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PubMed1987

The binding of decomposition products of UDP-galactose to the microsomes and polyribosomes isolated from rat liver.

UDP-D-[U-14C]galactose is decomposed to [U-14C]galactose-1-phosphate and [U-14C]galactose by rat liver microsomal and crude polyribosomal fractions, under conditions commonly used to assay of glycosyltransferase activities. UDP-D-[U-14C]galactose, at neutral pH, is also chemically degraded to the [U-14C]galactose-1,2-cyclic phosphate. The 1,2-cyclic phosphate derivative of galactose also exists in the commercial UDP-D-[U-14C]galactose. It is a very important finding that products of the UDP-D-[U-14C]galactose decomposition are tightly, although nonenzymatically, bound to tested subcellular fractions and may create a false impression of protein glycosylation. The application of controls containing all radioactive substances present in suitable samples is recommended in order to avoid incorrect interpretations of the results.

Animals↗
PubMed2005

The effect of diet on total antioxidant status, erythrocyte membrane Na+,K+-ATPase and Mg2+-ATPase activities in patients with classical galactosaemia.

OBJECTIVE: Classical galactosaemia is characterized by high levels of galactose-1-phosphate (Gal-1-P), galactose and galactitol. In vitro studies have shown modulation of the rat brain Na+,K+-ATPase and Mg2+-ATPase activities by Gal-1-P. The aim of this study was to evaluate the erythrocyte membrane Na+,K+-ATPase and Mg2+-ATPase activities in galactosaemic patients and to correlate them to Gal-1-P, total antioxidant status (TAS) and membrane protein content (PC). PATIENTS AND METHODS: Nine patients (N=9) originally on "loose diet" (group B) were requested to follow their diet strictly (group A). Twelve healthy children were the controls (group C). The activities of the enzymes, TAS and Gal-1-P in blood were determined spectrophotometrically. In the in vitro study, erythrocyte membranes from controls were preincubated with Gal-1-P (300 microM), and then with l-cysteine (0.83 mM) or reduced glutathione (0.83 mM) whereas these from the patients with the antioxidants only. RESULTS: Na+,K+-ATPase, Mg2+-ATPase, TAS and PC were significantly (P<0.001) reduced (0.31+/-0.03, 1.7+/-0.2 micromol Pi/hxmg protein, 0.89+/-0.02 mmol/l, 36.8+/-2.0 g/l, respectively) in group B as compared with those of group A (0.58+/-0.06, 2.5+/-0.2 micromol Pi/hxmg protein, 1.41+/-0.11 mmol/l, 51.5+/-3.1g/l, respectively) and controls (0.67+/-0.05, 3.2+/-0.2 micromol Pi/hxmg protein, 1.65+/-0.12 mmol/l, 64.0+/-3.5 g/l, respectively). Gal-1-P levels in group B was significantly higher than those in group A and controls. Positive correlation coefficients were found between the enzyme activities, PC and TAS whereas Gal-1-P inversely correlated to the enzyme activities. Incubation of the erythrocyte membranes from the patients with the antioxidants failed to restore the activities of inhibited enzymes, whereas the inhibition by Gal-1-P in controls was reversed. CONCLUSIONS: High blood Gal-1-P concentrations resulted in low TAS and PC. The inhibition of Na+,K+-ATPase and Mg2+-ATPase may be due to the presence of free radicals and/or the elevated Gal-1-P.

Antioxidants↗
PubMed2004

Protective effect of L-cysteine and glutathione on the modulated suckling rat brain Na+, K+, -ATPase and Mg2+ -ATPase activities induced by the in vitro galactosaemia.

