The glyoxylate cycle in Candida albicans infection

Candida albicans is a commensal yeast that inhabits the gastrointestinal tract of humans. The master regulator of the white-opaque transition WOR1 has been implicated in the adaptation to this commensal status. A proteomic analysis of cells overexpressing this transcription factor (WOR1OE) suggested an altered metabolism of carbon sources and a phenotypic analysis confirmed this alteration. The WOR1OE cells are deficient in using trehalose and xylose and are unable to use 2C sources, which is consistent with a reduction in the amount of Icl1, the isocitrate lyase enzyme. The icl1Δ/Δ mutants overexpressing WOR1 are deficient in the production of phloxine B positive cells, a main characteristic of opaque cells, a phenotype also observed in mating type hemizygous mtla1Δ icl1Δ/Δ cells, suggesting the involvement of Icl1 in the adaptation to the commensal state. In fact, icl1Δ/Δ cells have reduced fitness in mouse gastrointestinal tract as compared with essentially isogenic heterozygous ICL1/icl1Δ, but overproduction of WOR1 in an icl1Δ/Δ mutant does not restore fitness. These results implicate the glyoxylate shunt in the adaptation to commensalism of C. albicans by mechanisms that are partially independent of WOR1.

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The glyoxylate cycle and alternative carbon metabolism as metabolic adaptation strategies of Candida glabrata: perspectives from Candida albicans and Saccharomyces cerevisiae

Journal of Biomedical Science ◽

10.1186/s12929-019-0546-5 ◽

2019 ◽

Vol 26 (1) ◽

Cited By ~ 5

Author(s):

Shu Yih Chew ◽

Wallace Jeng Yang Chee ◽

Leslie Thian Lung Than

Keyword(s):

Saccharomyces Cerevisiae ◽

Candida Albicans ◽

Carbon Metabolism ◽

Candida Glabrata ◽

Glyoxylate Cycle ◽

Adaptation Strategies ◽

Metabolic Adaptation ◽

The Glyoxylate Cycle

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Inhibitory Effects of Diketopiperazines from Marine-Derived Streptomyces puniceus on the Isocitrate Lyase of Candida albicans

Molecules ◽

10.3390/molecules24112111 ◽

2019 ◽

Vol 24 (11) ◽

pp. 2111 ◽

Cited By ~ 4

Author(s):

Heegyu Kim ◽

Ji-Yeon Hwang ◽

Jongheon Shin ◽

Ki-Bong Oh

Keyword(s):

Candida Albicans ◽

Cyclic Peptides ◽

Inhibitory Concentration ◽

Isocitrate Lyase ◽

Glyoxylate Cycle ◽

Malate Synthase ◽

Wild Type ◽

Inhibitory Effects ◽

Reported Data ◽

The Glyoxylate Cycle

The glyoxylate cycle is a sequence of anaplerotic reactions catalyzed by the key enzymes isocitrate lyase (ICL) and malate synthase, and plays an important role in the pathogenesis of microorganisms during infection. An icl-deletion mutant of Candida albicans exhibited reduced virulence in mice compared with the wild type. Five diketopiperazines, which are small and stable cyclic peptides, isolated from the marine-derived Streptomyces puniceus Act1085, were evaluated for their inhibitory effects on C. albicans ICL. The structures of these compounds were elucidated based on spectroscopic data and comparisons with previously reported data. Cyclo(L-Phe-L-Val) was identified as a potent ICL inhibitor, with a half maximal inhibitory concentration of 27 μg/mL. Based on the growth phenotype of the icl-deletion mutants and icl expression analyses, we demonstrated that cyclo(L-Phe-L-Val) inhibits the gene transcription of ICL in C. albicans under C2-carbon-utilizing conditions.

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Inhibitory Effects of Epipolythiodioxopiperazine Fungal Metabolites on Isocitrate Lyase in the Glyoxylate Cycle of Candida albicans

Marine Drugs ◽

10.3390/md19060295 ◽

2021 ◽

Vol 19 (6) ◽

pp. 295

Author(s):

Ji-Yeon Hwang ◽

Beomkoo Chung ◽

Oh-Seok Kwon ◽

Sung Chul Park ◽

Eunji Cho ◽

...

Keyword(s):

Candida Albicans ◽

Inhibitory Concentration ◽

Isocitrate Lyase ◽

Glyoxylate Cycle ◽

Spectroscopic Techniques ◽

Fungal Metabolites ◽

Inhibitory Effects ◽

Polymerase Chain ◽

Reported Data ◽

The Glyoxylate Cycle

Four epipolythiodioxopiperazine fungal metabolites (1–4) isolated from the sponge-derived Aspergillus quadrilineatus FJJ093 were evaluated for their capacity to inhibit isocitrate lyase (ICL) in the glyoxylate cycle of Candida albicans. The structures of these compounds were elucidated using spectroscopic techniques and comparisons with previously reported data. We found secoemestrin C (1) (an epitetrathiodioxopiperazine derivative) to be a potent ICL inhibitor, with an inhibitory concentration of 4.77 ± 0.08 μM. Phenotypic analyses of ICL-deletion mutants via growth assays with acetate as the sole carbon source demonstrated that secoemestrin C (1) inhibited C. albicans ICL. Semi-quantitative reverse-transcription polymerase chain reaction analyses indicated that secoemestrin C (1) inhibits ICL mRNA expression in C. albicans under C2-assimilating conditions.

