Galactose Metabolism

Galactose, which is metabolized from the milk sugar, lactose (a disaccharide of glucose and galactose), enters glycolysis by its conversion to glucose-1-phosphate (G1P). This occurs through a series of steps. First the galactose is phosphorylated by galactokinase to yield galactose-1-phosphate. Epimerization of galactose-1-phosphate to G1P requires the transfer of UDP from uridine diphosphoglucose (UDP-glucose) catalyzed by galactose-1-phosphate uridyl transferase. This generates UDP-galactose and G1P. The UDP-galactose is epimerized to UDP-glucose by UDP-galactose-4 epimerase. The UDP portion is exchanged for phosphate generating glucose-1-phosphate which then is converted to G6P by phosphoglucose mutase.

Reactions of galactose metabolism

Entry of galactose carbon atoms into the glycolytic pathway. The full name for the enzyme UDP-Glc pyrophos. is UDP-glucose pyrophosphorylase, that of UDP-Glc:Gal-1-P uridylyltransferase is UDP-glucose:α-D-galactose-1-phosphate uridylyltransferase. Place mouse over intermediate names to see structure.

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Clinical Significances of Galactose Metabolism

Three inherited disorders of galactose metabolism have been delineated. Classic galactosemia is a major symptom of two enzyme defects. One results from loss of the enzyme galactose-1-phosphate uridyl transferase. The second form of galactosemia results from a loss of galactokinase. These two defects are manifest by a failure of neonates to thrive. Vomiting and diarrhea occur following ingestion of milk, hence individuals are termed lactose intolerant. Clinical findings of these disorders include impaired liver function (which if left untreated leads to severe cirrhosis), elevated blood galactose, hypergalactosemia, hyperchloremic metabolic acidosis, urinary galactitol excretion and hyperaminoaciduria. Unless controlled by exclusion of galactose from the diet, these galactosemias can go on to produce blindness and fatal liver damage. Even on a galactose-restricted diet, transferase-deficient individuals exhibit urinary galacitol excretion and persistently elevated erythrocyte galactose-1-phosphate levels. Blindness is due to the conversion of circulating galactose to the sugar alcohol galacitol, by an NADPH-dependent galactose reductase that is present in neural tissue and in the lens of the eye. At normal circulating levels of galactose this enzyme activity causes no pathological effects. However, a high concentration of galacitol in the lens causes osmotic swelling, with the resultant formation of cataracts and other symptoms. The principal treatment of these disorders is to eliminate lactose from the diet.

The third disorder of galactose metabolism result from a deficiency of UDP-galactose-4-epimerase. Two different forms of this deficiency have been found. One is benign affecting only red and white blood cells. The other affects multiple tissues and manifests symptoms similar to the transferase deficiency. Treatment involves restriction of dietary galactose.

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Mannose Metabolism

The digestion of many polysaccharides and glycoproteins yields mannose which is phosphorylated by hexokinase to generate mannose-6-phosphate. Mannose-6-phosphate is converted to fructose-6-phosphate, by the enzyme phosphomannose isomerase, and then enters the glycolytic pathway or is converted to glucose-6-phosphate by the gluconeogenic pathway of hepatocytes.

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Glycerol Metabolism

The predominant source of glycerol is adipose tissue. This molecule is the backbone for the triacylglycerols. Following release of the fatty acid portions of triacylglycerols the glycerol backbone is transported to the liver where it it phosphorylated by glycerol kinase yielding glycerol-3-phosphate. Glycerol-3-phosphate is oxidized to DHAP by glycerol-3-phosphate dehydrogenase. DHAP then enters the glycolytic if the liver cell needs energy. However, the more likely fate of glycerol is to enter the gluconeogenesis pathway in order for the liver to produce glucose for use by the rest of the body.

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Glucuronate Metabolism

Glucuronate is a highly polar molecule which is incorporated into proteoglycans as well as combining with bilirubin and steroid hormones; it can also be combined with certain drugs to increase their solubility. Glucuronate is derived from glucose in the uronic acid pathway.

Reactions of glucuronate synthesis

The uronic acid pathway is utilized to synthesize UDP-glucuronate, glucuronate and L-ascorbate. The pathway involves the oxidation of glucosae-6-phosphate to UDP-glucuronate. The oxidation is uncoupled from energy production. UDP-glucuronate is used in the synthesis of glycosaminoglycan and proteoglycans as well as forming complexes with bilirubin, steroids and certain drugs. The glucuronate complexes form to solubilize compounds for excretion. The synthesis of ascorbate (vitamin C) does not occur in primates. Place mouse over intermediate names to see structure.

The uronic acid pathway is an alternative pathway for the oxidation of glucose that does not provide a means of producing ATP, but is utilized for the generation of the activated form of glucuronate, UDP-glucuronate. The uronic acid pathway of glucose conversion to glucuronate begins by conversion of glucose-6-phosphate is to glucose-1-phosphate by phosphoglucomutase, and then activated to UDP-glucose by UDP-glucose pyrophosphorylase. UDP-glucose is oxidized to UDP-glucuronate by the NAD⁺-requiring enzyme, UDP-glucose dehydrogenase. UDP-glucuronate then serves as a precursor for the synthesis of iduronic acid and UDP-xylose and is incorporated into proteoglycans and glycoproteins or forms conjugates with bilirubin, steroids, xenobiotics, drugs and many compounds containing hydroxyl (–OH) groups.

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Clinical Significance of Glucuronate

In the adult human, a significant number of erythrocytes die each day. This turnover releases significant amounts of the iron-free portion of heme, porphyrin, which is subsequently degraded. The primary sites of porphyrin degradation are found in the reticuloendothelial cells of the liver, spleen and bone marrow. The breakdown of porphyrin yields bilirubin, a product that is non-polar and therefore, insoluble. In the liver, to which is transported in the plasma bound to albumin, bilirubin is solubilized by conjugation to glucuronate. The soluble conjugated bilirubin diglucuronide is then secreted into the bile. An inability to conjugate bilirubin, for instance in hepatic disease or when the level of bilirubin production exceeds the capacity of the liver, is a contributory cause of jaundice.

The conjugation of glucuronate to certain non-polar drugs is important for their solubilization in the liver. Glucuronate-conjugated drugs are more easily cleared from the blood by the kidneys for excretion in the urine. The glucuronate-drug conjugation system can, however, lead to drug resistance; chronic exposure to certain drugs, such as barbiturates and AZT, leads to an increase in the synthesis of the UDP-glucuronyltransferases in the liver that are involved in glucuronate-drug conjugation. The increased levels of these hepatic enzymes result in a higher rate of drug clearance leading to a reduction in the effective dose of glucuronate-cleared drugs.

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