Intracellular acetyl unit transport in fungal carbon metabolism

Abstract

Acetyl coenzyme A (acetyl-CoA) is a central metabolite in carbon and energy metabolism. Because of its amphiphilic nature and bulkiness, acetyl-CoA cannot readily traverse biological membranes. In fungi, two systems for acetyl unit transport have been identified: a shuttle dependent on the carrier carnitine and a (peroxisomal) citrate synthase-dependent pathway. In the carnitine-dependent pathway, carnitine acetyltransferases exchange the CoA group of acetyl-CoA for carnitine, thereby forming acetyl-carnitine, which can be transported between subcellular compartments. Citrate synthase catalyzes the condensation of oxaloacetate and acetyl-CoA to form citrate that can be transported over the membrane. Since essential metabolic pathways such as fatty acid β-oxidation, the tricarboxylic acid (TCA) cycle, and the glyoxylate cycle are physically separated into different organelles, shuttling of acetyl units is essential for growth of fungal species on various carbon sources such as fatty acids, ethanol, acetate, or citrate. In this review we summarize the current knowledge on the different systems of acetyl transport that are operational during alternative carbon metabolism, with special focus on two fungal species: Saccharomyces cerevisiae and Candida albicans.

Fig. 1.

Central carbon metabolism in C. albicans. (A) Morphology of peroxisomes and mitochondria in glucose-grown C. albicans cells expressing green fluorescent protein (GFP)-tagged 3-ketoacyl-CoA thiolase (POT1/orf19.7520). Peroxisomes were visualized by GFP fluorescence and mitochondria by MitoTracker Red staining. (B) Model for acetyl-CoA transport between peroxisomal, cytosolic, and mitochondrial compartments in C. albicans. Depicted biochemical pathways are β-oxidation of fatty acids, carnitine shuttle, glyoxylate cycle, TCA cycle, glycolysis, gluconeogenesis, and fatty acid biosynthesis. Abbreviations: Acc, acetyl-CoA carboxylase; Aco, aconitase; Acs1/2, acetyl-CoA synthase; Adh, alcohol dehydrogenase; Ald, acetaldehyde dehydrogenase; α-Kgdh, α-ketoglutarate dehydrogenase; Cit, citrate synthase; Cyb2, l-lactate dehydrogenase; Fum, Fumarase; Icl1, isocitrate lyase; Idh, isocitrate dehydrogenase; Mdh, malate dehydrogenase; mitCat2, mitochondrial Cat2; Mls1, malate synthase; Pda, pyruvate dehydrogenase complex; Pdc, pyruvate decarboxylase; perCat2, peroxisomal Cat2; Scs, succinyl-CoA synthetase; Sdh, succinate dehydrogenase; Tes, thioesterase; Yat1, carnitine acetyltransferase. •, putative carrier/transporter. Question marks indicate uncertainty about conversions or means of transport. (Adapted from reference with permission of the publisher.)

Fig. 2.

Acetyl unit transport pathways in fungi. (A and B) Schematic representation of acetyl unit transport pathways in C. albicans and S. cerevisiae, respectively. (C) Growth phenotypes of deletion mutant strains on different carbon sources. Phenotypes of S. cerevisiae strains with a disrupted CIT2 gene were assessed in media containing l-carnitine (*). Abbreviations: Aco1, aconitase; β-ox, β-oxidation of fatty acids; Cit2, peroxisomal citrate synthase; Icl1, isocitrate lyase; mitCat2, mitochondrial Cat2; Mls1, malate synthase; perCat2, peroxisomal Cat2; TCA cycle, tricarboxylic acid cycle; Yat1/Yat2, carnitine acetyltransferase; Glu, glucose; Cit, citrate; Eth, ethanol; Ac, acetate; Ol, oleate. +, growth; ±, weak growth; −, no growth.