The synthesis, regulation, and functions of sterols in Candida albicans: Well-known but still lots to learn

Abstract

Sterols are the basal components of the membranes of the fungal pathogen Candida albicans, and these membranes determine the susceptibility of C. albicans cells to a variety of stresses, such as ionic, osmotic and oxidative pressures, and treatment with antifungal drugs. The common antifungal azoles in clinical use are targeted to the biosynthesis of ergosterol. In the past years, the synthesis, storage and metabolism of ergosterol in Saccharomyces cerevisiae has been characterized in some detail; however, these processes has not been as well investigated in the human opportunistic pathogen C. albicans. In this review, we summarize the genes involved in ergosterol synthesis and regulation in C. albicans. As well, genes in S. cerevisiae implicated in ergosterol storage and conversions with other lipids are noted, as these provide us clues and directions for the study of the homologous genes in C. albicans. In this report we have particularly focused on the essential roles of ergosterol in the dynamic process of cell biology and its fundamental status in the biological membrane system that includes lipid rafts, lipid droplets, vacuoles and mitochondria. We believe that a thorough understanding of this classic and essential pathway will give us new ideas about drug resistance and morphological switching in C. albicans.

Keywords: Candida albicans; biosynthesis; function; regulation; sterols.

Figure 1.

The conserved pathway of sterol synthesis, storage and transformation in C. albicans and S. cerevisiae. A. Schematic representation of the common ergosterol synthesis process including the enzymes and intermediate products in C. albicans. The storage and transformation between steryl esters and fatty acids or sterols is uncharacterized in C. albicans and labeled with dotted boxes, based on the homologous genes and their roles in S. cerevisiae. B. Accumulated intermediates when ERG3 function is lost. C. Bypass pathway when C. albicans is treated with Erg11p inhibitors. The resulting aberrant sterol 14-methylergosta-8,24(28)-dien-3β,6α-diol is produced by ERG3. Solid arrows, single enzymatic process; dashed arrows, multiple enzymatic processes; underlined genes, S. cerevisiae genes and their homologous genes in C. albicans are shown in parentheses.

Figure 2.

Model of sterol regulon evolution in Saccharomycotina illustrated by Maguire et al. in Plos Genetics (50). The ERG genes and filamentation genes are both regulated by SREBP and SCAP in the fungal progenitor. Upc2p gains binding sites in the promoters of ERG genes and the DUF2014 domain of SREBP, which may be important for interaction with Scap and retention of SREBP in the membrane, is lost but the protein still plays a role in regulation of filamentation in C. albicans.

Figure 3.

The effects of ergosterol are labeled on the C. albicans cell pattern diagram based on the picture from the Atlas of Fungal Infection. The functions and cellular properties of ergosterol in C. albicans are described in solid boxes, while the functions verified in S. cerevisiae but yet uncharacterized in C. albicans are noted in dotted boxes. Candida albicans Mutations in the Ergosterol Biosynthetic Pathway and Resistance to Several Antifungal Agents.