Influence of Mutations in Hexose‐Transporter Genes on Glucose Repression in <i>Kluyveromyces Lactis</i>

Weirich, Jorg; Goffrini, P; Kuger, P.; Ferrero, Iliana; Breunig, Karin D.

doi:10.1111/j.1432-1033.1997.t01-1-00248.x

Cited by 53 publications

(64 citation statements)

References 55 publications

(67 reference statements)

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“…This implies that the balance between respiration and fermentation in this yeast depends on oxygen availability and not on glucose concentration (Weirich et al, 1997;Kiers et al, 1998;González-Siso et al, 2000). The key point of the balance between respiration and fermentation is the branch point of pyruvate metabolism, with pyruvate being either oxidized by the respiratory enzyme pyruvate dehydrogenase (PDH) or decarboxylated by the fermentative enzyme pyruvate decarboxylase (PDC).…”

Section: Introductionmentioning

confidence: 99%

A dual signalling pathway for the hypoxic expression of lipid genes, dependent on the glucose sensor Rag4, is revealed by the analysis of the KlMGA2 gene in Kluyveromyces lactis

et al. 2012

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A dual signalling pathway for the hypoxic expression of lipid genes, dependent on the glucose sensor Rag4, is revealed by the analysis of the KlMGA2 gene in Kluyveromyces lactis In the respiratory yeast Kluyveromyces lactis, little is known about the factors regulating the metabolic response to oxygen shortage. After searching for homologues of characterized Saccharomyces cerevisiae regulators of the hypoxic response, we identified a gene that we named KlMGA2, which is homologous to MGA2. The deletion of KlMGA2 strongly reduced both the fermentative and respiratory growth rate and altered fatty acid composition and the unsaturation index of membranes. The reciprocal heterologous expression of MGA2 and KlMGA2 in the corresponding deletion mutant strains suggested that Mga2 and KlMga2 are functional homologues. KlMGA2 transcription was induced by hypoxia and the glucose sensor Rag4 mediated the hypoxic induction of KlMGA2. Transcription of lipid biosynthetic genes KlOLE1, KlERG1, KlFAS1 and KlATF1 was induced by hypoxia and was dependent on KlMga2, except for KlOLE1. Rag4 was required for hypoxic induction of transcription for both KlMga2-dependent (KlERG1) and KlMga2-independent (KlOLE1) structural genes.

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Section: Introductionmentioning

confidence: 99%

A dual signalling pathway for the hypoxic expression of lipid genes, dependent on the glucose sensor Rag4, is revealed by the analysis of the KlMGA2 gene in Kluyveromyces lactis

et al. 2012

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“…The mechanism of glucose signaling in glucose-repressible strains of the Crabtree-negative yeast Kluyveromyces lactis, used increasingly as a model organism in comparative functional genomics (10 -12), is largely unknown; however, the unique hexokinase KlHxk1 encoded by the RAG5 gene, the expression of glucose transporters, and the capacity for glucose transport seem to be involved (13)(14)(15).…”

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confidence: 99%

Crystal Structure of Hexokinase KlHxk1 of Kluyveromyces lactis

Kuettner

Kettner

Keim

et al. 2010

Journal of Biological Chemistry

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Crystal structures of the unique hexokinase KlHxk1 of the yeast Kluyveromyces lactis were determined using eight independent crystal forms. In five crystal forms, a symmetrical ringshaped homodimer was observed, corresponding to the physiological dimer existing in solution as shown by small-angle x-ray scattering. The dimer has a head-to-tail arrangement such that the small domain of one subunit interacts with the large domain of the other subunit. Dimer formation requires favorable interactions of the 15 N-terminal amino acids that are part of the large domain with amino acids of the small domain of the opposite subunit, respectively. The head-to-tail arrangement involving both domains of the two KlHxk1 subunits is appropriate to explain the reduced activity of the homodimer as compared with the monomeric enzyme and the influence of substrates and products on dimer formation and dissociation. In particular, the structure of the symmetrical KlHxk1 dimer serves to explain why phosphorylation of conserved residue Ser-15 may cause electrostatic repulsions with nearby negatively charged residues of the adjacent subunit, thereby inducing a dissociation of the homologous dimeric hexokinases KlHxk1 and ScHxk2. The enzymes of the hexokinase family catalyze the intracellular trapping and the initiation of metabolism of glucose, fructose, and mannose. In addition to their role in glycolysis, an increasing number of yeast, plant, and mammalian hexokinases have been found to represent multifunctional proteins that are implicated in glucose sensing and signaling (1-4), whereas their glycolytic sugar substrate plays a dual role as a carbon source and hormone-like regulator (4, 5). The molecular basis underlying the involvement of hexokinases in the transcriptional control of glucose metabolism and in glucose homeostasis is their ability to interact with mitochondria and to reversibly translocate to nuclei (3, 6 -9).In the Crabtree-positive yeast Saccharomyces cerevisiae, glucose abundance is accompanied by the translocation of the cytosolic hexokinase isoenzyme 2 (ScHxk2) 4 and the transcriptional repressor Mig1 (ScMig1) into the nucleus, where both proteins participate in the formation of a hetero-oligomeric complex that suppresses the transcription of ScMig1 target genes like SUC2 encoding invertase (9). The mechanism of glucose signaling in glucose-repressible strains of the Crabtree-negative yeast Kluyveromyces lactis, used increasingly as a model organism in comparative functional genomics (10 -12), is largely unknown; however, the unique hexokinase KlHxk1 encoded by the RAG5 gene, the expression of glucose transporters, and the capacity for glucose transport seem to be involved (13)(14)(15).Contrary to the situation in bakers' yeast, glucose and fructose limitation causes the translocation of the mammalian hexokinase isoenzyme IV (also referred to as "glucokinase" or hexokinase D) to the nucleus of the liver parenchymal cell where it binds to its regulatory protein, GKRP, and retranslocates when glucose is abundantly av...

