Regulation of Genes Controlling Synthesis of the Galactose Pathway Enzymes in Yeast

Douglas, H. C.; Hawthorne, Donald C.

doi:10.1093/genetics/54.3.911

Cited by 215 publications

(34 citation statements)

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“…Sc99 was a gift of ROGERS YOCUM, Sc258R10 was a gift OfJACQUELINE BROMBERG, and Sc272 was a gift of KUNIHIRO MATSUMOTO. Sc99 was isolated as a Gal+ revertant of a p-GAL4 GAL80 gal3 strain (for details, see DOUGLAS and HAWTHORNE 1966). Sc252 was isolated as a Gal+ revertant of a GAL4 GAL80S"" strain (JOHNSTON and HOPPER 1982).…”

Section: Methodsmentioning

confidence: 99%

“…T HE GAL4 gene of Saccharomyces cerevisiae encodes a protein that activates transcription of galactose and melibiose catabolic enzyme genes (DOUGLAS and HAWTHORNE 1966;JOHNSTON and HOPPER 1982;LAUGHON and GESTELAND 1982;HASHIMOTO et al 1983). Activation is achieved primarily through two functions of the GAL4 protein; an amino-terminal DNA binding function which positions GAL4 upstream of regulated structural genes (GUARENTE, YOCUM and GIFFORD 1982;JOHNSTON and DAVIS 1984;WEST, YOCUM and PTASHNE 1984;BRAM and KORNBERG 1985;GI-NIGER, VARNUM and PTASHNE 1985;BRAM, LUE and KORNBERG 1986;KEEGAN, GILL and PTASHNE 1986), and a carboxy-terminal "activation" function which interacts with cellular transcription factors (BRENT and PTASHNE 1985;JOHNSTON et al 1986; JOHNSTON, SALMERON and DINCHER 1987;MA and PTASHNE 1987a).…”

mentioning

confidence: 99%

“…Activation is achieved primarily through two functions of the GAL4 protein; an amino-terminal DNA binding function which positions GAL4 upstream of regulated structural genes (GUARENTE, YOCUM and GIFFORD 1982;JOHNSTON and DAVIS 1984;WEST, YOCUM and PTASHNE 1984;BRAM and KORNBERG 1985;GI-NIGER, VARNUM and PTASHNE 1985;BRAM, LUE and KORNBERG 1986;KEEGAN, GILL and PTASHNE 1986), and a carboxy-terminal "activation" function which interacts with cellular transcription factors (BRENT and PTASHNE 1985;JOHNSTON et al 1986; JOHNSTON, SALMERON and DINCHER 1987;MA and PTASHNE 1987a). Expression of the wild-type galactose/melibiose regulon is not constitutive, due to the activity of the negative regulatory gene GAL80 (DOUGLAS and HAWTHORNE 1966;NOGI et al 1984;YOCUM and JOHNSTON 1984). In the absence of the regulon inducer (galactose or a metabolite thereof), the GAL4 protein binds target DNA sequences but does not activate transcription, due to the binding of the GAL80-encoded protein to GAL4 (JOHNSTON and HOPPER 1982;GINIGER, VARNUM and PTASHNE 1985;SELLECK and MAJORS 1987;LUE et al 1987;MA and PTASHNE (1988).…”

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confidence: 99%

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GAL4 mutations that separate the transcriptional activation and GAL80-interactive functions of the yeast GAL4 protein.

Salmeron¹,

Leuther²,

Johnston³

1990

Genetics

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The carboxy-terminal 28 amino acids of the Saccharomyces cerevisiae transcriptional activator protein GAL4 execute two functions--transcriptional activation and interaction with the negative regulatory protein, GAL80. Here we demonstrate that these two functions are separable by single amino acid changes within this region. We determined the sequences of four GAL4C-mutations, and characterized the abilities of the encoded GAL4C proteins to activate transcription of the galactose/melibiose regulon in the presence of GAL80 and superrepressible GAL80S alleles. One of the GAL4C mutations can be compensated by a specific GAL80S mutation, resulting in a wild-type phenotype. These results support the idea that while the GAL4 activation function tolerates at least minor alterations in the GAL4 carboxyl terminus, the GAL80-interactive function is highly sequence-specific and sensitive even to single amino acid alterations. They also argue that the GAL80S mutations affect the affinity of GAL80 for GAL4, and not the ability of GAL80 to bind inducer.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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GAL4 mutations that separate the transcriptional activation and GAL80-interactive functions of the yeast GAL4 protein.

Salmeron¹,

Leuther²,

Johnston³

1990

Genetics

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“…6,[14][15][16] Second, although a ga17-deleted (i.e., GALT-deficient) yeast stops growing upon addition of galactose to the growth medium, a ga17 ga11 double knockout strain deficient in both GALT and GALK enzyme activities is no longer sensitive to galactose and grows well. 17,18 Third, our laboratory recently demonstrated that galactose challenge to isogenic GALTdeficient (but not GALK-deficient) yeast led to overt manifestation of environmental stress response (ESR). 19 All these studies indicate that gal-1-p is the major, if not sole, culprit for the galactose toxicity observed in GALT-deficient cells.…”

