Phosphorylation of glucosamine-6-phosphate synthase is important but not essential for germination and mycelial growth of Candida albicans

Gabriel, Iwona; Olchowy, Jarosław; Stanisławska-Sachadyn, Anna; Mio, Toshiyuki; Kur, Józef; Milewski, Sławomir

doi:10.1016/j.femsle.2004.04.013

Cited by 5 publications

(3 citation statements)

References 39 publications

(59 reference statements)

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“…Many of the other differentially expressed transcripts identified in the current studies have been identified in prior array analysis of fluconazole-resistant C. albicans strains (6,11,22,37). Among the most highly expressed were those related to cell and plasma membrane maintenance (TAT2, YAH1, RTA1, GFA1, SGE1, and SUR2) (14,18,20,31,44,45). The expression of these genes may implicate cell membrane changes contributing to resistance or may simply represent a response to cell-damaging conditions.…”

Section: Discussionmentioning

confidence: 73%

In Vivo Fluconazole Pharmacodynamics and Resistance Development in a Previously SusceptibleCandida albicansPopulation Examined by Microbiologic and Transcriptional Profiling

Andes

Lepak

Nett

et al. 2006

Antimicrob Agents Chemother

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Antimicrobial drug resistance can limit the ability to effectively treat patients. Numerous factors have been proposed to impact the development of antimicrobial resistance, including those specific to the drug and the dosing regimen. The field of investigation that examines the relationship between dosing regimen and outcome is termed antimicrobial pharmacokinetics and pharmacodynamics. Our prior in vivo investigations examined the relationship between fluconazole pharmacodynamics and the modulation of isogenic resistant and susceptible Candida albicans populations in a mixed-inoculum design (1). The goal of the current studies was to examine the impact of fluconazole pharmacodynamics on resistance emergence from a susceptible parent population over time using a murine systemic-candidiasis model. Both microbiologic and transcriptional endpoints were examined during the evolution of cell populations. As in our previous investigation, the more frequently administered dosing regimen prevented the emergence of a resistant cell phenotype. Conversely, dosing regimens that produced prolonged sub-MIC concentrations were associated with resistance development. The studies also demonstrated a striking relationship between fluconazole pharmacodynamic exposures and the mRNA abundance of drug resistance-associated efflux pumps. Global transcriptional profiling of cell populations during the progressive emergence of a resistance phenotype provides insight into the mechanisms underlying this complex physiologic process.Antimicrobial resistance has become an increasingly serious public health problem in a wide range of infectious diseases (5,15,24,26,34,42,47,48). Thus, it is imperative to understand the factors that lead to the evolution of resistance and to design strategies to prevent or delay the emergence of antimicrobial-resistant pathogens.It is well accepted that antimicrobial exposure is correlated with the prevalence of antimicrobial resistance (7,8,13,16,17,19,21). However, the relationship in the context of use pattern and resistance development is complex and remains for the most part undefined. A recent study examined these relationships for the fungistatic triazole antifungal fluconazole in an in vivo candidiasis model (1). The experimental model utilized isogenic strain pairs of Candida albicans in which the parent population was fluconazole susceptible and the other isolate was drug resistant. The treatment studies examined modulation of the resistant and susceptible cell populations from an initial inoculum consisting of a small percentage of the less susceptible group of cells. Study of the relationship between fluconazole pharmacokinetics and amplification of each cell population was undertaken with six strain pairs. Fluconazole dosing regimens producing prolonged sub-MIC exposures or a brief period of time in which drug concentrations exceeded the MIC (%T Ͼ MIC) resulted in the selection of resistant cells in each of the experiments.The current studies further examined the relationship between the dose lev...

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Section: Discussionmentioning

confidence: 73%

In Vivo Fluconazole Pharmacodynamics and Resistance Development in a Previously SusceptibleCandida albicansPopulation Examined by Microbiologic and Transcriptional Profiling

Andes

Lepak

Nett

et al. 2006

Antimicrob Agents Chemother

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“…This process provides building blocks for de novo chitin synthesis and glycosylation of secreted proteins bypassing the need to re-synthesise GlcNAc-6P from fructose-6P by means of the first two enzymes of UDP-GlcNAc biosynthesis, GlcN-6P synthase (EC 2.6.1.16) and GlcN-6P acetyltransferase (EC 2.3.1.4) (note: these enzymes catalyse the reverse reactions of DAM1 and DAC1 respectively). Indeed, diploid C. albicans strains, homozygote for GlcN-6P synthase deletion could not grow unless the growth medium contained GlcNAc (Gabriel et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The N‐acetylglucosamine catabolic gene cluster in Trichoderma reesei is controlled by the Ndt80‐like transcription factor RON1

