glycogen and Galactosemias

Topics: Blood Glucose; Carbohydrate Metabolism, Inborn Errors; Carbohydrates; Citric Acid Cycle; Clinical Enzyme Tests; DNA; Down Syndrome; Galactosemias; Glucosephosphate Dehydrogenase Deficiency; Glycogen; Glycogen Storage Disease; Glycolysis; Glycosaminoglycans; Humans; Leukemia; Leukocytes; Muramidase; Neutrophils; Pentosephosphates; Phagocytosis; Propionates; RNA

Classic galactosemia is an inborn error of metabolism caused by deleterious mutations in the GALT gene. A number of evidences indicate that the galactose-1-phosphate accumulation observed in patient cells is a cause of toxicity in this disease. Nevertheless, the consequent molecular events caused by the galactose-1-phosphate accumulation remain elusive. Here we show that intracellular inorganic phosphate levels decreased when yeast models of classic galactosemia were exposed to galactose. The decrease in phosphate levels is probably due to the trapping of phosphate in the accumulated galactose-1-phosphate since the deletion of the galactokinase encoding gene GAL1 suppressed this phenotype. Galactose-induced phosphate depletion caused an increase in glycogen content, an expected result since glycogen breakdown by the enzyme glycogen phosphorylase is dependent on inorganic phosphate. Accordingly, an increase in intracellular phosphate levels suppressed the galactose effect on glycogen content and conferred galactose tolerance to yeast models of galactosemia. These results support the hypothesis that the galactose-induced decrease in phosphate levels leads to toxicity in galactosemia and opens new possibilities for the development of better treatments for this disease.

Topics: Galactokinase; Galactose; Galactosemias; Glycogen; Humans; Models, Biological; Phosphates; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins

We have compared the effects of administration of oral galactose or glucose (1 g/kg) to 24-h fasted rats to examine the mechanism by which galactose regulates its own incorporation into liver glycogen in vivo. Liver glycogen increased to a maximum more slowly after galactose than after glucose administration (0.14 vs. 0.29 mumol.g liver-1.min-1). Glycogen accumulation after the galactose load was 70% of that after the glucose load (149 vs. 214 mumol), and the net increase in liver glycogen represented the same proportion (24 vs. 22%) of added carbohydrate after urinary loss of galactose was accounted for. Slower glycogen accumulation after galactose vs. glucose loading could not be explained by galactosuria, by differences in the active forms of synthase or phosphorylase, by end product (glycogen) inhibition of synthase phosphatase, or by different concentrations of the known allosteric effectors of synthase R plus I and phosphorylase a. Similar increases in glucose 6-phosphate were observed after both hexoses. AMP and ADP increased only transiently after galactose administration, and ATP, UTP, and Pi concentrations were unchanged. The UDP-glucose concentration decreased, whereas the UDP-galactose concentration increased two- to threefold after galactose but not glucose administration. The UDP-glucose pyrophosphorylase reaction is inhibited competitively by UDP-galactose. This could explain the decreased UDP-glucose concentration and the reduced rate of glycogen synthesis after galactose was given.

Topics: Absorption; Administration, Oral; Animals; Blood Glucose; Galactose; Galactosemias; Glucose; Glycogen; Glycogen Synthase; Liver; Male; Osmolar Concentration; Rats; Rats, Inbred Strains; Time Factors

Topics: Blood Glucose; Fanconi Syndrome; Galactosemias; Glycogen; Glycogen Storage Disease; Humans; Infant; Mitochondria, Muscle; Muscles

The extent to which platelets can metabolize galactose has been unknown. We have studied this question by incubating platelets with radiolabeled galactose for periods of time and analyzing the cells for radioactive metabolites. The sugar was observed to accumulate quickly in cells isolated by filtration. Within seconds at room temperature, galactose metabolites were detectable by thin-layer chromatography, and within 20 minutes at 37 degrees C, radioactivity appeared in trichloroacetic acid (TCA) precipitates of the suspensions. The TCA-precipitable radioactivity was degraded by alpha-amylase as well as by protease. However, the TCA-soluble material released by protease digestion had an elution volume on Sepharose CL-4B too small for glycopeptides and in addition was degraded by alpha-amylase. The majority of the galactose metabolized by platelets, therefore, becomes incorporated into glycogen, rather than glycoprotein. The reversibility of the galactose metabolic pathway was demonstrated by the addition of an excess of the unlabeled sugar to the labeled platelets and by the effect of thrombin and collagen on the TCA-precipitable radioactivity.

Topics: alpha-Amylases; Blood Platelets; Chromatography, Gel; Chromatography, Thin Layer; Filtration; Galactosemias; Glycogen; Glycoproteins; Humans; In Vitro Techniques; Temperature; Time Factors; Trichloroacetic Acid

Topics: Adolescent; Bile; Body Weight; Carbohydrate Metabolism, Inborn Errors; Child; Child, Preschool; Cystic Fibrosis; Female; Galactosemias; Glycogen; Hepatitis A; Hepatolenticular Degeneration; Humans; India; Infant; Infant Nutritional Physiological Phenomena; Liver Diseases; Male; Tyrosine

Topics: Adult; Amino Acid Metabolism, Inborn Errors; Amino Acids; Carcinoma, Hepatocellular; Child, Preschool; Cysteine; Diet Therapy; Female; Galactosemias; Glycogen; Humans; Infant; Intellectual Disability; Liver Neoplasms; Male; Maple Syrup Urine Disease; Methionine; Middle Aged; Neuroblastoma; Phenylketonurias; Portal Vein; Pyridoxine; Serine; Sulfisoxazole; Tyrosine

Topics: Galactose; Galactosemias; Glycogen; Glycogen Storage Disease

Topics: Child; Galactosemias; Glycogen; Glycogen Storage Disease; Growth; Humans; Infant