Section: Introductionmentioning

confidence: 99%

High-Throughput Screening for Human Galactokinase Inhibitors

et al. 2008

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Inherited deficiency of galactose-1-phosphate uridyltransferase (GALT) can result in a potentially lethal disorder called classic galactosemia. Although the neonatal lethality associated with this disease can be prevented through early diagnosis and a galactoserestricted diet, the lack of effective therapy continues to have consequences: developmental delay, neurological disorders, and premature ovarian failure are common sequelae in childhood and adulthood. Several lines of evidence indicate that an elevated level of galactose-1-phosphate (gal-1-p), the product of galactokinase (GALK), is a major, if not sole, pathogenic mechanism in patients with classic galactosemia. The authors hypothesize that elimination of gal-1-p production by inhibiting GALK will relieve GALT-deficient cells from galactose toxicity. To test this hypothesis, they obtained human GALK using a bacterial expression system. They developed a robust, miniaturized, high-throughput GALK assay (Z′ factor = 0.91) and used this assay to screen against libraries composed of 50,000 chemical compounds with diverse structural scaffolds. They selected 150 compounds that, at an average concentration of 33.3 μM, inhibited GALK activity in vitro more than 86.5% and with a reproducibility score of at least 0.7 for a confirmatory screen under identical experimental conditions. Of these 150 compounds, 34 were chosen for further characterization. Preliminary results indicated that these 34 compounds have potential to serve as leads to the development of more effective therapy of classic galactosemia. (Journal of Biomolecular Screening 2008:415-423)

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“…It is historically interesting that PONTECORVO (1950) in his early studies of Aspergillus postulated clusters of functionally related genes, but that no cases of clearly functionally distinct groupings were found (ROPER 1960;PONTECORVO 1952). Although such clusters are now well known in bacteria (DEMEREC 1964), they have been clearly demonstrated in eucaryotic microorganisms only in the above-cited studies of histidine biosynthesis in Neurospora and yeast and in studies of aromatic synthesis in Neurospora (GROSS and FEIN 1960;GILES 1965;GILES, CASE and PARTRIDGE 1965) and the galactose pathway in yeast (DOUGLAS and HAWTHORNE 1966). It is important to determine if this type of organization is widespread and can be observed in other organisms as well.…”

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confidence: 99%

GENE-ENZYME RELATIONSHIPS IN HISTIDINE BIOSYNTHESIS IN ASPERGILLUS NIDULANS

Berlyn¹

1967

Genetics

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ALTHOUGH many nutritional mutants have been isolated and utilized in genetic investigations in Aspergillus nidulans, enzymological characterizations of only a few loci have been made (DORN 1965; ROBERTS 1964; FOLEY, GILES and ROBERTS 1965; ROBERTS 1967; HUTTER and DEMOSS 1967). The present study of histidine mutants undertakes a systematic analysis of gene-enzyme relationships for an entire biosynthetic pathway in Aspergillus. Such extensive correlations in eucaryotic organisms were first established in studies of histidine biosynthesis in Neurospora crassa ( AHMED 1964) and in Saccharomyces cereuisiae (FINK 1964). These studies and the present work have drawn heavily from the biochemical techniques used to elucidate histidine biosynthesis in Salmonella typhimirium by AMES and his colleagues (cf. AMES and HARTMAN 1963; SMITH and AMES 1965). The histidine pathway, as determined in Salmonella, is shown in Figure 1.Most of the loci for histidine enzymes in Neurospora and yeast are widely dispersed, in contrast to the linear contiguity of the loci of the well known histidine operon of Salmonella (AMES and HARTMAN 1963). However, a biochemically heterogeneous continuous genetic region, affecting three of the ten enzymatic activities (reactions 2, 3. and 10 in Figure 1) was found in both these organisms (AHMED, CASE, and GILES 1964; FINK 1966). Each group of mutants defective for only one of the activities occupied a distinct part of the region. A class of noncomplementing mutants defective for all three enzymatic functions was restricted to the terminally located cyclohydrolase (reaction 3 ) cistron. Another mutant class defective for reactions 2 (pyrophosphohydrolase) and 10 (histidinol dehydrogenase), but demonstrating cyclohydrolase activity in complementation tests, mapped in the central region, among the pyrophosphohydrolase mutants. This polarity in complementation responses and restricted distribution of noncomplementing mutants led the authors to postulate a polycistronic messenger (cf. MARTIN 1963) for this region, which was thus interpreted as a polarized unit of genetic transcription, an operon according to the definition of JACOB and MONOD (1961 ) . In yeast, the suppression of noncomplementing mutants by general (super-) suppressors was interpreted as further evidence that these are ' Based on a dissertation submitted to the Graduate School of Yale University in partial fulfillment of the require-' T h i s iesearch was supported by Public IIealth Service Genetics Training Grant GM 397 administered by Dr. nieiits for the degree of Doctor of Philosophy.

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Regulation of Genes Controlling Synthesis of the Galactose Pathway Enzymes in Yeast

Cited by 215 publications

References 2 publications

GAL4 mutations that separate the transcriptional activation and GAL80-interactive functions of the yeast GAL4 protein.

GAL4 mutations that separate the transcriptional activation and GAL80-interactive functions of the yeast GAL4 protein.

High-Throughput Screening for Human Galactokinase Inhibitors

GENE-ENZYME RELATIONSHIPS IN HISTIDINE BIOSYNTHESIS IN ASPERGILLUS NIDULANS

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