Role of Acetyl Coenzyme A Synthesis and Breakdown in Alternative Carbon Source Utilization in Candida albicans

Abstract

Acetyl coenzyme A (acetyl-CoA) is the central intermediate of the pathways required to metabolize nonfermentable carbon sources. Three such pathways, i.e., gluconeogenesis, the glyoxylate cycle, and ␤-oxidation, are required for full virulence in the fungal pathogen Candida albicans. These processes are compartmentalized in the cytosol, mitochondria, and peroxosomes, necessitating transport of intermediates across intracellular membranes. Acetyl-CoA is trafficked in the form of acetate by the carnitine shuttle, and we hypothesized that the enzymes that convert acetyl-CoA to/from acetate, i.e., acetyl-CoA hydrolase (ACH1) and acetyl-CoA synthetase (ACS1 and ACS2), would regulate alternative carbon utilization and virulence. We show that C. albicans strains depleted for ACS2 are unviable in the presence of most carbon sources, including glucose, acetate, and ethanol; these strains metabolize only fatty acids and glycerol, a substantially more severe phenotype than that of Saccharomyces cerevisiae acs2 mutants. In contrast, deletion of ACS1 confers no phenotype, though it is highly induced in the presence of fatty acids, perhaps explaining why acs2 mutants can utilize fatty acids. Strains lacking ACH1 have a mild growth defect on some carbon sources but are fully virulent in a mouse model of disseminated candidiasis. Both ACH1 and ACS2 complement mutations in their S. cerevisiae homolog. Together, these results show that acetyl-CoA metabolism and transport are critical for growth of C. albicans on a wide variety of nutrients. Furthermore, the phenotypic differences between mutations in these highly conserved genes in S. cerevisiae and C. albicans support recent findings that significant functional divergence exists even in fundamental metabolic pathways between these related yeasts.

Protein Acetylation and Acetyl Coenzyme A Metabolism in Budding Yeast

“…ACL-encoding genes are also present in many fungi; however, with the exception of Yarrowia lipolytica, members of the Saccharomycotina subphylum do not contain ACL-encoding genes (71). In Saccharomyces cerevisiae and most other members of Saccharomycotina, nucleocytosolic acetyl-CoA is synthesized by acetylCoA synthetase (10,71,72).…”

Intracellular Acetyl Unit Transport in Fungal Carbon Metabolism

“…1B). Of the two acetyl-CoA synthetases that have been identified in these yeast species (ACS1 and ACS2), ACS2 seems to play a major role in the generation of cytosolic acetyl-CoA when glucose is the carbon source (4,50). Transcription factors Tye7 and Gal4 were shown to be the mayor regulators of expression of genes involved in glycolysis in C. albicans (2).…”

Enzymatic Dysfunction of Mitochondrial Complex I of the Candida albicansgoa1Mutant Is Associated with Increased Reactive Oxidants and Cell Death

“…To cause disease, the organism utilizes a variety of factors to adhere to, break down host substrates, and invade tissue. There is also evidence that both glycolytic and nonglycolytic metabolism is critical to survival of the organism in the host, a phenomenon termed host nichespecific metabolic adaptation (9,14,21,41,50). The paradigm is that when blood-borne glucose is plentiful, cells metabolize by glycolysis to produce energy.…”