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Mutations in Alternative Carbon Utilization Pathways in Candida albicans Attenuate Virulence and Confer Pleiotropic Phenotypes

Eukaryotic Cell ◽

10.1128/ec.00372-06 ◽

2006 ◽

Vol 6 (2) ◽

pp. 280-290 ◽

Cited By ~ 111

Author(s):

Melissa A. Ramírez ◽

Michael C. Lorenz

Keyword(s):

Candida Albicans ◽

Carbon Metabolism ◽

Innate Immune System ◽

Glyoxylate Cycle ◽

Transcriptional Profiling ◽

Carbon Sources ◽

Innate Immune ◽

Carbon Utilization ◽

The Glyoxylate Cycle

ABSTRACT The interaction between Candida albicans and cells of the innate immune system is a key determinant of disease progression. Transcriptional profiling has revealed that C. albicans has a complex response to phagocytosis, much of which is similar to carbon starvation. This suggests that nutrient limitation is a significant stress in vivo, and we have shown that glyoxylate cycle mutants are less virulent in mice. To examine whether other aspects of carbon metabolism are important in vivo during an infection, we have constructed strains lacking FOX2 and FBP1, which encode key components of fatty acid β-oxidation and gluconeogenesis, respectively. As expected, fox2Δ mutants failed to utilize several fatty acids as carbon sources. Surprisingly, however, these mutants also failed to grow in the presence of several other carbon sources, whose assimilation is independent of β-oxidation, including ethanol and citric acid. Mutants lacking the glyoxylate enzyme ICL1 also had more severe carbon utilization phenotypes than were expected. These results suggest that the regulation of alternative carbon metabolism in C. albicans is significantly different from that in other fungi. In vivo, fox2Δ mutants show a moderate but significant reduction in virulence in a mouse model of disseminated candidiasis, while disruption of the glyoxylate cycle or gluconeogenesis confers a severe attenuation in this model. These data indicate that C. albicans often encounters carbon-poor conditions during growth in the host and that the ability to efficiently utilize multiple nonfermentable carbon sources is a virulence determinant. Consistent with this in vivo requirement, C. albicans uniquely regulates carbon metabolism in a more integrated manner than in Saccharomyces cerevisiae, such that defects in one part of the machinery have wider impacts than expected. These aspects of alternative carbon metabolism may then be useful as targets for therapeutic intervention.

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The Transcription Factor Homolog CTF1 Regulates β-Oxidation in Candida albicans

Eukaryotic Cell ◽

10.1128/ec.00206-09 ◽

2009 ◽

Vol 8 (10) ◽

pp. 1604-1614 ◽

Cited By ~ 40

Author(s):

Melissa A. Ramírez ◽

Michael C. Lorenz

Keyword(s):

Candida Albicans ◽

Carbon Metabolism ◽

Regulatory Network ◽

Glyoxylate Cycle ◽

Carbon Sources ◽

Microbial Pathogens ◽

Peroxisomal Biogenesis ◽

Expression Of Genes ◽

Genes Encoding ◽

The Glyoxylate Cycle

ABSTRACT Carbon starvation is one of the many stresses to which microbial pathogens are subjected while in the host. Pathways necessary for the utilization of alternative carbon sources, such as gluconeogenesis, the glyoxylate cycle, and β-oxidation of fatty acids, have been shown to be required for full virulence in several systems, including the fungal pathogen Candida albicans. We have investigated the regulatory network governing alternative carbon metabolism in this organism through characterization of transcriptional regulators identified based on the model fungi, Saccharomyces cerevisiae and Aspergillus nidulans. C. albicans has homologs of the ScCAT8/AnFacB and ScADR1/AnAmdX transcription factors that regulate induction of genes encoding the proteins of gluconeogenesis, the glyoxylate cycle, and ethanol utilization. Surprisingly, C. albicans mutants lacking CAT8 or ADR1 have no apparent phenotypes and do not regulate genes for key enzymes of these pathways. Fatty acid degradation and peroxisomal biogenesis are controlled by nonhomologous regulators, OAF1/PIP2 in S. cerevisiae and FarA/FarB in A. nidulans; C. albicans is missing OAF1 and PIP2 and, instead, has a single homolog of the Far proteins, CTF1. We have shown that CTF1 is required for growth on lipids and for expression of genes necessary for β-oxidation, such as FOX2. ctf1Δ/ctf1Δ (ctf1Δ/Δ) strains do not, however, show the pleiotropic phenotypes observed for fox2Δ/Δ mutants. The ctf1Δ/Δ mutant confers a mild attenuation in virulence, like the fox2Δ/Δ mutant. Thus, phenotypic and genotypic observations highlight important differences in the regulatory network for alternative carbon metabolism in C. albicans compared to the paradigms developed in other model fungi.

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