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Eukaryotic Cell doi:10.1128/EC.00253-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The role of acetyl-CoA synthesis and breakdown in alternative carbon source utilization in Candida albicans

^* To whom correspondence should be addressed. Email: Michael.Lorenz{at}uth.tmc.edu.

	Abstract

Acetyl-CoA is the central intermediate of the pathways required to metabolize non-fermentable carbon sources. Three such pathways, 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, acetyl-CoA hydrolase (ACH1) and acetyl-CoA synthetase (ACS1, ACS2), would regulate alternative carbon utilization and virulence. We show that C. albicans strains depleted for ACS2 are inviable 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 S. 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.