Harper's Illustrated Biochemistry, Volume 1 - Murray R. 1993

Bioenergetics and Carbohydrate and Lipid Metabolism
Metabolism of Major Hexoses
Galactose Metabolism

Galactose is formed during the intestinal Hydrolysis of the disaccharide lactose (milk sugar). In the Liver, it is readily converted into glucose. The liver's capacity to carry out this conversion can be utilized as a functional test—the galactose tolerance test. The pathway of galactose conversion to glucose is shown in Fig. 21.3.

Galactose is phosphorylated via reaction 1, catalyzed by galactokinase (with ATP serving as the phosphate donor). The reaction product, galactose-1-phosphate, reacts with uridine diphosphate-glucose (UDP-glucose) to yield uridine diphosphate-galactose (UDP-galactose) and glucose-1-phosphate. At this stage (reaction 2), catalyzed by the enzyme galactose-1-phosphate uridylyltransferase, galactose replaces glucose in UDP-glucose to form UDP-galactose. The conversion of galactose to glucose (reaction 3) takes place within the galactose-containing nucleotide. This reaction, which yields UDP-glucose, is catalyzed by epimerase. The epimerization reaction presumably involves Oxidation and reduction steps at C-4, utilizing NAD as a coenzyme. Finally, glucose is released from UDP-glucose as glucose-1-phosphate (reaction 4), likely after incorporation into Glycogen followed by its phosphorolysis.

Reaction 3 is readily reversible, allowing glucose to be converted into galactose by this pathway; consequently, galactose is not an essential dietary component. Galactose is required for the synthesis not only of lactose, but also of Glycolipids (cerebrosides), Proteoglycans, and Glycoproteins.

During lactose synthesis in the mammary gland, UDP-galactose is first formed from glucose and a nucleotide through the action of the aforementioned Enzymes. It then undergoes a reaction with glucose catalyzed by lactose synthase, resulting in The formation of lactose.

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Fig. 21.3. Pathway of galactose conversion to glucose and pathway of lactose synthesis.

Fig. 21.4. Interrelationship scheme of amino sugar METABOLISM. UDP-glucosamine is an analogue of UDP-Glc. Other purine or pyrimidine NUCLEOTIDES can similarly bind sugars or amino sugars. Examples of such compounds include TDP-glucosamine and TDP-N-acetylglucosamine.

Clinical Aspects

Impaired Galactose Metabolism is observed in galactosemia, which can result from inherited defects in any of the three enzymes designated 1, 2, and 3 in Fig. 21.3. The best-characterized defect is uridylyltransferase (2) deficiency. As Blood galactose concentrations rise, so do its levels in Tissues. In ocular tissues, it is reduced by aldose reductase to form the corresponding polyol (galactitol). The accumulation of galactitol contributes to cataract development. Severe consequences are associated with uridylyltransferase deficiency: galactose-1-phosphate accumulates in the liver, accompanied by a corresponding drop in inorganic phosphate levels. This leads to impaired liver function, followed by neurological and psychological disorders.

If epimerase (reaction 3) is present in sufficient amounts despite a hereditary deficiency of galactose-1-phosphate uridylyltransferase (reaction 2)—which disrupts galactose metabolism in The Liver and red Blood Cells—affected patients can still synthesize UDP-galactose from glucose. This explains why children with this condition can grow and develop normally when placed on a galactose-free diet (prescribed to prevent severe forms of the disease). Several distinct genetic defects have been described that cause partial rather than complete transferase deficiency. Because this enzyme is normally present in excess, a reduction in its activity to 50% (or even lower) may not be accompanied by clinical manifestations; the latter are observed in homozygous individuals. In cases where there is an erythrocyte epimerase deficiency while the enzyme remains present in the liver and other Organs, symptoms of the disease are absent.

Amino Sugar (Hexosamine) Metabolism (Fig. 21.4)

Amino sugars are crucial components of glycoproteins (see Ch. 54), certain glycosphingolipids (e.g., gangliosides, see Ch. 15), and glycosaminoglycans (see Ch. 54). The most prominent among them are glucosamine, galactosamine, mannosamine (all of which are hexosamines), and the C-9 compound sialic acid. The major sialic acid found in human tissues is N-acetylneuraminic acid (NeuAc). The interconversion PATHWAYS OF AMINO sugars are illustrated in Fig. 21.4, with the key highlights being: (1) glucosamine is the primary amino sugar, formed from fructose-6-phosphate as glucosamine-6-phosphate, with glutamine acting as the amino group donor; (2) amino sugars function primarily in their N-acetylated form, with acetyl-CoA serving as the acetyl donor; (3) N-acetylmannosamine-6-phosphate is formed via the epimerization of N-acetylglucosamine-6-phosphate; (4) NeuAc is produced by the Condensation of mannosamine-6-phosphate with phosphoenolpyruvate; (5) galactosamine is formed through the epimerization of UDP-N-acetylglucosamine (UDPGlcNAc) to UDP-N-acetylgalactosamine (UDP-GalNAc); (6) amino sugars are utilized for The Biosynthesis of glycoproteins and Other Compounds in the form of nucleotide sugars, the principal ones being UDPGlcNAc, UDPGalNAc, and CMPNeuAc.

References

Brown D.H., Brown B. I. Some inborn errors of Carbohydrate Metabolism. Page 391. In: MTP International Review of Science, Vol 5, Whelan W. J. (ed.), Butterworth, 1975.

Dickens F., Randle P. J., Whelan W. J. (ed.). Carbohydrate Metabolism and Its Disorders, 2 vols, Academic Press, 1968. Huijing F. Textbook errors, Galactose metabolism and galactosemia, Trends Biochem. Sci., 1978, 3, N 129.

James H. M. et al. Models for the metabolic production of oxalate from xylitol in humans, Aust. J. Exp. Biol. Med. Sci., 1982, 60, 117.

Kador P. F., Akagi Y., Kinoshita J. H. The effects of aldose reductase and its inhibition on sugar cataract formation, Metabolism, 1986, 35, 15.

Macdonald I., Vrana A. (eds). Metabolic Effects of Dietary CARBOHYDRATES, Karger, 1986.

Randle P. J., Steiner D. F., Whelan W. J. (eds). Carbohydrate Metabolism and Its Disorders, Vol 3, Academic Press, 1981.

Sperling O., de Vries A. (eds). Inborn Errors of Metabolism in Man, Karger, 1978.

Stanbury J. B. et al. (eds). The Metabolic Basis of Inherited Disease, 5th ed. McGraw-Hill, 1983.