UNLABELLED: Galactosaemia is an inborn error of galactose (Gal) metabolism characterized by irreversible brain damage. The aim of this study was to evaluate whether the antioxidants L-cysteine (Cys) and the reduced glutathione (GSH) could reverse the alterations of brain total antioxidant status (TAS) and the modulated activities of the enzymes Na+,K+ -ATPase and Mg2+ -ATPase in in vitro galactosaemia. Mixture A (mix. A: galactose-1-phosphate (Gal-1-P, 2mM) plus galactitol (Galtol, 2mM) plus Gal (4mM) = classical galactosaemia) or Mixture B (mix. B: Galtol (2mM) plus Gal (1mM) = galactokinase deficiency galactosaemia) were preincubated in the presence or absence of Cys (0.83mM) or GSH (0.83 mM) with whole brain homogenates of suckling rats at 37 degrees C for 1h. TAS and the enzyme activities were determined spectrophotometrically. The preincubation of brain homogenates with mix. A or mix. B resulted in a decrease of TAS to 30% (P < 0.01), while the presence of Cys or GSH increased TAS to 20% (P < 0.01) and 60% ( P < 0.001), respectively. The antioxidants reversed the inhibited Na+,K+ -ATPase by mix. A or mix. B and the stimulated Mg2+ -ATPase by mix. B to control values, whereas no effect was observed on the enormously activated Mg2+ -ATPase by mix. A. CONCLUSIONS: (a) Gal and its derivatives may produce free radicals in the suckling rat brain, reported for first time, (b) Na+,K+ -ATPase inhibition and Mg2+ -ATPase activation are probably due to the oxidative stress from the above compounds, (c) Cys or GSH could play a protective role reversing the inhibited Na+,K+ -ATPase toward normal in in vitro galactosaemia and (d) the addition of the above antioxidants may reduce the consequences of brain Mg2+ -ATPase activation by Gal and Galtol in galactokinase deficiency galactosaemia.

Animals↗
PubMed2005

Mg2+-ATPase activity in suckling rat brain regions in galactosaemia in vitro. L-Cysteine and glutathione effects.

UNLABELLED: Mg2+-ATPase activity is implicated with Mg2+ homeostasis, maintaining high brain intracellular Mg2+ content. We determined the in vitro effects of galactose-1-phosphate (Gal-1-P), galactitol (Galtol) and galactose (Gal) {mix A=Gal-1-P(2 mM)+Galtol(2 mM)+Gal(4 mM) concentrations commonly found in patients with classical galactosaemia} or Galtol and Gal {mix B=Galtol(2 mM)+Gal(1 mM) concentrations usually measured in patients with galactokinase deficiency galactosaemia} on Mg2+-ATPase activity in suckling rat brain frontal cortex, hippocampus or hypothalamus homogenates. Gal-1-P significantly (p<0.001) enhanced enzyme activity in all the brain areas measured, whereas Galtol and Gal failed to cause any effect in the same regions. Mix A remarkably (p<0.001) stimulated Mg2+-ATPase in the studied areas. On the contrary, mix B had no effect. The supplementation of antioxidant l-cysteine (Cys) or reduced Glutathione (GSH) in mix A failed to reverse to normal the activated enzyme in frontal cortex and hypothalamus, while they significantly reduced Mg2+-ATPase activation in hippocampus. CONCLUSIONS: (a) Gal-1-P enormously activated Mg2+-ATPase in all the studied brain regions, (b) Mix A, also, excessively activated the enzyme in the same areas, (c) the production of free radicals may be implicated with the enzyme activation and (d) Cys or GSH significantly decreased the activated hippocampal Mg2+-ATPase.

Animals↗
PubMedDate not supplied

Differential roles of the Leloir pathway enzymes and metabolites in defining galactose sensitivity in yeast.

The metabolism of galactose via enzymes of the Leloir pathway: galactokinase, galactose-1-P uridylyltransferase, and UDP galactose-4'-epimerase, is a process that has been conserved from Escherichia coli through humans. Impairment of this pathway in patients results in the disease galactosemia. Despite decades of study, the underlying pathophysiology in galactosemia remains unknown. Here we have defined the functional and metabolic implications of impaired galactose metabolism in yeast, by asking two questions: (1) What is the impact of loss of each of the three Leloir enzymes on the ability of cells to metabolize galactose, and on their sensitivity to galactose, and (2) what is the relationship between gal-1P and galactose-sensitivity in yeast? Our results demonstrate that only transferase-null cells are able to deplete their medium of galactose; deletion of kinase or epimerase halts this process. In contrast, only kinase-null cultures grow well in glycerol/ethanol medium despite the addition of galactose; both transferase and epimerase-null yeast arrest growth under these conditions. Indeed, epimerase-null yeast arrest growth at galactose concentrations 10-fold lower than do their transferase-null counterparts. Secondary deletion of kinase relieves growth arrest in both strains. Finally, rather than a continuous relationship between gal-1P and growth arrest, we observed a threshold level of gal-1P (approximately 10 nmol/mg cell DM) above which both transferase-null and epimerase-null cultures could not grow. These results both confirm and significantly extend prior knowledge of galactose metabolism in yeast, and set the stage for future studies into the mediators and mechanism of Leloir-impaired galactose sensitivity in eukaryotes.

