Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 12, Pages 8151-8169Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.517672
Keywords
Amino Acid; Candida albicans; Enzyme Kinetics; Fatty Acid Metabolism; Fatty Acid Oxidation; Pathogenesis; CUG clade; -Hydroxypropionate; Odd-chain Fatty Acids
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Funding
- Hans-Knoell-Institute
- Jena School for Microbial Communication
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Background: Propionyl-CoA is a common metabolic intermediate that requires degradation to avoid intoxication of cellular metabolism. Results: A key enzyme involved in a modified -oxidation pathway in Candida albicans has been identified. Conclusion: Although fungi generally use the methyl citrate cycle to degrade propionyl-CoA, CUG clade yeasts form an exception. Significance: The modified -oxidation pathway could provide a target for new antifungal compounds. Propionyl-CoA arises as a metabolic intermediate from the degradation of propionate, odd-chain fatty acids, and some amino acids. Thus, pathways for catabolism of this intermediate have evolved in all kingdoms of life, preventing the accumulation of toxic propionyl-CoA concentrations. Previous studies have shown that fungi generally use the methyl citrate cycle for propionyl-CoA degradation. Here, we show that this is not the case for the pathogenic fungus Candida albicans despite its ability to use propionate and valerate as carbon sources. Comparative proteome analyses suggested the presence of a modified -oxidation pathway with the key intermediate 3-hydroxypropionate. Gene deletion analyses confirmed that the enoyl-CoA hydratase/dehydrogenase Fox2p, the putative 3-hydroxypropionyl-CoA hydrolase Ehd3p, the 3-hydroxypropionate dehydrogenase Hpd1p, and the putative malonate semialdehyde dehydrogenase Ald6p essentially contribute to propionyl-CoA degradation and its conversion to acetyl-CoA. The function of Hpd1p was further supported by the detection of accumulating 3-hydroxypropionate in the hpd1 mutant on propionyl-CoA-generating nutrients. Substrate specificity of Hpd1p was determined from recombinant purified enzyme, which revealed a preference for 3-hydroxypropionate, although serine and 3-hydroxyisobutyrate could also serve as substrates. Finally, virulence studies in a murine sepsis model revealed attenuated virulence of the hpd1 mutant, which indicates generation of propionyl-CoA from host-provided nutrients during infection.
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