scholarly journals Carbon Catabolite Control in Candida albicans: New Wrinkles in Metabolism

mBio ◽  
2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Michael C. Lorenz
Keyword(s):  
Candida Albicans ◽  
Carbon Source ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Isocitrate Lyase ◽  
Glyoxylate Cycle ◽  
Carbon Sources ◽  
Fungal Species ◽  
Content Type ◽  
Catabolite Control

ABSTRACTMost microorganisms maintain strict control of nutrient assimilation pathways to ensure that they preferentially use compounds that generate the most energy or are most efficiently catabolized. In doing so, they avoid potentially inefficient conflicts between parallel catabolic and metabolic pathways. The regulation of carbon source utilization in a wide array of bacterial and fungal species involves both transcriptional and posttranscriptional mechanisms, and while the details can vary significantly, carbon catabolite control is widely conserved. In many fungi, the posttranslational aspect (carbon catabolite inactivation [CCI]) involves the ubiquitin-mediated degradation of catabolic enzymes for poor carbon sources when a preferred one (glucose) becomes available. A recent article presents evidence for a surprising exception to CCI in the fungal pathogenCandida albicans, an organism that makes use of gluconeogenic carbon sources during infection (D. Sandai, Z. Yin, L. Selway, D. Stead, J. Walker, M. D. Leach, I. Bohovych, I. V. Ene, S. Kastora, S. Budge, C. A. Munro, F. C. Odds, N. A. Gow, and A. J. Brown,mBio3[6]:e00495-12).In vitro, addition of glucose to cells grown in a poor carbon source rapidly represses transcripts encoding gluconeogenic and glyoxylate cycle enzymes, such as phosphoenolpyruvate carboxykinase (Pck1p) and isocitrate lyase (Icl1p), in bothC. albicansandSaccharomyces cerevisiae. Yet, uniquely, theC. albicansproteins persist, permitting parallel assimilation of multiple carbon sources, likely because they lack consensus ubiquitination sites found in the yeast homologs. Indeed, the yeast proteins are rapidly degraded when expressed inC. albicans, indicating a conservation of the machinery needed for CCI. How this surprising metabolic twist contributes to fungal commensalism or pathogenesis remains an open question.

Metabolic control in Acinetobacter sp. I. Effect of C4 versus C2 and C3 substrates on isocitrate lyase synthesis

1970 ◽  
Vol 16 (8) ◽  
pp. 769-774 ◽  
Author(s):  
Norma J. Herman ◽  
Emily J. Bell
Keyword(s):  
Carbon Source ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Specific Activity ◽  
Isocitrate Lyase ◽  
Tricarboxylic Acid Cycle ◽  
Glyoxylate Cycle ◽  
Enzyme Synthesis ◽  
Synthetase Activity ◽  
The Glyoxylate Cycle

The comparative effects of various substrates serving as sole carbon and energy source or as a supplemental nutrient on the synthesis of isocitrate lyase by a species of Acinetobacter have been investigated. Previous work has shown that succinate, as carbon source, allows some late, limited induction of enzyme synthesis. No increase in synthesis is seen above the basal level, however, in cultures growing in a medium containing L-malate as a sole carbon source. The addition of acetate to cultures growing in media containing either of the C4 intermediates results in rapid enzyme induction. Further, Acinetobacter grows very well in pyruvate medium and isocitrate lyase is synthesized to a significant extent, indicating that the glyoxylate cycle is acting anaplerotically under these conditions. Phosphoenolpyruvate synthetase activity has been demonstrated in this organism; levels comparable to those observed in Escherichia coli have been detected; the levels of NAD- and NADP-linked "malic enzyme" and phosphoenolpyruvate carboxykinase, enzymes functioning in C4 to C3 conversion, do not fluctuate with the various carbon sources tested; i.e. no correlation between the in vitro specific activity of these enzymes and the levels of isocitrate lyase activity may be made. All of the data are consistent with the hypothesis that, in this aerobic organism, as opposed to the facultative E. coli, the C4 intermediates of the tricarboxylic acid cycle may be more direct "coarse" control metabolites regulating the rate of the glyoxylate cycle.

