Nikkomycin Z supersensitivity of an echinocandin-resistant mutant of Saccharomyces cerevisiae

El-Sherbeini, Mohamed; Clemas, Joseph

doi:10.1128/aac.39.1.200

Cited by 45 publications

(44 citation statements)

References 57 publications

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“…We have previously shown that FKS1 is likely to encode a subunit of 1,3-␤-D-glucan synthase (18). This conclusion was based primarily on the observation that certain mutations in FKS1 result in whole-cell resistance to the glucan synthase inhibitor L-733,560, a member of the echinocandin class of antifungal agents (45,72), as well as in glucan synthase activity which is resistant to L-733,560 in vitro (19,20). The high degree of similarity between Fks2p and Fks1p indicates that Fks2p is also likely to be a subunit of this enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…1,3-␤-D-Glucan synthase (UDP-glucose:1,3-␤-D-glucan 3-␤-D-glucosyltransferase; EC 2.4.1.34) is a membrane enzyme activated by GTP which has been fractionated into soluble (GTP-binding) and membrane-bound (catalytic) components (39, 53). Members of the echinocandin family of antifungal agents inhibit 1,3-␤-D-glucan synthase and have been used to isolate mutations in the FKS1 gene, which encodes a subunit of this enzyme (18)(19)(20). The resistance mutations result in echinocandin-resistant enzyme activity which is associated with the membrane fraction (19).…”

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confidence: 99%

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Differential Expression and Function of Two Homologous Subunits of Yeast 1,3-β-D-Glucan Synthase

Mazur

Morin

Baginsky

et al. 1995

Molecular and Cellular Biology

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395

461

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1,3-␤-D-Glucan is a major structural polymer of yeast and fungal cell walls and is synthesized from UDP-glucose by the multisubunit enzyme 1,3-␤-D-glucan synthase. Previous work has shown that the FKS1 gene encodes a 215-kDa integral membrane protein (Fks1p) which mediates sensitivity to the echinocandin class of antifungal glucan synthase inhibitors and is a subunit of this enzyme. We have cloned and sequenced FKS2, a homolog of FKS1 encoding a 217-kDa integral membrane protein (Fks2p) which is 88% identical to Fks1p. The residual glucan synthase activity present in strains with deletions of fks1 is (i) immunodepleted by antibodies prepared against FKS2 peptides, demonstrating that Fks2p is also a component of the enzyme, and (ii) more sensitive to the echinocandin L-733,560, explaining the increased sensitivity of fks1 null mutants to this drug. Simultaneous disruption of FKS1 and FKS2 is lethal, suggesting that Fks1p and Fks2p are alternative subunits with essential overlapping function. Analysis of FKS1 and FKS2 expression reveals that transcription of FKS1 is regulated in the cell cycle and predominates during growth on glucose, while FKS2 is expressed in the absence of glucose. FKS2 is essential for sporulation, a process which occurs during nutritional starvation. FKS2 is induced by the addition of Ca 2؉ to the growth medium, and this induction is completely dependent on the Ca 2؉ /calmodulin-dependent phosphoprotein phosphatase calcineurin. We have previously shown that growth of fks1 null mutants is highly sensitive to the calcineurin inhibitors FK506 and cyclosporin A. Expression of FKS2 from the heterologous ADH1 promoter results in FK506-resistant growth. Thus, the sensitivity of fks1 mutants to these drugs can be explained by the calcineurin-dependent transcription of FKS2. Moreover, FKS2 is also highly induced in response to pheromone in a calcineurin-dependent manner, suggesting that FKS2 may also play a role in the remodeling of the cell wall during the mating process.The cell wall of Saccharomyces cerevisiae is essential for the integrity and shape of the cell and is a highly dynamic structure the composition and architecture of which vary widely depending upon the composition of the growth medium and the stage of the cell cycle (41). In addition, when haploid cells encounter pheromone of the opposite mating type, the cells transiently arrest in the G 1 phase of the cell cycle and develop an elongated projection requiring new cell wall synthesis (12). Furthermore, diploid cells which are nutritionally starved undergo meiosis and sporulation, a process requiring the formation of new cell wall around the developing spores (reviewed in reference 42).An important component of each of these cell wall types is the glucose polymer 1,3-␤-D-glucan (10, 38, 41). 1,3-␤-D-Glucan synthase (UDP-glucose:1,3-␤-D-glucan 3-␤-D-glucosyltransferase; EC 2.4.1.34) is a membrane enzyme activated by GTP which has been fractionated into soluble (GTP-binding) and membrane-bound (catalytic) components (39, 53). Members of...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Differential Expression and Function of Two Homologous Subunits of Yeast 1,3-β-D-Glucan Synthase

