Engineering industrial fungus Aspergillus oryzae for the sustainable biosynthesis of ergot alkaloids†

IF 9.3 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Green Chemistry Pub Date : 2024-12-03 DOI:10.1039/D4GC04643A
Meili Xiao, Yan Wang, Lu Yu, Xing Yan, Zhihua Zhu, Ernuo Tian, Yinmei Wang, Gen Zou, Zhihua Zhou and Pingping Wang
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引用次数: 0

Abstract

Ergot alkaloids (EAs) are a class of indole derivatives used as prescription drugs for the treatment of neurological diseases. Due to the limited production of EAs by Claviceps and the enantioselective difficulties encountered in chemical synthesis, a sustainable supply of EAs remains challenging. Recently, numerous attempts have been made to produce EAs using heterologous hosts. However, these efforts have only resulted in the production of the precursor, lysergic acid (LA), with low efficiency. Here, we report the de novo high-efficient biosynthesis of LA and a series of LA-derived EAs in Aspergillus oryzae cell factories. Based on genome sequencing of the EA-producing strain, C. purpurea 22.07, an EA biosynthetic gene cluster was annotated and characterized. After introducing and optimizing the agroclavine (AG) biosynthetic pathway in A. oryzae, we constructed an efficient chassis strain for AG production. We then confirmed the function of the annotated CloA′ to catalyze the successive oxidation of AG into LA and isolysergic acid (ILA) in this AG-producing chassis and realize their de novo production with titers of 52.68 ± 1.49 and 6.32 ± 2.08 mg L−1, respectively. The subsequent introduction of the downstream non-ribosomal peptide synthetase genes LpsB′ and LpsC′ enabled the complete biosynthesis of ergometrine and a series of its analogs, achieving a total titer of more than 160 mg L−1. The unexpected biosynthesis of isolysergyl-glycine and lysergyl-glycine revealed a novel function of LpsC′, which utilizes glycine as a substrate. Our work successfully realized the complete biosynthesis of a series of EAs in an industrially feasible fungus, which will open new avenues for manufacturing EAs in a green and sustainable manner.

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来源期刊
Green Chemistry
Green Chemistry 化学-化学综合
CiteScore
16.10
自引率
7.10%
发文量
677
审稿时长
1.4 months
期刊介绍: Green Chemistry is a journal that provides a unique forum for the publication of innovative research on the development of alternative green and sustainable technologies. The scope of Green Chemistry is based on the definition proposed by Anastas and Warner (Green Chemistry: Theory and Practice, P T Anastas and J C Warner, Oxford University Press, Oxford, 1998), which defines green chemistry as the utilisation of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture and application of chemical products. Green Chemistry aims to reduce the environmental impact of the chemical enterprise by developing a technology base that is inherently non-toxic to living things and the environment. The journal welcomes submissions on all aspects of research relating to this endeavor and publishes original and significant cutting-edge research that is likely to be of wide general appeal. For a work to be published, it must present a significant advance in green chemistry, including a comparison with existing methods and a demonstration of advantages over those methods.
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