Fungal Δ9-fatty acid desaturase: a unique enzyme at the core of lipid metabolism in Aspergillus fumigatus and a promising target for the search for antifungal strategies

ABSTRACT Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans are the leading fungal pathogens that cause life-threatening deep mycosis, posing significant challenges to immunocompromised patients and increasing healthcare costs worldwide. Lipid metabolism is crucial for the growth and development of all organisms. Increasing evidence highlights that complex structural lipids in the fungal cell membrane emerge as important factors involved in cell signaling, stress response, and immune recognition. Membrane fluidity is primarily regulated by the ratio of saturated and unsaturated fatty acids (UFAs), structural components of membrane phospholipids, and sphingolipids, which comprise UFAs with varying degrees of unsaturation. A notable group of UFA found in these molecules contains a cis double bond located at the C9 position of the carbon chain. The synthesis of such molecules is dependent on Δ9-fatty acid (FA) desaturase enzymes. In the absence of Δ9-FA desaturase, fungal cells become auxotrophic for palmitoleic and oleic acids (C16 and C18 UFA, respectively), suggesting that this essential enzyme family is fundamental for fungal physiology and virulence. However, the extent of phenotypes and especially the biochemical properties of fungal Δ9-FA desaturases remain poorly understood. In this manuscript, we summarize the current information and fundamental findings on Δ9-FA desaturase, gathered from functional studies on relevant fungal pathogens with a focus on A. fumigatus or deduced from model organisms, including yeasts and their mammalian counterparts. We also discuss its unique domain organization and its implications for the catalytic mechanism and the potential of fungal Δ9-FA desaturase as a chemotherapeutic target.