Mazur

Morin

Baginsky

et al. 1995

Molecular and Cellular Biology

Self Cite

395

461

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“…The link between FKS1 and the cell wall was established by the finding that ETG1 and PBR1 (whose mutants are resistant to ␤-1,3-GS inhibitors), CWH53 (required for resistance to calcofluor white), and CND1 (with mutant alleles requiring a functional calcineurin pathway) are all identical to FKS1 (44,76,80,91,231). FKS1 mutants show decreased ␤-1,3-GS activity, while Fks1 cofractionates with GS activity, implicating Fks1 as a ␤-1,3-GS catalytic subunit (76,119).…”

Section: ␤-13-glucanmentioning

confidence: 99%

Cell Wall Assembly in Saccharomyces cerevisiae

Lesage

Bussey

2006

Microbiol Mol Biol Rev

719

749

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SUMMARY An extracellular matrix composed of a layered meshwork of β-glucans, chitin, and mannoproteins encapsulates cells of the yeast Saccharomyces cerevisiae. This organelle determines cellular morphology and plays a critical role in maintaining cell integrity during cell growth and division, under stress conditions, upon cell fusion in mating, and in the durable ascospore cell wall. Here we assess recent progress in understanding the molecular biology and biochemistry of cell wall synthesis and its remodeling in S. cerevisiae. We then review the regulatory dynamics of cell wall assembly, an area where functional genomics offers new insights into the integration of cell wall growth and morphogenesis with a polarized secretory system that is under cell cycle and cell type program controls.

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“…The hyperaccumulation of chitin in response to cell wall stress is not limited to S. cerevisiae and is also found in other yeasts such as Kluyveromyces lactis (Uccelletti et al, 2000) and Candida albicans (Kapteyn et al, 2000). Inability of the cells to respond to cell wall damage by increasing chitin levels, either by disrupting the major chitin synthaseencoding gene (ScChs3p) or by adding the chitin synthase inhibitor nikkomycin Z, results in cell lysis, indicating the importance of the chitin response to prevent cell death (Douglas et al, 1994;el-Sherbeini & Clemas, 1995;Popolo et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

The cell wall stress response in Aspergillus niger involves increased expression of the glutamine : fructose-6-phosphate amidotransferase-encoding gene (gfaA) and increased deposition of chitin in the cell wall

Ram

2004

Microbiology

120

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Perturbation of cell wall synthesis in Saccharomyces cerevisiae, either by mutations in cell wall synthesis-related genes or by adding compounds that interfere with normal cell wall assembly, triggers a compensatory response to ensure cell wall integrity. This response includes an increase in chitin levels in the cell wall. Here it is shown that Aspergillus niger also responds to cell wall stress by increasing chitin levels. The increased chitin level in the cell wall was accompanied by increased transcription of gfaA, encoding the glutamine : fructose-6-phosphate amidotransferase enzyme, which is responsible for the first and a rate-limiting step in chitin synthesis. Cloning and disruption of the gfaA gene in A. niger showed that it was an essential gene, but that addition of glucosamine to the growth medium could rescue the deletion strain. When the plant-pathogenic fungus Fusarium oxysporum and food spoilage fungus Penicillium chrysogenum were subjected to cell wall stress, the transcript level of their gfa gene increased as well. These observations suggest that cell wall stress in fungi may generally lead to activation of the chitin biosynthetic pathway.

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Nikkomycin Z supersensitivity of an echinocandin-resistant mutant of Saccharomyces cerevisiae

Cited by 45 publications

References 57 publications

Differential Expression and Function of Two Homologous Subunits of Yeast 1,3-β-D-Glucan Synthase

Differential Expression and Function of Two Homologous Subunits of Yeast 1,3-β-D-Glucan Synthase

Cell Wall Assembly in Saccharomyces cerevisiae

The cell wall stress response in Aspergillus niger involves increased expression of the glutamine : fructose-6-phosphate amidotransferase-encoding gene (gfaA) and increased deposition of chitin in the cell wall

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