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

2019 ◽  
Vol 26 (1) ◽  
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

scholarly journals Transcriptomic and proteomic profiling revealed reprogramming of carbon metabolism in acetate-grown human pathogen Candida glabrata

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Shu Yih Chew ◽  
Alistair J. P. Brown ◽  
Benjamin Yii Chung Lau ◽  
Yoke Kqueen Cheah ◽  
Kok Lian Ho ◽  
...  
Keyword(s):  
Carbon Source ◽  
Carbon Metabolism ◽  
Candida Glabrata ◽  
Glyoxylate Cycle ◽  
Glucose Deprivation ◽  
Malate Synthase ◽  
Metabolic Responses ◽  
Metabolic Adaptation ◽  
High Morbidity ◽  
The Glyoxylate Cycle

Abstract Background Emergence of Candida glabrata, which causes potential life-threatening invasive candidiasis, has been widely associated with high morbidity and mortality. In order to cause disease in vivo, a robust and highly efficient metabolic adaptation is crucial for the survival of this fungal pathogen in human host. In fact, reprogramming of the carbon metabolism is believed to be indispensable for phagocytosed C. glabrata within glucose deprivation condition during infection. Methods In this study, the metabolic responses of C. glabrata under acetate growth condition was explored using high-throughput transcriptomic and proteomic approaches. Results Collectively, a total of 1482 transcripts (26.96%) and 242 proteins (24.69%) were significantly up- or down-regulated. Both transcriptome and proteome data revealed that the regulation of alternative carbon metabolism in C. glabrata resembled other fungal pathogens such as Candida albicans and Cryptococcus neoformans, with up-regulation of many proteins and transcripts from the glyoxylate cycle and gluconeogenesis, namely isocitrate lyase (ICL1), malate synthase (MLS1), phosphoenolpyruvate carboxykinase (PCK1) and fructose 1,6-biphosphatase (FBP1). In the absence of glucose, C. glabrata shifted its metabolism from glucose catabolism to anabolism of glucose intermediates from the available carbon source. This observation essentially suggests that the glyoxylate cycle and gluconeogenesis are potentially critical for the survival of phagocytosed C. glabrata within the glucose-deficient macrophages. Conclusion Here, we presented the first global metabolic responses of C. glabrata to alternative carbon source using transcriptomic and proteomic approaches. These findings implicated that reprogramming of the alternative carbon metabolism during glucose deprivation could enhance the survival and persistence of C. glabrata within the host.

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

2006 ◽  
Vol 6 (2) ◽  
pp. 280-290 ◽  
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.

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

2009 ◽  
Vol 8 (10) ◽  
pp. 1604-1614 ◽  
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.

The glyoxylate cycle enzyme activities in the pathogenic isolates of Candida albicans obtained from HIV/AIDS, diabetic and burn patients

Mycoses ◽  
2006 ◽  
Vol 49 (2) ◽  
pp. 85-90 ◽  
Author(s):  
Ali Abdul Lattif ◽  
Rajendra Prasad ◽  
Uma Banerjee ◽  
Nivedita Gupta ◽  
Sameer Mohammad ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Enzyme Activities ◽  
Glyoxylate Cycle ◽  
Burn Patients ◽  
Cycle Enzyme ◽  
The Glyoxylate Cycle ◽  
Hiv Aids

scholarly journals Anaplerotic reactions active during growth of Saccharomyces cerevisiae on glycerol

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Joeline Xiberras ◽  
Mathias Klein ◽  
Celina Prosch ◽  
Zahabiya Malubhoy ◽  
Elke Nevoigt
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Growth Rate ◽  
Specific Growth Rate ◽  
Pyruvate Carboxylase ◽  
Reference Strain ◽  
Specific Growth ◽  
Glyoxylate Cycle ◽  
Maximum Specific Growth Rate ◽  
The Glyoxylate Cycle ◽  
Anaplerotic Reactions

