Institute for Biotechnology and Bioengineering, Centre for Biological and Chemical Engineering, Instituto Superior Técnico, Technical University of Lisbon, Lisboa, Portugal.
OMICS. 2010 Oct;14(5):525-40. doi: 10.1089/omi.2010.0072.
Weak acids are widely used as food preservatives (e.g., acetic, propionic, benzoic, and sorbic acids), herbicides (e.g., 2,4-dichlorophenoxyacetic acid), and as antimalarial (e.g., artesunic and artemisinic acids), anticancer (e.g., artesunic acid), and immunosuppressive (e.g., mycophenolic acid) drugs, among other possible applications. The understanding of the mechanisms underlying the adaptive response and resistance to these weak acids is a prerequisite to develop more effective strategies to control spoilage yeasts, and the emergence of resistant weeds, drug resistant parasites or cancer cells. Furthermore, the identification of toxicity mechanisms and resistance determinants to weak acid-based pharmaceuticals increases current knowledge on their cytotoxic effects and may lead to the identification of new drug targets. This review integrates current knowledge on the mechanisms of toxicity and tolerance to weak acid stress obtained in the model eukaryote Saccharomyces cerevisiae using genome-wide approaches and more detailed gene-by-gene analysis. The major features of the yeast response to weak acids in general, and the more specific responses and resistance mechanisms towards a specific weak acid or a group of weak acids, depending on the chemical nature of the side chain R group (R-COOH), are highlighted. The involvement of several transcriptional regulatory networks in the genomic response to different weak acids is discussed, focusing on the regulatory pathways controlled by the transcription factors Msn2p/Msn4p, War1p, Haa1p, Rim101p, and Pdr1p/Pdr3p, which are known to orchestrate weak acid stress response in yeast. The extrapolation of the knowledge gathered in yeast to other eukaryotes is also attempted.
弱酸被广泛用作食品防腐剂（如乙酸、丙酸、苯甲酸和山梨酸）、除草剂（如 2,4-二氯苯氧乙酸）以及抗疟药（如青蒿酸和青蒿素酸）、抗癌药（如青蒿酸）和免疫抑制剂（如霉酚酸）等，还有其他可能的应用。了解弱酸适应性反应和耐药性的机制是开发更有效的策略来控制腐败酵母、耐药杂草、耐药寄生虫或癌细胞的前提。此外，确定基于弱酸的药物的毒性机制和耐药决定因素可以增加对其细胞毒性作用的现有认识，并可能导致新的药物靶点的鉴定。
本综述综合了使用全基因组方法和更详细的基因对基因分析在模式真核生物酿酒酵母中获得的关于弱酸应激毒性和耐受性机制的现有知识。一般来说，酵母对弱酸的反应的主要特征，以及对特定弱酸或一组弱酸的更具体的反应和耐药机制，取决于侧链 R 基团（R-COOH）的化学性质。
还讨论了几个转录调控网络在基因组对不同弱酸的反应中的参与，重点是受转录因子 Msn2p/Msn4p、War1p、Haa1p、Rim101p 和 Pdr1p/Pdr3p 控制的调控途径，这些转录因子已知在酵母中协调弱酸应激反应。还尝试将在酵母中收集的知识外推到其他真核生物。