scholarly journals The Evolutionary Rewiring of Ubiquitination Targets Has Reprogrammed the Regulation of Carbon Assimilation in the Pathogenic Yeast Candida albicans

mBio ◽  
2012 ◽  
Vol 3 (6) ◽  
Author(s):  
Doblin Sandai ◽  
Zhikang Yin ◽  
Laura Selway ◽  
David Stead ◽  
Janet Walker ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Fatty Acids ◽  
Candida Albicans ◽  
Isocitrate Lyase ◽  
Carbon Sources ◽  
Carbon Assimilation ◽  
Pathogenic Yeast ◽  
Content Type ◽  
Catabolite Inactivation ◽  
Accelerated Degradation

ABSTRACTMicrobes must assimilate carbon to grow and colonize their niches. Transcript profiling has suggested thatCandida albicans, a major pathogen of humans, regulates its carbon assimilation in an analogous fashion to the model yeastSaccharomyces cerevisiae, repressing metabolic pathways required for the use of alterative nonpreferred carbon sources when sugars are available. However, we show that there is significant dislocation between the proteome and transcriptome inC. albicans. Glucose triggers the degradation of theICL1andPCK1transcripts inC. albicans, yet isocitrate lyase (Icl1) and phosphoenolpyruvate carboxykinase (Pck1) are stable and are retained. Indeed, numerous enzymes required for the assimilation of carboxylic and fatty acids are not degraded in response to glucose. However, when expressed inC. albicans,S. cerevisiaeIcl1 (ScIcl1) is subjected to glucose-accelerated degradation, indicating that likeS. cerevisiae, this pathogen has the molecular apparatus required to execute ubiquitin-dependent catabolite inactivation.C. albicansIcl1 (CaIcl1) lacks analogous ubiquitination sites and is stable under these conditions, but the addition of a ubiquitination site programs glucose-accelerated degradation of CaIcl1. Also, catabolite inactivation is slowed inC. albicans ubi4cells. Ubiquitination sites are present in gluconeogenic and glyoxylate cycle enzymes fromS. cerevisiaebut absent from theirC. albicanshomologues. We conclude that evolutionary rewiring of ubiquitination targets has meant that following glucose exposure,C. albicansretains key metabolic functions, allowing it to continue to assimilate alternative carbon sources. This metabolic flexibility may be critical during infection, facilitating the rapid colonization of dynamic host niches containing complex arrays of nutrients.IMPORTANCEPathogenic microbes must assimilate a range of carbon sources to grow and colonize their hosts. Current views about carbon assimilation in the pathogenic yeastCandida albicansare strongly influenced by theSaccharomyces cerevisiaeparadigm in which cells faced with choices of nutrients first use energetically favorable sugars, degrading enzymes required for the assimilation of less favorable alternative carbon sources. We show that this is not the case inC. albicansbecause there has been significant evolutionary rewiring of the molecular signals that promote enzyme degradation in response to glucose. As a result, this major pathogen of humans retains enzymes required for the utilization of physiologically relevant carbon sources such as lactic acid and fatty acids, allowing it to continue to use these host nutrients even when glucose is available. This phenomenon probably enhances efficient colonization of host niches where sugars are only transiently available.

scholarly journals Delicate Metabolic Control and Coordinated Stress Response Critically Determine Antifungal Tolerance of Candida albicans Biofilm Persisters

2015 ◽  
Vol 59 (10) ◽  
pp. 6101-6112 ◽  
Author(s):  
Peng Li ◽  
Chaminda J. Seneviratne ◽  
Emanuele Alpi ◽  
Juan A. Vizcaino ◽  
Lijian Jin
Keyword(s):  
Candida Albicans ◽  
Stress Response ◽  
Metabolic Control ◽  
Isocitrate Lyase ◽  
Tricarboxylic Acid Cycle ◽  
Glyoxylate Cycle ◽  
Malate Synthase ◽  
Content Type ◽  
Liquid Chromatography Tandem Mass ◽  
Metabolic Activities

