Abstract
Ergosterol is an essential component of fungal cell membranes that determines the fluidity, permeability and activity of membrane-associated proteins. Ergosterol biosynthesis is a complex and highly energy-consuming pathway that involves the participation of many enzymes. Deficiencies in sterol biosynthesis cause pleiotropic defects that limit cellular proliferation and adaptation to stress. Thereby, fungal ergosterol levels are tightly controlled by the bioavailability of particular metabolites (e.g., sterols, oxygen and iron) and environmental conditions. The regulation of ergosterol synthesis is achieved by overlapping mechanisms that include transcriptional expression, feedback inhibition of enzymes and changes in their subcellular localization. In the budding yeast Saccharomyces cerevisiae, the sterol regulatory element (SRE)-binding proteins Upc2 and Ecm22, the heme-binding protein Hap1 and the repressor factors Rox1 and Mot3 coordinate ergosterol biosynthesis (ERG) gene expression. Here, we summarize the sterol biosynthesis, transport and detoxification systems of S. cerevisiae, as well as its adaptive response to sterol depletion, low oxygen, hyperosmotic stress and iron deficiency. Because of the large number of ERG genes and the crosstalk between different environmental signals and pathways, many aspects of ergosterol regulation are still unknown. The study of sterol metabolism and its regulation is highly relevant due to its wide applications in antifungal treatments, as well as in food and pharmaceutical industries.
Highlights
Sterols are essential components of eukaryotic cellular membranes that maintain membrane structural integrity, fluidity and permeability.They have further functions in regulating membrane-bound enzyme activity, lipid raft formation and function, substance transportation and cell cycle
The double mutant are1∆are2∆ does not display any altered growth under normal conditions, despite overall sterol biosynthesis drops and the level of free sterols increases [44,48]. These findings suggest that sterol biosynthesis and steryl esters (SE) formation are interconnected through a regulatory mechanism
The yeast S. cerevisiae is used as a reliable model to study multiple aspects of lipid biology due to its well characterized genome, the relative simplicity of its lipid metabolism and homeostasis, and the conservation of genes, routes and networks in other eukaryotes
Summary
Sterols are essential components of eukaryotic cellular membranes that maintain membrane structural integrity, fluidity and permeability They have further functions in regulating membrane-bound enzyme activity, lipid raft formation and function, substance transportation and cell cycle. Molecular oxygen is the electron acceptor in the enzymatic steps catalyzed by Erg, Erg, Erg, Erg and Erg; and heme, whose biosynthesis requires oxygen and iron, directly associates to Erg and Erg, as well as to Erg and Erg as a cytochrome b5 cofactor (Figure 1). Erg belongenzymes to the cytochrome of enzymes that functionfamily in association with regulators oxo-diiron of the fattyP450 acidfamily hydroxylase/sterol desaturase (Figure 1). Erg are and iron are associated with reduced activity of Dap1 These enzymes andErg changes in sterol oxo-diiron enzymes of the fatty acid hydroxylase/sterol desaturase family (Figure 1). Iron depletion are associated with reduced activity of these enzymes and changes in sterol production
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