Physiological Implications of Sterol Biosynthesis in Yeast

Parks, Leo W.; Casey, Warren

doi:10.1146/annurev.mi.49.100195.000523

Cited by 302 publications

(170 citation statements)

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“…The requirement for a functional mitochondrion in ergosterol biosynthesis is well characterised and arises from the provision of NADPH for squalene dimerisation (Parks & Casey, 1995). In addition, Erg1 encodes squalene epoxidase, which converts squalene to 2,3-oxidosqualene.…”

Section: Discussionmentioning

confidence: 99%

Metal complexes of 1,10-phenanthroline-5,6-dione alter the susceptibility of the yeast Candida albicans to Amphotericin B and Miconazole

Eshwika

Coyle

Devereux³

et al. 2004

Biometals

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Growth of the pathogenic yeast Candida albicans in sub-MIC (minimum inhibitory concentration) levels of Cu(ClO 4 ) 2 · 6H 2 O and [Cu(phendio) 3 ](ClO 4 ) 2 · 4H 2 O (phendio = 1,10-phenanthroline-5,6-dione) increased the concentration of miconazole and amphotericin B required to achieve the MIC 90 whereas pre-growth in AgClO 4 and [Ag(phendio) 2 ]ClO 4 resulted in a small decrease in the relevant MIC 90 values. The copper complexes reduce the oxygen consumption of C. albicans while the silver complexes increase oxygen consumption. In addition, pregrowth of cells in the copper complexes resulted in a lower ergosterol content while the silver complexes induced an elevation in ergosterol synthesis.The ability of copper and silver complexes to alter the susceptibility of C. albicans to miconazole and amphotericin B may be influenced by their action on respiration, since reduced respiration rates correlate with reduced cellular ergosterol which is the target for amphotericin B. Lower levels of ergosterol have previously been associated with elevated tolerance to this drug. In the case of reduced sensitivity to miconazole, tolerance may be mediated by lower ergosterol synthesis giving rise to fewer toxic side products once biosynthesis is inhibited by miconazole.Abbreviations: phendio = 1,10-phenanthroline-5,6-dione. phen = 1,10-phenanthroline

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Section: Discussionmentioning

confidence: 99%

Metal complexes of 1,10-phenanthroline-5,6-dione alter the susceptibility of the yeast Candida albicans to Amphotericin B and Miconazole

Eshwika

Coyle

Devereux³

et al. 2004

Biometals

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“…The physiological significance of this phenomenon, termed aerobic sterol exclusion, is poorly understood (Lewis et al, 1985). It may be a way for cells to ensure that only the best fitting sterols accumulate in its membranes (Parks and Casey, 1995). In contrast, under anaerobic conditions, when sterol biosynthesis is compromised, cells become capable of importing sterols whose presence in the medium is then required for growth.…”

mentioning

confidence: 99%

The Cdc42 Effectors Ste20, Cla4, and Skm1 Down-Regulate the Expression of Genes Involved in Sterol Uptake by a Mitogen-activated Protein Kinase-independent Pathway

