De novo biosynthesis of diverse plant-derived styrylpyrones in Saccharomyces cerevisiae

IF 3.7 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Metabolic Engineering Communications Pub Date : 2022-06-01 DOI:10.1016/j.mec.2022.e00195
Yinan Wu , Maple N. Chen , Sijin Li
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引用次数: 5

Abstract

Plant styrylpyrones exerting well-established neuroprotective properties have attracted increasing attention in recent years. The ability to synthesize each individual styrylpyrone in engineered microorganisms is important to understanding the biological activity of medicinal plants and the complex mixtures they produce. Microbial biomanufacturing of diverse plant-derived styrylpyrones also provides a sustainable and efficient approach for the production of valuable plant styrylpyrones as daily supplements or potential drugs complementary to the prevalent agriculture-based approach. In this study, we firstly demonstrated the heterogenous biosynthesis of two 7,8-saturated styrylpyrones (7,8-dihydro-5,6-dehydrokavain (DDK) and 7,8-dihydroyangonin (DHY)) and two 7,8-unsaturated styrylpyrones (desmethoxyyangonin (DMY) and yangonin (Y)), in Saccharomyces cerevisiae. Although plant styrylpyrone biosynthetic pathways have not been fully elucidated, we functionally reconstructed the recently discovered kava styrylpyrone biosynthetic pathway that has high substrate promiscuity in yeast, and combined it with upstream hydroxycinnamic acid biosynthetic pathways to produce diverse plant-derived styrylpyrones without the native plant enzymes. We optimized the de novo pathways by engineering yeast endogenous aromatic amino acid metabolism and endogenous double bond reductases and by CRISPR-mediated δ-integration to overexpress the rate-limiting pathway genes. These combinatorial engineering efforts led to the first three yeast strains that can produce diverse plant-derived styrylpyrones de novo, with the titers of DDK, DMY and Y at 4.40 μM, 1.28 μM and 0.10 μM, respectively. This work has laid the foundation for larger-scale styrylpyrone biomanufacturing and the complete biosynthesis of more complicated plant styrylpyrones.

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不同植物源苯丙酮在酿酒酵母中的重新生物合成
植物苯丙酮具有良好的神经保护作用,近年来受到越来越多的关注。在工程微生物中合成每个单独的苯乙烯吡啶酮的能力对于了解药用植物的生物活性及其产生的复杂混合物是重要的。多种植物源苯丙酮的微生物生物制造也为生产有价值的植物苯丙酮提供了一种可持续和有效的方法,作为日常补充剂或潜在的药物补充,以普遍的农业为基础的方法。在本研究中,我们首次在酿酒酵母菌中异质合成了两个7,8饱和的苯基pyro酮(7,8-二氢-5,6-脱氢钾素(DDK)和7,8-二氢阳根素(DHY))和两个7,8不饱和的苯基pyro酮(去甲氧基阳根素(DMY)和阳根素(Y))。虽然植物苯丙酮生物合成途径尚未完全阐明,但我们对最近在酵母中发现的具有高底物混杂性的卡瓦苯丙酮生物合成途径进行了功能重构,并将其与上游羟肉桂酸生物合成途径结合,在不使用天然植物酶的情况下生产了多种植物源苯丙酮。我们通过改造酵母内源性芳香氨基酸代谢和内源性双键还原酶,并通过crispr介导的δ-整合来过表达限速途径基因,从而优化了从头途径。通过这些组合工程的努力,首次获得了3株能够产生多种植物源性苯丙酮的酵母菌,其DDK、DMY和Y的滴度分别为4.40 μM、1.28 μM和0.10 μM。本研究为更大规模的苯乙烯吡咯酮生物制造和更复杂的植物苯乙烯吡咯酮的完全生物合成奠定了基础。
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来源期刊
Metabolic Engineering Communications
Metabolic Engineering Communications Medicine-Endocrinology, Diabetes and Metabolism
CiteScore
13.30
自引率
1.90%
发文量
22
审稿时长
18 weeks
期刊介绍: Metabolic Engineering Communications, a companion title to Metabolic Engineering (MBE), is devoted to publishing original research in the areas of metabolic engineering, synthetic biology, computational biology and systems biology for problems related to metabolism and the engineering of metabolism for the production of fuels, chemicals, and pharmaceuticals. The journal will carry articles on the design, construction, and analysis of biological systems ranging from pathway components to biological complexes and genomes (including genomic, analytical and bioinformatics methods) in suitable host cells to allow them to produce novel compounds of industrial and medical interest. Demonstrations of regulatory designs and synthetic circuits that alter the performance of biochemical pathways and cellular processes will also be presented. Metabolic Engineering Communications complements MBE by publishing articles that are either shorter than those published in the full journal, or which describe key elements of larger metabolic engineering efforts.
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