ABSTRACTCandidainfection has emerged as a critical health care burden worldwide, owing to the formation of robust biofilms against common antifungals. Recent evidence shows that multidrug-tolerant persisters critically account for biofilm recalcitrance, but their underlying biological mechanisms are poorly understood. Here, we first investigated the phenotypic characteristics ofCandidabiofilm persisters under consecutive harsh treatments of amphotericin B. The prolonged treatments effectively killed the majority of the cells of biofilms derived from representative strains ofCandida albicans,Candida glabrata, andCandida tropicalisbut failed to eradicate a small fraction of persisters. Next, we explored the tolerance mechanisms of the persisters through an investigation of the proteomic profiles ofC. albicansbiofilm persister fractions by liquid chromatography-tandem mass spectrometry. TheC. albicansbiofilm persisters displayed a specific proteomic signature, with an array of 205 differentially expressed proteins. The crucial enzymes involved in glycolysis, the tricarboxylic acid cycle, and protein synthesis were markedly downregulated, indicating that major metabolic activities are subdued in the persisters. It is noteworthy that certain metabolic pathways, such as the glyoxylate cycle, were able to be activated with significantly increased levels of isocitrate lyase and malate synthase. Moreover, a number of important proteins responsible forCandidagrowth, virulence, and the stress response were greatly upregulated. Interestingly, the persisters were tolerant to oxidative stress, despite highly induced intracellular superoxide. The current findings suggest that delicate metabolic control and a coordinated stress response may play a crucial role in mediating the survival and antifungal tolerance ofCandidabiofilm persisters.

scholarly journals The Glyoxylate Cycle Is Involved in White-Opaque Switching in Candida albicans

2021 ◽  
Vol 7 (7) ◽  
pp. 502
Author(s):  
Susana Hidalgo Vico ◽  
Daniel Prieto ◽  
Rebeca Alonso Monge ◽  
Elvira Román ◽  
Jesús Pla
Keyword(s):  
Transcription Factor ◽  
Candida Albicans ◽  
Gastrointestinal Tract ◽  
Isocitrate Lyase ◽  
Glyoxylate Cycle ◽  
Carbon Sources ◽  
Glyoxylate Shunt ◽  
Phenotypic Analysis ◽  
Altered Metabolism ◽  
The Glyoxylate Cycle

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.

scholarly journals Intracellular Acetyl Unit Transport in Fungal Carbon Metabolism

2010 ◽  
Vol 9 (12) ◽  
pp. 1809-1815 ◽  
Author(s):  
Karin Strijbis ◽  
Ben Distel
Keyword(s):  
Carbon Metabolism ◽  
Citrate Synthase ◽  
Current Knowledge ◽  
Glyoxylate Cycle ◽  
Carbon Sources ◽  
Fungal Species ◽  
Special Focus ◽  
Acetyl Coa ◽  
Content Type ◽  
Dependent Pathway

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.

scholarly journals Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

2012 ◽  
Vol 81 (1) ◽  
pp. 238-248 ◽  
Author(s):  
Iuliana V. Ene ◽  
Shih-Chin Cheng ◽  
Mihai G. Netea ◽  
Alistair J. P. Brown
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Immune System ◽  
Carbon Source ◽  
Immune Responses ◽  
Immune Cells ◽  
Carbon Sources ◽  
Innate Immune ◽  
Phagocytic Cells ◽  
Content Type

Candida albicansis a normal resident of the human gastrointestinal and urogenital tracts and also a prevalent fungal pathogen. During both commensalism and infection, it must match the immunological defenses of its host while adapting to environmental cues and the local nutrient status.C. albicansregularly colonizes glucose-poor niches, thereby depending upon alternative carbon sources for growth. However, most studies of host immune responses toC. albicanshave been performed on fungal cells grown on glucose, and the extent to which alternative physiologically relevant carbon sources impact innate immune responses has not been studied. The fungal cell wall is decorated with multifarious pathogen-associated molecular patterns and is the main target for recognition by host innate immune cells. Cell wall architecture is both robust and dynamic, and it is dramatically influenced by growth conditions. We found that growth ofC. albicanscells on lactate, a nonfermentative carbon source available in numerous anatomical niches, modulates their interactions with immune cells and the resultant cytokine profile. Notably, lactate-grownC. albicansstimulated interleukin-10 (IL-10) production while decreasing IL-17 levels, rendering these cells less visible to the immune system than were glucose-grown cells. This trend was observed in clinicalC. albicansisolates from different host niches and from different epidemiological clades. In addition, lactate-grownC. albicanscells were taken up by macrophages less efficiently, but they were more efficient at killing and escaping these phagocytic cells. Our data indicate that carbon source has a major impact upon theC. albicansinteraction with the innate immune system.