Lin

Unden

Jacquier

et al. 2009

MBoC

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In Saccharomyces cerevisiae, the Rho-type GTPase Cdc42 regulates polarized growth through its effectors, including the p21-activated kinases (PAKs) Ste20, Cla4, and Skm1. Previously, we demonstrated that Ste20 interacts with several proteins involved in sterol synthesis that are crucial for cell polarization. Under anaerobic conditions, sterols cannot be synthesized and need to be imported into cells. Here, we show that Ste20, Cla4, and Skm1 form a complex with Sut1, a transcriptional regulator that promotes sterol uptake. All three PAKs can translocate into the nucleus and down-regulate the expression of genes involved in sterol uptake, including the Sut1 targets AUS1 and DAN1 by a novel mechanism. Consistently, deletion of either STE20, CLA4, or SKM1 results in an increased sterol influx and PAK overexpression inhibits sterol uptake. For Ste20, we demonstrate that the down-regulation of gene expression requires nuclear localization and kinase activity of Ste20. Furthermore, the Ste20-mediated control of expression of sterol uptake genes depends on SUT1 but is independent of a mitogen-activated protein kinase signaling cascade. Together, these observations suggest that PAKs translocate into the nucleus, where they modulate expression of sterol uptake genes via Sut1, thereby controlling sterol homeostasis. INTRODUCTIONThe small Rho GTPase Cdc42 plays a central role in the regulation of cellular polarity in eukaryotic cells (EtienneManneville, 2004;Jaffe and Hall, 2005). In the budding yeast Saccharomyces cerevisiae, Cdc42 regulates different types of polarized growth during various phases of its life cycle, including budding during vegetative growth, mating between haploid cells of opposite mating types, and filamentous growth upon nutrient limitation (Park and Bi, 2007). Cdc42 promotes polarized growth through multiple pathways, including polarization of the actin cytoskeleton and directed vesicle trafficking. Among the Cdc42 effectors that trigger these pathways are Ste20, Cla4 and Skm1, members of the p21-activated kinase (PAK) family of serine/threonine protein kinases (Hofmann et al., 2004;Park and Bi, 2007).Cdc42 recruits Ste20 and Cla4 from the cytoplasm and activates them at the plasma membrane at sites of polarized growth. Therefore, Ste20 and Cla4 are enriched at tips of buds and mating projections (Peter et al., 1996;Leberer et al., 1997;Holly and Blumer, 1999). The recruitment of Ste20 and Cla4 to these sites is governed by protein-protein as well as protein-lipid interactions. PAKs carry a conserved Cdc42/ Rac-interactive binding (CRIB) domain that mediates binding to Cdc42 and regulates their activity (Cvrckova et al., 1995;Peter et al., 1996;Leberer et al., 1997;Lamson et al., 2002;Ash et al., 2003). Ste20 and Cla4 also bind to Bem1, a scaffold protein that brings Cdc42, its activator Cdc24 and either Ste20 or Cla4, into proximity (Leeuw et al., 1998;Gulli et al., 2000;Bose et al., 2001;Yamaguchi et al., 2007). In addition, phosphoinositide-binding domains promote the association with membrane lip...

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“…In Sac. cerevisiae, homocysteine has been reported to interfere with ergosterol biosynthesis (Hatanaka et al, 1974;Parks & Casey, 1995). The methionine biosynthetic pathway is linked indirectly to purine biosynthesis via metabolism of folic acid (Fig.…”

Section: Discussionmentioning

confidence: 99%

Homocysteine accumulation causes a defect in purine biosynthesis: further characterization of Schizosaccharomyces pombe methionine auxotrophs

et al. 2006

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Methionine synthase (EC2.1.1.14) catalyses the final step in methionine synthesis, i.e. methylation of homocysteine. A search of the Schizosaccharomyces pombe genomic database revealed a gene designated SPAC9.09, encoding a protein with significant homology to methionine synthase. Disruption of SPAC9.09 caused methionine auxotrophy, and thus the gene was identified as a methionine synthase and designated met26. The met26 mutant was found to exhibit a remarkable growth defect in the absence of adenine even in medium supplemented with methionine. This phenotype was not observed in other methionine auxotrophs. In the budding yeast Saccharomyces cerevisiae, which has been reported to utilize homocysteine in cysteine synthesis, lack of a functional methionine synthase did not cause a requirement for adenine. The introduction of genes from Sac. cerevisiae constituting the cystathionine pathway (CYS4 and CYS3) into Sch. pombe Δmet26 cells restored growth in the absence of adenine. HPLC analysis showed that total homocysteine content in Δmet26 cells was higher than in other methionine auxotrophs and that introduction of the Sac. cerevisiae cystathionine pathway decreased total homocysteine levels. These data demonstrate that accumulation of homocysteine causes a defect in purine biosynthesis in the met26 mutant.

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Physiological Implications of Sterol Biosynthesis in Yeast

Cited by 302 publications

References 31 publications

Metal complexes of 1,10-phenanthroline-5,6-dione alter the susceptibility of the yeast Candida albicans to Amphotericin B and Miconazole

Metal complexes of 1,10-phenanthroline-5,6-dione alter the susceptibility of the yeast Candida albicans to Amphotericin B and Miconazole

The Cdc42 Effectors Ste20, Cla4, and Skm1 Down-Regulate the Expression of Genes Involved in Sterol Uptake by a Mitogen-activated Protein Kinase-independent Pathway

Homocysteine accumulation causes a defect in purine biosynthesis: further characterization of Schizosaccharomyces pombe methionine auxotrophs

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