Kappel

Gaderer

Flipphi

et al. 2015

Molecular Microbiology

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SummaryChitin is an important structural constituent of fungal cell walls composed of N‐acetylglucosamine (GlcNAc) monosaccharides, but catabolism of GlcNAc has not been studied in filamentous fungi so far. In the yeast C andida albicans, the genes encoding the three enzymes responsible for stepwise conversion of GlcNAc to fructose‐6‐phosphate are clustered. In this work, we analysed GlcNAc catabolism in ascomycete filamentous fungi and found that the respective genes are also clustered in these fungi. In contrast to C . albicans, the cluster often contains a gene for an Ndt80‐like transcription factor, which we named RON1 (regulator of N‐acetylglucosamine catabolism 1). Further, a gene for a glycoside hydrolase 3 protein related to bacterial N‐acetylglucosaminidases can be found in the GlcNAc gene cluster in filamentous fungi. Functional analysis in T richoderma reesei showed that the transcription factor RON1 is a key activator of the GlcNAc gene cluster and essential for GlcNAc catabolism. Furthermore, we present an evolutionary analysis of Ndt80‐like proteins in Ascomycota. All GlcNAc cluster genes, as well as the GlcNAc transporter gene ngt1, and an additional transcriptional regulator gene, csp2, encoding the homolog of N eurospora crassa CSP2/GRHL, were functionally characterised by gene expression analysis and phenotypic characterisation of knockout strains in T . reesei.

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“…Hsp21 contributes to the formation of filaments 38 , but homozygous deletion mutants are not fully blocked in the yeast to filament transition implicating additional factors. Analysis of our Ydj1 interactors highlighted several positive regulators of filamentation in response to serum: Gfa1 42 , Cdc48, Tbp1 and Mas1 43 . However, these proteins are essential for C. albicans growth, thus it is important to distinguish specific functions in filamentation from confounding effects on viability.…”

Section: Resultsmentioning

confidence: 99%

Ydj1 governs fungal morphogenesis and stress response, and facilitates mitochondrial protein import via Mas1 and Mas2

et al. 2017

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Mitochondria underpin metabolism, bioenergetics, signalling, development and cell death in eukaryotes. Most of the ~1,000 yeast mitochondrial proteins are encoded in the nucleus and synthesised as precursors in the cytosol, with mitochondrial import facilitated by molecular chaperones. Here, we focus on the Hsp40 chaperone Ydj1 in the fungal pathogen Candida albicans, finding that it is localised to both the cytosol and outer mitochondrial membrane, and is required for cellular stress responses and for filamentation, a key virulence trait. Mapping the Ydj1 protein interaction network highlighted connections with co-chaperones and regulators of filamentation. Furthermore, the mitochondrial processing peptidases Mas1 and Mas2 were highly enriched for interaction with Ydj1. Additional analysis demonstrated that loss of MAS1, MAS2 or YDJ1 perturbs mitochondrial morphology and function. Deletion of YDJ1 impairs import of Su9, a protein that is cleaved to a mature form by Mas1 and Mas2. Thus, we highlight a novel role for Ydj1 in cellular morphogenesis, stress responses, and mitochondrial import in the fungal kingdom.

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Phosphorylation of glucosamine-6-phosphate synthase is important but not essential for germination and mycelial growth of Candida albicans

Cited by 5 publications

References 39 publications

In Vivo Fluconazole Pharmacodynamics and Resistance Development in a Previously SusceptibleCandida albicansPopulation Examined by Microbiologic and Transcriptional Profiling

In Vivo Fluconazole Pharmacodynamics and Resistance Development in a Previously SusceptibleCandida albicansPopulation Examined by Microbiologic and Transcriptional Profiling

The N‐acetylglucosamine catabolic gene cluster in Trichoderma reesei is controlled by the Ndt80‐like transcription factor RON1

Ydj1 governs fungal morphogenesis and stress response, and facilitates mitochondrial protein import via Mas1 and Mas2

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