武汉植物园利用酵母合成白桦脂酸 避免对植物资源的严重依赖

中国科学院武汉植物园天然产物合成生物学学科组利用酵母合成白桦脂酸，该研究成果革新了白桦脂酸的合成方式，可避免对植物资源的严重依赖。相关文章发表于《Applied Microbiology and Biotechnology》杂志上。

白桦脂酸(betulinic acid，简称BA)是一种五环三萜类化合物，其衍生物具有显著的抗肿瘤和抗艾滋病毒的活性，在合适浓度下对黑色瘤细胞具有专一的杀死作用，而对于人体正常体细胞无任何副作用，更为重要的是近期白桦酯酸衍生物抗HIV二期临床实验已经取得成功，因此，白桦酯酸目前已被认为是最具潜力的药物先导化合物之一。

白桦酯酸的主要来源是从白桦树的树皮中进行提取纯化，由于该化合物在白桦树皮中的含量很低，大约只有万分之几，每年就中国市场大约消耗23万吨的白桦树树皮，长期的采伐已导致白桦树资源的严重短缺，更是严重影响着白桦酯酸的开发利用。

中国科学院武汉植物园天然产物合成生物学学科组博士研究生李晶在章焰生研究员的指导下，将植物中白桦酯酸的整个代谢通路装入酵母细胞，成功地利用微生物合成了白桦脂酸。通过组合生物合成学研究方法，深入研究了关键基因和代谢通路对酵母生物合成白桦脂酸的影响。

结果发现脂肪酸和萜类前体合成途径的代谢流平衡对白桦脂酸合成影响显著，并通过协同表达这两个代谢通路中的关键调控基因(HFA1，HMG1和ERG9)可以显著提高白桦脂酸产量，该工程菌每升培养基已能合成毫克级的白桦酯酸。

该研究成果革新了白桦脂酸的合成方式，可避免对植物资源的严重依赖，相关结果已在国际学术期刊Applied Microbiology and Biotechnology 上在线发表。

原文摘要：

Increase of betulinic acid production inSaccharomyces cerevisiae by balancing fatty acids and betulinic acid forming pathways

Jing Li, Yansheng Zhang

Betulinic acid is a plant-based triterpenoid that has been recognized for its antitumor and anti-HIV activities. The level of betulinic acid in its natural hosts is extremely low. In the present study, we constructed betulinic acid biosynthetic pathway in Saccharomyces cerevisiae by metabolic engineering. Given the betulinic acid forming pathways sharing the common substrate acetyl-CoA with fatty acid synthesis, the metabolic fluxes between the two pathways were varied by changing gene expressions, and their effects on betulinic acid production were investigated. We constructed nine S. cerevisiae strains representing nine combinations of the flux distributions between betulinic acid and fatty acid pathways. Our results demonstrated that it was possible to improve the betulinic acid production in S. cerevisiae while keeping a desirable growth phenotype by optimally balancing the carbon fluxes of the two pathways. Through modulating the expressions of the key genes on betulinic acid and fatty acid pathways, the difference in betulinic acid yield varied largely in the range of 0.01–1.92 mg L−1 OD−1. The metabolic engineering approach used in this study could be extended for synthesizing other triterpenoids in S. cerevisiae.

标签: 酵母 植物资源 白桦脂酸

作者：中科院 点击：次

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