METABOLISM OF MONOSACCHARIDES AND DISACCHARIDES DR. A. TARAB DEPT. OF BIOCHEMISTRY HKMU

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1 METABOLISM OF MONOSACCHARIDES AND DISACCHARIDES DR. A. TARAB DEPT. OF BIOCHEMISTRY HKMU

2 OVERVIEW Glucose is the most common monosaccharide consumed by humans, and its metabolism has been discussed extensively However, two other monosaccharides - fructose and galactose occur in significant amounts in the diet, and make important contributions to energy metabolism In addition, galactose is an important component of cell structural carbohydrates

3 FRUCTOSE METABOLISM The major source of fructose is the disaccharide sucrose, which, when cleaved in the intestine, releases equimolar amounts of fructose and glucose Fructose is also found as a free monosaccharide in many fruits, and in honey Entry of fructose into cells is not insulindependent (unlike that of glucose into certain tissues), and, in contrast to glucose, fructose does not promote the secretion of insulin

4 A. Phosphorylation of fructose For fructose to enter the pathways of intermediary metabolism, it must first be phosphorylated This can be accomplished by either hexokinase or fructokinase (also called ketohexokinase). Hexokinase phosphorylates glucose in all cells of the body, and several additional hexoses can serve as substrates for this enzyme

5 However, it has a low affinity (that is, a high k m ) for fructose Therefore, unless the intracellular concentration of fructose becomes unusually high, the normal presence of saturating concentrations of glucose means that little fructose is converted to fructose 6-phosphate by hexokinase. Fructokinase provides the primary mechanism for fructose phosphorylation

6 It is found in the liver (which processes most of the dietary fructose), kidney, and the small intestinal mucosa, and converts fructose to fructose 1-phosphate using ATP as the phosphate donor B. Cleavage of fructose 1-phosphate Fructose 1-phosphate is not converted to fructose as is fructose 6-phosphate, but is cleaved by aldolase B (also called fructose 1-phosphate aldolase) to dihydroxyacetone phosphate (DHAP) and glyceraldehyde

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8 DHAP can directly enter glycolysis or gluconeogenesis, whereas glyceraldehyde can be metabolized by a number of pathways

9 C. Disorders of fructose metabolism A deficiency of one of the key enzymes required for the entry of fructose into intermediary metabolic pathways can result in either a benign condition (fructokinase deficiency), or a severe disturbance of liver and kidney metabolism as a result of aldolase B deficiency (hereditary fructose intolerance, HFI), which is estimated to occur in 1:20,000 live births

10 The first symptoms appear when a baby is weaned and begins to be fed food containing sucrose or fructose Fructose 1-phosphate accumulates, and ATP and inorganic phosphate levels fall significantly, with adenine being converted to uric acid, causing hyperuricemia

11 ESSENTIAL FRUCTOSURIA - Lack of fructokinase - Autosomal recessive (1 in 130,000 births) - Benign, asymptomatic condition - Fructose accumulates in the urine

12 HEREDITARY FRUCTOSE INTOLERANCE ( FRUCTOSE POISONING ) - Absence of aldolase B leads to intracellular trapping of fructose 1-phosphate - Causes severe hypoglycemia, vomiting, jaundice, haemorrhage, hepatomegaly and hyperuricemia - Can cause hepatic failure and death Therapy: Rapid detection and removal of fructose and sucrose from the diet

13 D. Conversion of mannose to fructose 6- phosphate Mannose, the C-2 epimer of glucose, is an important component of glycoproteins Hexokinase phosphorylates mannose, producing mannose 6-phosphate, which, in turn, is (reversibly) isomerized to fructose 6- phosphate by phosphomannose isomerase

14 GALACTOSE METABOLISM The major dietary source of galactose is lactose (galactosyl β-1,4-glucose) obtained from milk and milk products Some galactose can also be obtained by lysosomal degradation of complex carbohydrates, such as glycoproteins, and glycolipids, which are important membrane components Like fructose, the entry of galactose into cells is not insulin-dependent.

15 A. Phosphorylation of galactose Like fructose, galactose must be phosphorylated before it can be further metabolized Most tissues have a specific enzyme for this purpose, galactokinase, which produces galactose 1-phosphate ATP is the phosphate donor

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17 B. Formation of UDP-galactose Galactose 1- phosphate cannot enter the glycolytic pathway unless it is first converted to UDP-galactose This occurs in an exchange reaction, in which UDP is removed from UDP-glucose (leaving behind glucose 1-phosphate), and is then transferred to the galactose 1-phosphate producing UDP-galactose

18 Structure of UDP-Galactose

19 The enzyme that catalyzes this reaction is galactose 1-phosphate uridyltransferase C. Use of UDP-galactose as a carbon source for glycolysis or gluconeogenesis In order for UDP-galactose to enter the mainstream of glucose metabolism, it must first be converted to its C-4 epimer, UDPglucose, by UDP-hexose 4-epimerase

20 This "new" UDP-glucose (produced from the original UDP-galactose), can then participate in many biosynthetic reactions, as well as being used in the uridyltransferase reaction described above, converting another galactose 1-phosphate into UDP-galactose, and releasing glucose 1-phosphate, whose carbons are those of the original galactose

21 D. Role of UDP-galactose in biosynthetic reactions UDP-galactose can serve as the donor of galactose units in a number of synthetic pathways, including synthesis of lactose, glycoproteins, glycolipids, and glycosaminoglycans

22 E. Disorders of galactose metabolism Galactose 1-phosphate uridyltransferase is missing in individuals with classic galactosemia In this disorder, galactose 1-phosphate and, therefore, galactose, accumulate in cells Physiologic consequences are similar to those found in essential fructose intolerance, but a broader spectrum of tissues is affected

23 CLASSIC GALACTOSEMIA Uridyltransferase deficiency Autosomal recessive disorder (1 in 23,000 births) It causes galactosemia and galactosuria, vomiting, diarrhea and jaundice Accumulation of galactose 1-phosphate in nerve, lens, liver and kidney tissues causes liver damage, severe mental retardation and cataracts

24 Antenatal diagnosis is possible by chorionic villus sampling Therapy: rapid diagnosis and removal of galactose (therefore lactose) from the diet

25 LACTOSE SYNTHESIS Lactose is a disaccharide that consists of a molecule of β-galactose attached by a β(1 4) linkage to glucose Therefore, lactose is galactosyl β(1 4)-glucose Lactose, known as the "milk sugar," is produced by the mammary glands of most mammals Therefore, milk and other dairy products are the dietary sources of lactose

26 Lactose is synthesized in the endoplasmic reticulum by lactose synthase (UDPgalactose:glucose galactosyltransferase), which transfers galactose from UDP-galactose to glucose, releasing UDP This enzyme is composed of two proteins, A and B Protein A is a β-d-galactosyltransferase and is found in a number of body tissues

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28 In tissues other than the lactating mammary gland, this enzyme transfers galactose from UDP-galactose to N-acetyl-D-glucosamine, forming the same β(1 4) linkage found in lactose, and producing N-acetyllactosamine a component of the structurally important N- linked glycoproteins In contrast, protein B is found only in lactating mammary glands

29 It is α-lactalbumin, and its synthesis is stimulated by the peptide hormone prolactin Protein B forms a complex with the enzyme, protein A, changing the specificity of that transferase so that lactose, rather than N- acetyllactosamine, is produced