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“…We propose that the upregulation of HXT7 observed in the HXT7-only strain, compared to the wild-type, is also due to relief of glucose repression resulting from reduced transport capacity and intracellular concentrations of glucose, and cannot be accounted for by alterations in glucose signalling that are independent of glucose metabolism (Liang and Gaber, 1996). A number of laboratories have found that wild-type levels of glucose transport capacity are required for normal glucose repression of various genes, including those involved in respiration, gluconeogenesis and utilization of alternative carbon sources such as sucrose and maltose (Gamo et al, 1994;Ö zcan et al, 1993;Reifenberger et al, 1997;Weirich et al, 1997;Ye et al, 1999). For example, the degree of glucose repression of maltase activity during growth on glucose plus maltose is correlated with the extent to which glucose transport capacity is reduced in HXT-only strains and the hxt1-hxt7 null strain.…”

Section: Glucose Repression and Glucose Transport Capacitymentioning

confidence: 99%

Expression and activity of the Hxt7 high‐affinity hexose transporter of Saccharomyces cerevisiae

Berden

Dam

et al. 2001

Yeast

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High-affinity hexose transport is required for efficient utilization of low hexose concentrations by the baker's yeast Saccharomyces cerevisiae. These low concentrations occur during the late exponential phase of batch growth on hexoses, during hexose-limited chemostat or fed-batch culture, or during growth on sugars such as sucrose and raffinose that are hydrolysed to hexoses outside the cell. The expression of the Hxt7 high-affinity glucose transporter of S. cerevisiae was examined during batch growth on glucose medium in a wild-type strain and a strain expressing only HXT7 (i.e. with null mutations in HXT1-HXT6). In the wild-type strain, HXT7 transcription was repressed at high glucose and was detected when the glucose in the culture approached depletion. In the HXT7-only strain, transcription of HXT7 was constitutive throughout the glucose growth phase and was increased further at low glucose concentrations. After glucose depletion, the levels of HXT7 mRNA declined rapidly in both strains. In contrast, the Hxt7 protein was relatively stable after glucose depletion. By monitoring the subcellular localization of an Hxt7::GFP fusion protein it was observed that Hxt7 was localized in the plasma membrane, even when expressed at high glucose concentrations in the HXT7-only strain. After glucose depletion Hxt7 was gradually endocytosed and targeted to the vacuole for degradation. The Hxt7::GFP fusion protein was a fully functional hexose transporter with a catalytic centre activity of approximately 200/sec. It is concluded that repression of HXT7 and degradation of Hxt7 at high glucose concentrations is dependent on a high glucose transport capacity.

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Influence of Mutations in Hexose‐Transporter Genes on Glucose Repression in Kluyveromyces Lactis

Cited by 53 publications

References 55 publications

A dual signalling pathway for the hypoxic expression of lipid genes, dependent on the glucose sensor Rag4, is revealed by the analysis of the KlMGA2 gene in Kluyveromyces lactis

A dual signalling pathway for the hypoxic expression of lipid genes, dependent on the glucose sensor Rag4, is revealed by the analysis of the KlMGA2 gene in Kluyveromyces lactis

Crystal Structure of Hexokinase KlHxk1 of Kluyveromyces lactis

Expression and activity of the Hxt7 high‐affinity hexose transporter of Saccharomyces cerevisiae

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