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The ergosterol biosynthesis pathway in fungi is a multi-enzyme metabolic pathway responsible for the production of ergosterol, the predominant sterol in fungal cell membranes. Ergosterol is essential for maintaining membrane structure, fluidity, and permeability, and is not found in human cells (which use cholesterol), making this pathway a selective antifungal target[1][2][3][5]. Major steps include the conversion of farnesyl diphosphate (FPP) to squalene, lanosterol, and ultimately ergosterol through a series of specific enzymes. Inhibition of key pathway enzymes disrupts fungal growth and survival, and forms the mechanistic basis for several major antifungal drug classes, notably azoles and polyenes[2][5]. Mutations in pathway enzymes are a common route to antifungal resistance, making the pathway central to both the development of new therapeutics and the monitoring of resistance[1][2][4][5]. Though ergosterol is the dominant sterol in most pathogenic fungi, some species produce alternative sterols through divergent pathways, which can have implications for drug sensitivity and resistance[4].
Inhibition of lanosterol 14α-demethylase (disrupts ergosterol synthesis, azoles); Inhibition of squalene epoxidase (blocks upstream sterol biosynthesis, allylamines); Direct binding and sequestration of ergosterol in membranes (polyenes); Blockage of other enzymatic steps (morpholines, etc.).
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