Cell Proliferation↗
PubMed2005

Intracellular galactose-1-phosphate accumulation leads to environmental stress response in yeast model.

In humans, deficiency of galactose-1-phosphate uridyltransferase (GALT) can lead a metabolic disorder Classic Galactosemia. Although the biochemical abnormalities associated with this disease have been described in detail, few attempts have been made to characterize the pathogenic mechanisms of this disorder at the molecular level. Here we report the use of high-throughput DNA microarray to examine how galactose affects gene expression in isogenic yeast models that are deficient in either galactokinase (GALK) or GALT, two enzymes which are essential for normal galactose metabolism. We confirmed that the growth of our GALT-deficient, but not GALK-deficient yeast strain ceased 4 h after challenge with 0.2% galactose. Such inhibition was not associated with a reduction of ATP content and was reversible after removal of galactose from medium. We compared the gene expression profiles of the GALT-deficient and GALK-deficient cells in the presence/absence of galactose. We revealed that in the absence of galactose challenge, a subset of genes involved in RNA metabolism was expressed at a level 3-fold lower in the GALT-deficient cells. Upon galactose challenge, significantly more genes involved in various aspects of RNA metabolism and almost all ribosomal protein genes were downregulated in the GALT-deficient, but not GALK-deficient cells. Remarkably, genes involved in inositol biosynthesis and turnover were exclusively induced at high level in the galactose-intoxicated GALT-deficient cells. Our data thus suggested that RNA metabolism, ribosome biogenesis, and inositol metabolism were likely targets for galactose-1-phosphate, a toxic intermediate that is uniquely accumulated under GALT-deficiency.

Environment↗
PubMed1986

Microassay for estimation of galactose and galactose-1-phosphate in dried blood specimens.

A fluorometric assay for blood galactose and galactose-1-phosphate has been modified and improved to shorten the analysis time and to increase sensitivity above other published methods. The method may be useful as a quantitative screening or routine clinical test to detect infants suspected of having a defect of galactose metabolism. It can also be used to monitor blood galactose or galactose-1-phosphate levels in children with galactosemia who are on a lactose-free diet.

Alkaline Phosphatase↗
PubMed1982

Galactose intolerance in individuals with double heterozygosity for Duarte variant and galactosemia.

The most frequent cause for an abnormal result during screening of newborn infants for galactosemia is double heterozygosity for Duarte variant and galactosemia, in which galactose-1-phosphate uridyl transferase activity is reduced to approximately 17% of normal. Thirty-nine oral galactose tolerance tests were performed in 27 infants and children with this condition. In comparison to age-matched controls, all children with this genetic variant reached much higher levels of blood galactose and galactose-1-phosphate following oral galactose challenge. The integrated plasma galactose response increased with the age of the child, whereas integrated erythrocyte galactose-1-phosphate responses were elevated to the same degree at all ages. Although all children appeared clinically normal, the marked abnormalities in the ability to dispose of ingested galactose raise questions concerning appropriate dietary recommendations for such children.

Blood Glucose↗
PubMed1985

Perinatal galactose metabolism.

Galactose is a major nutrient in normal newborn infants and serves as a substrate for energy production and fuel storage and a regulator of carbohydrate assimilation. Inborn errors of galactose metabolism have contributed to our understanding of the potential toxicity of this carbohydrate. In addition to the classic acute manifestations of neonatal galactosemia, long-term follow-up of surviving patients have revealed unusual neurodevelopmental and reproductive problems. Many investigators have suggested that the newborn infant can utilize galactose better than adults and that neonatal galactose assimilation exceeds that of glucose. Galactose may be an excellent substitute for glucose among hyperinsulinemic infants of diabetic mothers or premature infants with glucose intolerance. However, until further investigations are performed to define the role of galactose in newborn nutrition and to determine its potential toxicity, galactose should not be used as the primary carbohydrate in sick newborn infants.

Cell Membrane Permeability↗
PubMed1978

Association of presenile cataracts with heterozygosity for galactosaemic states and with riboflavin deficiency.

