在工程酿酒酵母中从头开始生物合成白桦脂酸

IF 4.5 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic Chemistry Pub Date : 2024-08-22 DOI:10.1016/j.bioorg.2024.107737
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引用次数: 0

摘要

白桦脂酸(BA)是从羽扇豆醇中提取的羽扇豆类五环三萜天然产物,具有良好的抗炎和抗肿瘤活性。目前,BA 主要通过植物提取法生产,这大大限制了它的广泛应用。为了促进疏水性 BA 的合成和储存,我们采用了过氧物酶体和脂滴双重工程策略来构建 BA 的生物合成途径。通过表达来源于斑叶桦树的羽扇豆醇 C-28 氧化酶(BPLO)和来源于拟南芥的 ATR1,我们成功培育出了一株能产生 BA 的菌株,并对 BPLO 和 ATR1 之间的连接物进行了多次表达优化,在摇瓶中 BA 滴度达到了 77.53 mg/L,随后在 5 L 生物反应器中通过饲料批量发酵达到了 205.74 mg/L。在这项研究中,我们开发了一种在工程酿酒葡萄孢中从头合成 BA 及其直接前体羽扇豆醇的可行方法。
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De novo biosynthesis of betulinic acid in engineered Saccharomyces cerevisiae

Betulinic acid (BA) is a lupinane-type pentacyclic triterpenoid natural product derived from lupeol that has favorable anti-inflammatory and anti-tumor activities. Currently, BA is mainly produced via botanical extraction, which significantly limits its widespread use. In this study, we investigated the de novo synthesis of BA in Saccharomyces cerevisiae, and to facilitate the synthesis and storage of hydrophobic BA, we adopted a dual-engineering strategy involving peroxisomes and lipid droplets to construct the BA biosynthetic pathway. By expressing Betula platyphylla-derived lupeol C-28 oxidase (BPLO) and Arabidopsis-derived ATR1, we succeeded in developing a BA-producing strain and following multiple expression optimizations of the linker between BPLO and ATR1, the BA titer reached 77.53 mg/L in shake flasks and subsequently reached 205.74 mg/L via fed-batch fermentation in a 5-L bioreactor. In this study, we developed a feasible approach for the de novo synthesis of BA and its direct precursor lupeol in engineered S. cerevisiae.

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来源期刊
Bioorganic Chemistry
Bioorganic Chemistry 生物-生化与分子生物学
CiteScore
9.70
自引率
3.90%
发文量
679
审稿时长
31 days
期刊介绍: Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.
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