成

Fig. 3 Biosynthesis of penicillin G and cephalosporin C

图4 棘白菌素类化合物生物合成途径

Fig. 4 Overview of the echinocandin biosynthesis

图5 环孢菌素A生物合成途径

Fig. 5 Biosynthesis pathway of cyclosporine A

图6 Enniatin B和beauverin生物合成途径

Fig. 6 Biosynthesis pathways of enniatin B and beauverin

图7 Ergometrine和ergotamine生物合成途径

Fig. 7 Biosynthesis pathways of ergometrine and ergotamine

图8 非核糖体肽的代谢工程

Fig. 8 Metabolic engineering of NRP

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