Lipid Biosynthesis as an Antifungal Target

Abstract

Lipids, commonly including phospholipids, sphingolipids, fatty acids, sterols, and triacylglycerols (TAGs), are important biomolecules for the viability of all cells. Phospholipids, sphingolipids, and sterols are important constituents of biological membranes. Many lipids play important roles in the regulation of cell metabolism by acting as signaling molecules. Neutral lipids, including TAGs and sterol esters (STEs), are important storage lipids in cells. In view of the importance of lipid molecules, this review briefly summarizes the metabolic pathways for sterols, phospholipids, sphingolipids, fatty acids, and neutral lipids in fungi and illustrates the differences between fungal and human (or other mammalian) cells, especially in relation to lipid biosynthetic pathways. These differences might provide valuable clues for us to find target proteins for novel antifungal drugs. In addition, the development of lipidomics technology in recent years has supplied us with a shortcut for finding new antifungal drug targets; this ability is important for guiding our research on pathogenic fungi.

Keywords: antifungal drugs; lipid metabolism; lipidomics; pathogenic fungi; target protein.

Figure 1

Representative structure of (a) fatty acids, (b) phospholipids, (c) sphingolipids, (d) glycerolipids, and (e) sterol lipids. This figure is adapted and modified from Ref. [4].

Figure 2

Antifungal interference with ergosterol biosynthesis. This figure is adapted and modified from Ref. [24]. HMG-CoA, β-Hydroxy-β-methylglutaryl-CoA.

Figure 3

Metabolic network of phospholipids in S. cerevisiae. G-3-P, Glycerol-3-phosphate; DHAP, Dihydroxyacetone phosphate; PA, Phosphatidic acid; Lyso-PA, Lyso- Phosphatidic acid; Acyl-DHAP, Acyl-Dihydroxyacetone phosphate; CDP-DAG, Cytidine diphosphate-diacylglycerol; PI, Phosphatidyl inositol; Ins, Inositol; PGP, Phosphatidylglycerol phosphate; PG, Phosphatidylglycerol; CL, Cardiolipin; PS, Phosphatidylserine; PE, Phosphatidylethanolamine; PME, Phosphatidyl monomethylaminoethanol; PDE, Phosphatidyl dimethylaminoethanol; PC, Phosphatidylcholine; DAG, Diacylglycerol; Etn, Ethanolamine; P-Etn, Phospho-ethanolamine; CDP-Etn, Cytidine diphosphate-ethanolamine; Cho, Choline; P-Cho, Phospho-choline; CDP-Cho, Cytidine diphosphate-choline.

Figure 4

De novo synthesis of sphingolipids in S. cerevisiae. This figure is adapted and modified from Ref. [38]. IPC, inositolphosphatyl-ceramide; MIPC, mannose inositol-P-ceramide; M(IP)₂C, mannose-(inositol-P)2-ceramide.