ABSTRACT Anaplerotic reactions replenish TCA cycle intermediates during growth. In Saccharomyces cerevisiae, pyruvate carboxylase and the glyoxylate cycle have been experimentally identified to be the main anaplerotic routes during growth on glucose (C6) and ethanol (C2), respectively. The current study investigates the importance of the two isoenzymes of pyruvate carboxylase (PYC1 and PYC2) and one of the key enzymes of the glyoxylate cycle (ICL1) for growth on glycerol (C3) as a sole carbon source. As the wild-type strains of the CEN.PK family are unable to grow in pure synthetic glycerol medium, a reverse engineered derivative showing a maximum specific growth rate of 0.14 h−1 was used as the reference strain. While the deletion of PYC1 reduced the maximum specific growth rate by about 38%, the deletion of PYC2 had no significant impact, neither in the reference strain nor in the pyc1Δ mutant. The deletion of ICL1 only marginally reduced growth of the reference strain but further decreased the growth rate of the pyc1 deletion strain by 20%. Interestingly, the triple deletion (pyc1Δ pyc2Δ icl1Δ) did not show any growth. Therefore, both the pyruvate carboxylase and the glyoxylate cycle are involved in anaplerosis during growth on glycerol.

Modelling the peroxisomal carbon leak during lipid mobilization in Arabidopsis

2010 ◽  
Vol 38 (5) ◽  
pp. 1230-1233 ◽  
Author(s):  
Mark A. Hooks ◽  
Elizabeth Allen ◽  
Jonathan A.D. Wattis
Keyword(s):  
Carbon Metabolism ◽  
Glyoxylate Cycle ◽  
Seedling Development ◽  
Wild Type ◽  
Acetyl Coa ◽  
Primary Metabolite ◽  
Lipid Mobilization ◽  
Acetate Assimilation ◽  
Development Levels ◽  
The Glyoxylate Cycle

Mutation of the ACN1 (acetate non-utilizing 1) locus of Arabidopsis results in altered acetate assimilation into gluconeogenic sugars and anapleurotic amino acids and leads to an overall depression in primary metabolite levels by approx. 50% during seedling development. Levels of acetyl-CoA were higher in acn1 compared with wild-type, which is counterintuitive to the activity of ACN1 as a peroxisomal acetyl-CoA synthetase. We hypothesize that ACN1 recycles free acetate to acetyl-CoA within peroxisomes in order that carbon remains fed into the glyoxylate cycle. When ACN1 is not present, carbon in the form of acetate can leak out of peroxisomes and is reactivated to acetyl-CoA within the cytosol. Kinetic models incorporating estimates of carbon input and pathway dynamics from a variety of literature sources have proven useful in explaining how ACN1 may prevent the carbon leak and even contribute to the control of peroxisomal carbon metabolism.

scholarly journals Structure of glyoxysomal malate dehydrogenase (MDH3) from Saccharomyces cerevisiae

2018 ◽  
Vol 74 (10) ◽  
pp. 617-624 ◽  
Author(s):  
Shu Moriyama ◽  
Kazuya Nishio ◽  
Tsunehiro Mizushima
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Malate Dehydrogenase ◽  
Ternary Complex ◽  
Tricarboxylic Acid Cycle ◽  
Glyoxylate Cycle ◽  
Tricarboxylic Acid ◽  
Mitochondrial Enzyme ◽  
Open Conformation ◽  
Metabolism Enzyme ◽  
The Glyoxylate Cycle

Malate dehydrogenase (MDH), a carbohydrate and energy metabolism enzyme in eukaryotes, catalyzes the interconversion of malate to oxaloacetate (OAA) in conjunction with that of nicotinamide adenine dinucleotide (NAD+) to NADH. Three isozymes of MDH have been reported in Saccharomyces cerevisiae: MDH1, MDH2 and MDH3. MDH1 is a mitochondrial enzyme and a member of the tricarboxylic acid cycle, whereas MDH2 is a cytosolic enzyme that functions in the glyoxylate cycle. MDH3 is a glyoxysomal enzyme that is involved in the reoxidation of NADH, which is produced during fatty-acid β-oxidation. The affinity of MDH3 for OAA is lower than those of MDH1 and MDH2. Here, the crystal structures of yeast apo MDH3, the MDH3–NAD+ complex and the MDH3–NAD+–OAA ternary complex were determined. The structure of the ternary complex suggests that the active-site loop is in the open conformation, differing from the closed conformations in mitochondrial and cytosolic malate dehydrogenases.

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