EukaryoticHopanoids: Deciphering the regulatory network behind unusual lipids in eukaryotes

真核生物使用类固醇来调节细胞膜的生物物理性质，而一些细菌产生类固醇作为类固醇。与甾醇不同，类胡萝卜素的生物合成不需要氧气。有趣的是，一些生长在低氧环境中的真核生物，包括几种病原真菌，似乎通过水平基因转移获得了角鲨烯-霍普烯环酶(SHC)，这种酶负责合成霍帕尼类化合物。SHC是如何“驯化”的，以及霍帕尼类和类固醇生产的调节是如何协调的，目前尚不清楚。我将使用比较生物学的方法来探讨这些基本问题。裂殖酵母日本裂殖酵母依靠SHC厌氧生长，而它的近缘裂殖酵母是缺乏SHC的专性好氧菌。我将使用分子遗传学、细胞生物学、蛋白质和脂肪生物化学以及下一代测序方法相结合的方法来解释1)类霍帕尼醇的产生是如何调节的；2)在有氧和无氧的情况下，霍帕诺类化合物如何对细胞和有机体的生理做出贡献；以及3)日本血吸虫如何根据环境条件平衡麦角甾醇和类霍帕诺醇的产生。了解类何首乌合成是如何调控的，以及它如何对细胞生理学做出贡献，可能有助于为抗真菌治疗定义新的靶点。它还可能在工业生物技术应用中发挥作用，例如在生物反应器的缺氧环境中支持酵母生长。重要的是，探索这种丰富的生物学还将为膜组织和功能的原理提供更广泛的见解，并揭示真核生物中水平转移基因“驯化”的潜在机制。

Eukaryotes use sterols to modulate biophysical properties of cellular membranes, whereas some bacteria produce hopanoids as sterol mimics. Unlike sterols, hopanoids do not require oxygen for their biosynthesis. Interestingly, some eukaryotic organisms populating hypoxic environments, including several species of pathogenic fungi, appear to have acquired squalene-hopene cyclase (SHC), the enzyme responsible for hopanoid production, through horizontal gene transfer. How SHC is "domesticated", and how the regulation of hopanoid and sterol production is coordinated, is unknown. I will probe these fundamental questions using a comparative biology approach. The fission yeast Schizosaccharomyces japonicus relies on SHC to grow anaerobically, whereas its relative, Schizosaccharomyces pombe, is an obligate aerobe lacking SHC. I will use a combination of molecular genetics, cell biology, protein and lipid biochemistry, and next generation sequencing approaches to explain 1) how hopanoid production is regulated; 2) how hopanoids contribute to cellular and organismal physiology in the presence and absence of oxygen; and 3) how S. japonicus balances the production of ergosterol and hopanoids depending on environmental conditions. Understanding how hopanoid synthesis is regulated and how it contributes to cellular physiology may help define new targets for antifungal therapies. It may also become useful in industrial biotechnology applications, for instance to support yeast growth in anoxic environment of bioreactors. Importantly, probing this rich biology will also provide wider insights into the principles of membrane organization and function and shed light on the mechanisms underlying "domestication" of horizontally transferred genes in eukaryotes.