Biosynthesis and metabolic engineering of fungal non-ribosomal peptides

CHEN Xiwei; ZHANG Huaran; ZOU Yi

doi:10.12211/2096-8280.2023-080

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Biosynthesis and metabolic engineering of fungal non-ribosomal peptides

Invited Review | 更新时间：2025-03-19

- Biosynthesis and metabolic engineering of fungal non-ribosomal peptides
- Synthetic Biology Journal Vol. 5, Issue 3, Pages: 571-592(2024)
- 作者机构：
  
  西南大学药学院，重庆 400715
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2023-080
  CLC： R93;Q936
- Received：20 November 2023，
  
  Revised：2024-01-05，
  
  Published：30 June 2024
- 稿件说明：
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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

CHEN Xiwei， ZHANG Huaran， ZOU Yi. Biosynthesis and metabolic engineering of fungal non-ribosomal peptides［J］. Synthetic Biology Journal， 2024， 5（3）： 571-592
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 DOI： 10.12211/2096-8280.2023-080.

CHEN Xiwei， ZHANG Huaran， ZOU Yi. Biosynthesis and metabolic engineering of fungal non-ribosomal peptides［J］. Synthetic Biology Journal， 2024， 5（3）： 571-592 DOI： 10.12211/2096-8280.2023-080.

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。

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.

关键词

Keywords

references

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