Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
Appl Environ Microbiol. 2024 Jul 24;90(7):e0087424. doi: 10.1128/aem.00874-24. Epub 2024 Jun 28.
Farnesol salvage, a two-step pathway converting farnesol to farnesyl pyrophosphate (FPP), occurs in bacteria, plants, and animals. This paper investigates the presence of this pathway in fungi. Through bioinformatics, biochemistry, and physiological analyses, we demonstrate its absence in the yeasts and , suggesting a likely absence across fungi. We screened 1,053 fungal genomes, including 34 from , for potential homologs to four genes (, , , and ) known to accomplish farnesol/prenol salvage in other organisms. Additionally, we showed that H-farnesol was not converted to FPP or any other phosphorylated prenol, and exogenous farnesol was not metabolized within 90 minutes at any phase of growth and did not rescue cells from the toxic effects of atorvastatin, but it did elevate the levels of intracellular farnesol (F). All these experiments were conducted with . In sum, we found no evidence for farnesol salvage in fungi.
The absence of farnesol salvage constitutes a major difference in the metabolic capabilities of fungi. In terms of fungal physiology, the lack of farnesol salvage pathways relates to how farnesol acts as a quorum-sensing molecule in and why farnesol should be investigated for use in combination with other known antifungal antibiotics. Its absence is essential for a model (K. W. Nickerson et al., Microbiol Mol Biol Rev 88:e00081-22, 2024), wherein protein farnesylation, protein chaperones, and the unfolded protein response are combined under the unifying umbrella of a cell's intracellular farnesol (F). In terms of human health, farnesol should have at least two different modes of action depending on whether those cells have farnesol salvage. Because animals have farnesol salvage, we can now see the importance of dietary prenols as well as the potential importance of farnesol in treating neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis.
法呢醇挽救途径是一种两步途径，可将法呢醇转化为法呢基焦磷酸（FPP），存在于细菌、植物和动物中。本文研究了该途径在真菌中的存在情况。通过生物信息学、生物化学和生理分析，我们证明了酵母和中不存在该途径，这表明真菌中可能不存在该途径。我们筛选了包括 34 种来自的 1053 种真菌基因组，以寻找已知在其他生物体中完成法呢醇/异戊烯醇挽救的四个基因（、、、和）的潜在同源物。此外，我们表明 H-法呢醇不能转化为 FPP 或任何其他磷酸化的异戊烯醇，并且在任何生长阶段的 90 分钟内，外源法呢醇都不会被代谢，也不能从阿托伐他汀的毒性作用中拯救细胞，但它确实提高了细胞内法呢醇（F）的水平。所有这些实验都是用进行的。总之，我们没有发现真菌中法呢醇挽救的证据。
法呢醇挽救途径的缺失构成了真菌代谢能力的主要差异。就真菌生理学而言，缺乏法呢醇挽救途径与法呢醇如何作为群体感应分子在中发挥作用以及为什么应该研究法呢醇与其他已知抗真菌抗生素联合使用有关。其缺失对于一个模型（K.W.Nickerson 等人，微生物学与分子生物学评论 88:e00081-22，2024）是必不可少的，其中蛋白质法尼基化、蛋白质伴侣和未折叠蛋白反应在细胞内法呢醇（F）的统一伞下结合在一起。就人类健康而言，法呢醇应该至少有两种不同的作用模式，具体取决于这些细胞是否具有法呢醇挽救途径。由于动物具有法呢醇挽救途径，我们现在可以看到饮食中的异戊烯醇以及法呢醇在治疗帕金森病、阿尔茨海默病和多发性硬化症等神经退行性疾病方面的潜在重要性。
