Analyzing and engineering of the biosynthetic pathway of mollemycin A for enhancing its production

IF 4.4 2区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Synthetic and Systems Biotechnology Pub Date : 2024-04-04 DOI:10.1016/j.synbio.2024.03.014
Shixue Jin , Huixue Chen , Jun Zhang , Zhi Lin , Xudong Qu , Xinying Jia , Chun Lei
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Abstract

Mollemycin A (MOMA) is a unique glyco-hexadepsipeptide-polyketide that was isolated from a Streptomyces sp. derived from the Australian marine environment. MOMA exhibits remarkable inhibitory activity against both drug-sensitive and multidrug-resistant malaria parasites. Optimizing MOMA through structural modifications or product enhancements is necessary for the development of effective analogues. However, modifying MOMA using chemical approaches is challenging, and the production titer of MOMA in the wild-type strain is low. This study identified and characterized the biosynthetic gene cluster of MOMA for the first time, proposed its complex biosynthetic pathway, and achieved an effective two-pronged enhancement of MOMA production. The fermentation medium was optimized to increase the yield of MOMA from 0.9 mg L−1 to 1.3 mg L−1, a 44% boost. Additionally, a synergistic mutant strain was developed by deleting the momB3 gene and overexpressing momB2, resulting in a 2.6-fold increase from 1.3 mg L−1 to 3.4 mg L−1. These findings pave the way for investigating the biosynthetic mechanism of MOMA, creating opportunities to produce a wide range of MOMA analogues, and developing an efficient strain for the sustainable and economical production of MOMA and its analogues.

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分析和改造莫来霉素 A 的生物合成途径以提高其产量
霉素 A(MOMA)是从澳大利亚海洋环境中的链霉菌中分离出来的一种独特的糖基六胜肽聚酮。MOMA 对药物敏感和耐多药的疟疾寄生虫都有显著的抑制活性。要开发出有效的类似物,就必须通过结构改造或产品改进来优化 MOMA。然而,使用化学方法改造 MOMA 具有挑战性,而且野生型菌株生产 MOMA 的滴度较低。本研究首次发现并鉴定了MOMA的生物合成基因簇,提出了其复杂的生物合成途径,并实现了双管齐下有效提高MOMA产量。通过优化发酵培养基,MOMA的产量从0.9 mg L-1提高到1.3 mg L-1,提高了44%。此外,还通过删除 momB3 基因和过表达 momB2 培育出了一种协同突变菌株,使产量从 1.3 mg L-1 提高到 3.4 mg L-1 ,提高了 2.6 倍。这些发现为研究MOMA的生物合成机制铺平了道路,为生产多种MOMA类似物创造了机会,并为可持续、经济地生产MOMA及其类似物开发了高效菌株。
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来源期刊
Synthetic and Systems Biotechnology
Synthetic and Systems Biotechnology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-
CiteScore
6.90
自引率
12.50%
发文量
90
审稿时长
67 days
期刊介绍: Synthetic and Systems Biotechnology aims to promote the communication of original research in synthetic and systems biology, with strong emphasis on applications towards biotechnology. This journal is a quarterly peer-reviewed journal led by Editor-in-Chief Lixin Zhang. The journal publishes high-quality research; focusing on integrative approaches to enable the understanding and design of biological systems, and research to develop the application of systems and synthetic biology to natural systems. This journal will publish Articles, Short notes, Methods, Mini Reviews, Commentary and Conference reviews.
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