Determining a suitable carbon source for the production of intracellular pigments from Monascus purpureus HBSD 08

2019 ◽  
Vol 48 (6) ◽  
pp. 547-554
Author(s):  
Zeng Huawei ◽  
Wang Chengtao ◽  
Qiao Jie ◽  
Zhang Bingjing ◽  
Zhao Bing ◽  
...  
Keyword(s):  
Food Safety ◽  
Carbon Source ◽  
Sugar Content ◽  
Carbon Sources ◽  
Monascus Purpureus ◽  
High Food ◽  
Antitumor Activities ◽  
Content Type ◽  
High Yields

Purpose The Monascus pigment has been widely applied in the food processing industry as a functional additive. Lovastatin and polysaccharides are two important bio-active materials found in Monascus. Citrinin is considered as mycotoxin. Thus, it is important to produce high yields of intracellular Monascus pigments with high yields of lovastatin and polysaccharides, while maintaining low citrinin yields under liquid fermentation. Design/methodology/approach The intracellular yields of pigments, lovastatin, polysaccharides and citrinin; biomass; and reducing the sugar content of Monascus purpureus HBSD 08 were determined every day during a 10-day culturing period using lactose, maltose, sucrose, glucose, glycerine and xylose as the sole carbon sources. Additionally, the pigment composition was analysed by a thin layer chromatography (TLC) and the in vitro antitumor activities of the pigments were determined. Findings The maximal yield of pigments (55.44 U/mL after six days of culture) and lovastatin content (1,475.30 µg/L after five days of culture) were obtained in the presence of glucose and maltose as the sole carbon sources, respectively. The suitable carbon sources for high intracellular polysaccharides yields were sucrose, maltose and xylose. Glucose should not be chosen as the sole carbon source because of its high food safety risk. In vitro antitumor activities of pigments in the presence of different carbon sources were in the order of xylose > glucose = maltose > glycerine > sucrose = lactose. The pigment compositions in the presence of different carbon sources were the same from the TLC analysis. Thus, maltose displayed high intracellular yields of pigments, lovastatin and polysaccharides; high food safety against citrinin, and high in vitro antitumor activity during the ten days culturing period. Originality/value This study shows us the benefits of using maltose as a substrate in the production of intracellular Monascus pigments while ensuring economic and food safety.

scholarly journals Global Adaptation to a Lipid Environment Triggers the Dormancy-Related Phenotype of Mycobacterium tuberculosis

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Juan G. Rodríguez ◽  
Adriana C. Hernández ◽  
Cecilia Helguera-Repetto ◽  
Diana Aguilar Ayala ◽  
Rosalina Guadarrama-Medina ◽  
...  
Keyword(s):  
Energy Source ◽  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Glyoxylate Cycle ◽  
Carbon Sources ◽  
Suitable Condition ◽  
Content Type ◽  
Dormant Stage ◽  
Reductive Stress

ABSTRACT Strong evidence supports the idea that fatty acids rather than carbohydrates are the main energy source of Mycobacterium tuberculosis during infection and latency. Despite that important role, a complete scenario of the bacterium’s metabolism when lipids are the main energy source is still lacking. Here we report the development of an in vitro model to analyze adaptation of M. tuberculosis during assimilation of long-chain fatty acids as sole carbon sources. The global lipid transcriptome revealed a shift toward the glyoxylate cycle, the overexpression of main regulators whiB3, dosR, and Rv0081, and the increased expression of several genes related to reductive stress. Our evidence showed that lipid storage seems to be the selected mechanism used by M. tuberculosis to ameliorate the assumed damage of reductive stress and that concomitantly the bacilli acquired a slowed-growth and drug-tolerant phenotype, all characteristics previously associated with the dormant stage. Additionally, intergenic regions were also detected, including the unexpected upregulation of tRNAs that suggest a new role for these molecules in the acquisition of a drug-tolerant phenotype by dormant bacilli. Finally, a set of lipid signature genes for the adaptation process was also identified. This in vitro model represents a suitable condition to illustrate the participation of reductive stress in drugs’ activity against dormant bacilli, an aspect scarcely investigated to date. This approach provides a new perspective to the understanding of latent infection and suggests the participation of previously undetected molecules. IMPORTANCE Mycobacterium tuberculosis establishes long-lasting highly prevalent infection inside the human body, called latent tuberculosis. The known involvement of fatty acids is changing our understanding of that silent infection; however, question of how tubercle bacilli globally adapt to a lipid-enriched environment is still an unanswered. With the single change of providing fatty acids as carbon sources, the bacilli switch on their program related to dormant stage: slowed growth, accumulation of lipid bodies, and development of drug tolerance. In this stage, unexpected and previously unknown participants were found to play putatively important roles during the process. For the first time, this work compares the global transcriptomics of bacteria by using strand-specific RNA sequencing under two different growth conditions. This study suggests novel targets for the control of tuberculosis and provides a new straightforward in vitro model that could help to test the activity of drugs against dormant bacilli from a novel perspective.

