酿酒酵母细胞器区室化合成化学品的研究进展

Advances in the production of chemicals by organelle compartmentalization in Saccharomyces cerevisiae

摘要:

公认食品安全的酿酒酵母(Saccharomyces cerevisiae)是合成生物学中被广泛研究的底盘细胞，常作为生产高值或大宗化学品的微生物细胞工厂。近年来，通过各种代谢工程改造策略，已有大量化学品的合成途径在酿酒酵母中建立并优化，且部分化学品具备了产业化价值。作为真核生物，酿酒酵母具有完整的细胞内膜系统及其组成的复杂细胞器区室，而这些细胞器区室往往含有某些化学品合成所必需的较高浓度前体底物(如线粒体中的乙酰辅酶A)，或更加充足的酶、辅因子、能量等，可为目标产物的生物合成提供更适宜的物理、化学环境，但同时不同细胞器的结构特点有时也成为特定化合物合成的障碍。为此，研究人员在深入分析不同细胞器自身特点的基础上，结合目标化学品合成途径与细胞器之间的适配度，对细胞器开展了大量针对性改造工作以提高产物合成效率。本文详细综述了酿酒酵母中线粒体、过氧化物酶体、高尔基体、内质网、脂滴和液泡等细胞器的途径改造及优化策略，以及利用细胞器区室化合成化学品的研究进展，并对目前存在的困难和挑战以及未来研究方向进行了总结与展望。

Abstract:

As a generally-recognized-as-safe microorganism, Saccharomyces cerevisiae is a widely studied chassis cell for the production of high-value or bulk chemicals in the field of synthetic biology. In recent years, a large number of synthesis pathways of chemicals have been established and optimized in S. cerevisiae by various metabolic engineering strategies, and the production of some chemicals have shown the potential of commercialization. As a eukaryote, S. cerevisiae has a complete inner membrane system and complex organelle compartments, and these compartments generally have higher concentrations of the precursor substrates (such as acetyl-CoA in mitochondria), or have sufficient enzymes, cofactors and energy which are required for the synthesis of some chemicals. These features may provide a more suitable physical and chemical environment for the biosynthesis of the targeted chemicals. However, the structural features of different organelles hinder the synthesis of specific chemicals. In order to ameliorate the efficiency of product biosynthesis, researchers have carried out a number of targeted modifications to the organelles grounded on an in-depth analysis of the characteristics of different organelles and the suitability of the production of target chemicals biosynthesis pathway to the organelles. In this review, the reconstruction and optimization of the biosynthesis pathways for production of chemicals by organelle mitochondria, peroxisome, golgi apparatus, endoplasmic reticulum, lipid droplets and vacuole compartmentalization in S. cerevisiae are reviewed in-depth. Current difficulties, challenges and future perspectives are highlighted.