Red cells and the lens of the eye are non-nucleated cells; moreover, they have metabolic similarities. Cataracts develop in childhood in homozygotes for galactosaemic abnormalities, which can be detected by biochemical measurements in red blood-cells. It has not been determined whether heterozygotes for these defects are at greater risk for cataract development later in life. Similarly, riboflavin deficiecy for which the erythrocyte is a sensitive indicator, has been associated with cataracts in animals. Red-cell studies were carried out in 22 patients, aged under 50, with cataracts. Heterozygosity for galactokinase deficiency was detected in 5 patients, for galactose-uridyl transferase in 2, and evidence of an erythrocytic deficiency of riboflavin in 8. Even when Black subjects were excluded from analysis because of their high incidence of polymorphism for galactokinase, these findings are significantly different from those expected from population surveys and suggest that many patients with presenile cataracts have a biochemical abnormality which can be detected by examination of red blood-cells and which may be corrected by dietary restrictions or supplements.

Adolescent↗
PubMed2000

Growth-phase regulation of the Escherichia coli thioredoxin gene.

The two promoters of Escherichia coli trxA gene were separately cloned into pKO100 as well as pJEL170. Galactokinase expression in cells containing the pKO100 derivatives was found to be negatively correlated with growth rate and was 6- to 20-fold higher in stationary cultures than in exponential cultures. The expression of trxA-galK was induced by amino acid starvation in a RelA(+) strain but not in an isogenic Rel(-) strain indicating that the control involves guanosine 3',5'-bispyrophosphate (ppGpp). RpoS, which appears to be essential for expression of most stationary phase expressed genes, is not required for trxA expression. Increased expression of relA, which increases ppGpp concentration, increases trxA expression.

Amino Acids↗
PubMed2002

Kinetic analysis of yeast galactokinase: implications for transcriptional activation of the GAL genes.

Galactokinase (EC 2.7.1.6) catalyses the first step in the catabolism of galactose. Yeast galactokinase, Gal1p, and the closely related but catalytically inactive Gal3p, also function as ligand sensors in the GAL genetic switch. In the presence of galactose and ATP (the substrates of the reaction catalysed by Gal1p) Gal1p or Gal3p can bind to Gal80p, a transcriptional repressor. This relieves the inhibition of a transcriptional activator, Gal4p, and permits expression of the GAL genes. In order to learn more about the mechanism of ligand sensing by Gal3p and Gal1p, we studied the kinetics of the reaction catalysed by Gal1p. Galactose-1-phosphate, a product of the reaction, is a mixed inhibitor both with respect to galactose and to ATP suggesting that the reaction proceeds via a compulsory, ordered, ternary complex mechanism. There is little variation in either the turnover number or the specificity constants in the pH range 6.0-9.5, implying that no catalytic base is required in the reaction. These data are discussed both in the context of galactokinase enzymology and their implications for the mechanism of transcriptional induction.

Adenosine Triphosphate↗
PubMed2003

Galactose-1-phosphate is a regulator of inositol monophosphatase: a fact or a fiction?

Classic galactosemia is due to the deficiency of galactose-1-phosphate uridyl transferase and is transmitted as an autosomal recessive disorder. Patients suffering from classic galactosemia display acute symptoms such as poor growth, feeding difficulties, jaundice, hepatomegaly etc., which disappear when the individual is on galactose free diet. However, these patients continue to suffer from defects such as neurological disturbances and ovarian dysfunction, due to the accumulation of galactose-1-phosphate, which is a normal intermediate of galactose metabolism. The biochemical mechanism of galactose-1-phosphate mediated toxicity is still an enigma. Recent experiments strongly suggest that galactose-1-phosphate is also a substrate for inositol monophosphatase (IMPase). Phosphatidylinositol bisphosphate [PI(P)2] dependent signaling serves as a second messenger for several neurotransmitters in the brain. Therefore, the brain is critically dependent on IMPase for the supply of free inositol in order to sustain [PI(P)2] signaling. Circumstantial evidence strongly supports the possibility that being a substrate, galactose-1-phosphate could modulate IMPase function in vivo. The implication of this idea is discussed in relation to classic galactosemia as well as bipolar disorder, which has been thought to be due to the hyper-activation of [PI(P)2] mediated second messenger pathways(s).

Galactosemias↗