Effect of carbon source on Phenobarbital metabolism by Rhizopus stolonifer

2010 ◽  
Vol 3 (2) ◽  
pp. 1022-1027
Author(s):  
Kavitha K ◽  
Asha S ◽  
Hima Bindu T.V.L ◽  
Vidyavathi M
Keyword(s):  
Carbon Source ◽  
High Performance ◽  
Carbon Sources ◽  
In Vitro Models ◽  
Rhizopus Stolonifer ◽  
Safety And Efficacy ◽  
Alternative Systems ◽  
Toxicological Studies ◽  
Microbial Model

The safety and efficacy of a drug is based on its metabolism or metabolite formed. The metabolism of drugs can be studied by different in vitro models, among which microbial model became popular. In the present study, eight microbes were screened for their ability to metabolize phenobarbital in a manner comparable to humans with a model to develop alternative systems to study human drug metabolism. Among the different microbes screened, a filamentous fungi Rhizopus stolonifer metabolized phenobarbital to its metabolite which is used for further pharmacological and toxicological studies. The transformation of phenobarbital was identified by high- performance liquid chromatography (HPLC). Interestingly, Rhizopus stolonifer sample showed an extra metabolite peak at 3.11min. compared to its controls. The influence of different carbon sources in media used for growth of fungus, on metabolite production was studied, to find its effect in production of metabolite as the carbon source may influence the growth of the cell.

scholarly journals In VitroAnalyses of the Effects of Heparin and Parabens on Candida albicans Biofilms and Planktonic Cells

2011 ◽  
Vol 56 (1) ◽  
pp. 148-153 ◽  
Author(s):  
Marisa H. Miceli ◽  
Stella M. Bernardo ◽  
T. S. Neil Ku ◽  
Carla Walraven ◽  
Samuel A. Lee
Keyword(s):  
Candida Albicans ◽  
Metabolic Activity ◽  
Biofilm Formation ◽  
High Dose ◽  
Dependent Manner ◽  
Planktonic Cells ◽  
Content Type ◽  
Heparin Sodium ◽  
The Individual

ABSTRACTInfections and thromboses are the most common complications associated with central venous catheters. Suggested strategies for prevention and management of these complications include the use of heparin-coated catheters, heparin locks, and antimicrobial lock therapy. However, the effects of heparin onCandida albicansbiofilms and planktonic cells have not been previously studied. Therefore, we sought to determine thein vitroeffect of a heparin sodium preparation (HP) on biofilms and planktonic cells ofC. albicans. Because HP contains two preservatives, methyl paraben (MP) and propyl paraben (PP), these compounds and heparin sodium without preservatives (Pure-H) were also tested individually. The metabolic activity of the mature biofilm after treatment was assessed using XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] reduction and microscopy. Pure-H, MP, and PP caused up to 75, 85, and 60% reductions of metabolic activity of the mature preformedC. albicansbiofilms, respectively. Maximal efficacy against the mature biofilm was observed with HP (up to 90%) compared to the individual compounds (P< 0.0001). Pure-H, MP, and PP each inhibitedC. albicansbiofilm formation up to 90%. A complete inhibition of biofilm formation was observed with HP at 5,000 U/ml and higher. When tested against planktonic cells, each compound inhibited growth in a dose-dependent manner. These data indicated that HP, MP, PP, and Pure-H havein vitroantifungal activity againstC. albicansmature biofilms, formation of biofilms, and planktonic cells. Investigation of high-dose heparin-based strategies (e.g., heparin locks) in combination with traditional antifungal agents for the treatment and/or prevention ofC. albicansbiofilms is warranted.

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