Overview of carbon and nitrogen catabolite metabolism in the virulence of human pathogenic fungi

Abstract

It is estimated that fungal infections, caused most commonly by Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, result in more deaths annually than malaria or tuberculosis. It has long been hypothesized the fungal metabolism plays a critical role in virulence though specific nutrient sources utilized by human pathogenic fungi in vivo has remained enigmatic. However, the metabolic utilisation of preferred carbon and nitrogen sources, encountered in a host niche-dependent manner, is known as carbon catabolite and nitrogen catabolite repression (CCR, NCR), and has been shown to be important for virulence. Several sensory and uptake systems exist, including carbon and nitrogen source-specific sensors and transporters, that allow scavenging of preferred nutrient sources. Subsequent metabolic utilisation is governed by transcription factors, whose functions and essentiality differ between fungal species. Furthermore, additional factors exist that contribute to the implementation of CCR and NCR. The role of the CCR and NCR-related factors in virulence varies greatly between fungal species and a substantial gap in knowledge exists regarding specific pathways. Further elucidation of carbon and nitrogen metabolism mechanisms is therefore required in a fungal species- and animal model-specific manner in order to screen for targets that are potential candidates for anti-fungal drug development.

Figure 1

Glucose sensing, uptake and metabolic pathways in C. albicans, A. fumigatus and C. neoformans (blue boxes: confirmed and putative sensors; green boxes: confirmed and putative transporters; red = metabolic enzymes, solid arrows = confirmed cellular processes, dashed arrows = cellular processes that are not elucidated; yellow = nucleus; purple = mitochondria). Glucose is sensed and taken up into the cell by specific hexose transporters (HXT) and is subsequently phosphorylated by the carbohydrate kinases hexokinase (HXK) or glucokinase (GLK). Further metabolic utilisation occurs via glycolysis and the TCA (tricarboxylic acid) cycle. Glucose uptake and subsequent phosphorylation serve as signals for the carbon catabolite repressor (CCR) Mig1p/CreA/Mig1 to translocate to the nucleus and repress target genes. Several factors, such as the protein kinase SNF, the de-ubiquitinylation complex CreB/CreC or the transcriptional regulator of iron metabolism HapX, have been shown to be involved in CCR by either interacting directly or indirectly, with Mig1p/CreA/Mig1 in a species-dependent manner.

Figure 2

Amino acid and ammonium sensing, uptake and metabolism in C. albicans, A. fumigatus and C. neoformans (blue boxes: confirmed and putative sensors; green boxes: confirmed and putative transporters; solid arrows = confirmed cellular processes, dashed arrows = cellular processes that are not elucidated; yellow = nucleus; purple = mitochondria). Proteins are degraded into peptides or proteins by secreted proteases (SAP = secreted aspartyl proteases). Peptides are internalised via oligopeptide (OPT) or peptide (PTR) transporters. Amino acids and ammonium are sensed and taken up by respective transporters and signals are relayed via several predicted pathways including cAMP and protein kinase A (PKA). Amino acids serve as precursors for TCA (tricarboxylic acid) cycle intermediates to generate ATP. Transcription factors (Gat1p, Gln3p/AreA, NmrA/Gat1) are activated and translocate to the nucleus where they regulate the catabolic and anabolic utilisation of different nitrogen sources.

Figure 3

ClustalW alignment of CreA/Mig1p/Mig1 amino acid sequences from A. fumigatus (AfCreA), A. nidulans (AnCreA), S. cerevisiae (ScMig1p), C. albicans (CaMig1p) and C. neoformans (CnMig1p). Percent identity is shown with shading, where darker shading indicates higher percent identity. Zinc-finger domains are outlined in black, based on SMART domain prediction of ScMig1p.