Ergosterol Biosynthesis and Regulation in Yeast Systems

Summary

Ergosterol is the principal sterol of fungal membranes and fulfils roles in membrane fluidity, permeability and organisation of membrane-associated proteins. Its synthesis proceeds through a multi-step pathway that converts acetyl-CoA via mevalonate and squalene to lanosterol, followed by sequential demethylations, reductions and desaturations catalysed by a cascade of ERG enzymes. In Saccharomyces cerevisiae, expression of ERG genes is orchestrated by zinc-finger transcription factors such as Upc2 and Ecm22, which respond to sterol depletion by upregulating biosynthetic genes. Feedback loops involving heme-sensing regulators (for example Hap1) and repressors (Rox1, Mot3) further fine-tune pathway flux in response to oxygen and iron availability. Non-vesicular lipid-transfer proteins distribute sterol from the endoplasmic reticulum to the plasma membrane, while lipid droplets serve as reserves during stress. In pathogenic yeasts such as Candida albicans and Cryptococcus neoformans, ergosterol homeostasis underpins virulence, stress adaptation and resistance to azole antifungals, which target sterol demethylase. Beyond medical relevance, modulation of ergosterol levels is exploited in biotechnological yeast strains to enhance tolerance to temperature, solvents or to direct flux towards valuable isoprenoids. Emerging studies reveal interconnections between sterol metabolism, autophagic pathways and lipid droplet dynamics, underscoring ergosterol’s multifaceted contributions to cellular physiology and its potential as an antifungal target.

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Ergosterol Biosynthesis and Regulation in Yeast Systems publication trend

The graph below shows the total number of articles in ergosterol biosynthesis and regulation in yeast systems across all publications each year (not limited to Nature Index journals).

Technical terms

Ergosterol: The principal sterol in fungal membranes responsible for structural integrity and fluidity.

Azoles: A class of antifungal agents that inhibit sterol demethylase, blocking ergosterol biosynthesis.

Upc2: A zinc-finger transcription factor in yeasts that senses sterol levels and activates ERG gene expression.

Lipid droplets: Intracellular organelles that store neutral lipids, including sterol esters, for membrane homeostasis.

Autophagy: A regulated process of cellular self-degradation that can be triggered by perturbations in lipid metabolism.

References

  1. Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans. Advanced Science (2024).
  2. Ergosterol Biosynthesis and Regulation Impact the Antifungal Resistance and Virulence of Candida spp.. Stresses (2024).
  3. Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae. Genes (2020).
  4. The wide‐ranging phenotypes of ergosterol biosynthesis mutants, and implications for microbial cell factories. Yeast (2020).

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