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Monosaccaride and Disaccarides Metabolism

Monosaccaride and Disaccarides Metabolism. ASSOC. PROF. DR. CEMİLE KOCA ANKARA ATATÜRK TRAINING AND RESEARCH HOSPITAL. Carbohydrates Are Aldehyde or Ketone Derivatives of Polyhydric Alcohols. Monosaccharides: carbohydrates that cannot be hydrolyzed into simpler carbohydrates.

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Monosaccaride and Disaccarides Metabolism

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  1. Monosaccaride and Disaccarides Metabolism ASSOC. PROF. DR.CEMİLE KOCA ANKARA ATATÜRK TRAINING AND RESEARCH HOSPITAL

  2. Carbohydrates Are Aldehyde or Ketone Derivatives of Polyhydric Alcohols • Monosaccharides: carbohydrates that cannot be hydrolyzed into simpler carbohydrates • Derivatives of trioses, tetroses, and pentoses and of a seven-carbon sugar (sedoheptulose) are formed as metabolic intermediates in glycolysis and the pentose phosphate pathway

  3. ManyMonosaccharidesArePhysiologicallyImportant

  4. Sources of Sugars in Diet • Glucose: lactose (dairy products) and sucrose (table sugar) • Fructose: fruits and sucrose • Galactose: lactose • Mannose: polysaccharides and glycoproteins

  5. Disaccharides digestion

  6. Galactose and fructose metabolism as part of the essential pathways of energy metabolism

  7. Fructose metabolism • ~ 10% of the calories contained in Western diet are supplied by fructose (~ 50g/day) • The major source in diet: ** sucrose (tablesugar) • Alsoas a free monosaccharide in * fruits, *honey, * high-fruct. corn syrup (used to sweeten soft drinks and many foods) • Entry of fructose into cells is not insulin-dependent • does not cause insulin release from beta cells

  8. Fructose Metabolism

  9. Fructose Metabolism • Phosphorylation of fructose « Hexokinase: product: fructose 6-phosphate has a low affinity (high Km) for fructose « Fructokinase: primary mechanism product: fructose 1-phosphate found in the liver (main place of metab.), kidney, & small intestinal mucosa use ATP as the P donor site of metabolism ¤ 75% liver ¤ 20% kidney ¤ 10% intestine

  10. FructoseMetabolism • metabolicfate of fructose: ¤ phosphorylatedtofructose 1-P ¤ Cleavage of fructose 1-P • F 1-P is not converted to F 1,6-BP as F-6-P, but is cleaved by aldolase B to DHAP & glyceraldehyde • Bothaldolase A (found in all tissues) & aldolase B cleave F 1,6-BP produced during glycolysis to DHAP & GA-3P. • DHAP can directly enter glycolysis or gluconeogenesis, • glyceraldehyde can be metabolized by a number of pathways

  11. FructoseMetabolism

  12. Kinetics of fructose metabolism • The rate of fructose metabolism is more rapid than that of glucose because the trioses formed from F-1-P bypass PFK, the major rate-limiting step in glycolysis Note: loading the liver with fructose, e.g., by intravenous infusion, can significantly elevate the rate of lipogenesis caused by enhanced production of acetyl CoA

  13. FructoseMetabolism

  14. Disorders of fructose metabolism Essential fructosuria • fructokinase deficiency  essential fructosuria, a benign condition • aldolase B deficiencyhereditary fructose intoleranceHFI-”fructose poisoning” : a severe disturbance of liver & kidney metabolism (in 1:20,000 live births) Hereditary fructose intolerance

  15. hereditary fructose intolerance • The 1st symptoms appear when a baby begins to be fed food containing sucrose or fructose • Fructose 1-phosphate accumulates, resulting in a drop in the level of inorganic phosphate (Pi) and, therefore, of ATP. As ATP falls, AMP rises. In the absence of Pi, AMP is degraded, causing hyperuricemia • The decreased availability of hepatic ATP affects gluconeogenesis (causing hypoglycemia with vomiting), & protein synthesis (causing a decrease in blood clotting factors & other essential proteins) • If fructose (& therefore, sucrose) is not removed from diet, liver failure & death can occur • Diagnosis of HFI can be made on basis of fructose in urine

  16. Conversion of mannose to fructose 6-phosphate • Mannose, the C-2 epimer of gluc, is an important component of glycoproteins • Hexokinase phosphorylates mannose  mannose 6-P,  is (reversibly) isomerized to F-6-P by phosphomannoseisomerase There is little mannose in dietary CHOs Most intracellular mannose is synthesized from fructose, or produced by degradation of structural CHO’s & salvaged by hexokinase

  17. The polyol pathway Conversion of glucose to fructose via sorbitol • Phosphorylation of sugars: • are rapidly phosphorylated following their entry into cells. They are thereby trapped within cells, because organic P’s can’t freely cross memb’s without specific transporters • Polyolpathway: • An alternate mechanism for metabolizing a monosaccharide • convert it to a polyol by reduction of an aldehyde group, thereby producing an additional hydoxyl group

  18. Sorbitol metabolism . Synthesis of sorbitol: • Aldose reductase:reduces glucose found in many tissues, including the lens, retina, Schwann cells of peripheral nerves, liver, kidney, placenta, RBCs, & cells of the ovaries & seminal vesicles • sorbitol dehydrogenase: oxidize sorbitol to produce fructose in liver, ovaries, sperm & seminal vesicles sperm cellsuse fruc as a major CHO energy source • The pathway from sorbitol to fruc in liver provides a mechanism by which any available sorbitol is converted into a substrate that can enter glycolysis or gluconeogenesis

  19. The effect of hyperglycemia on sorbitol metabolism • ↑glucose in the cells, and an adequate supply of NADPH → ↑ sorbitol production • Accumulated sorbitol remains trapped inside the cell • is exacerbated when sorbitol DH is low or absent (in retina, lens, kidney, nerve cells) • As a result, sorbitol accumulates, causing strong osmotic effects, cell swelling as a result of water retention cataract formation, peripheral neuropathy, and vascular problems leading to nephropathy and retinopathyindiabetes

  20. Lens metabolism in Diabetes: Diabetic cataract: ↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol accumulation → ↑osmolarity,swelling of cellandstructural changes of proteins

  21. Galactose metabolism • The major dietary source:lactose (galactosyl β 1,4-glucose) obtained from milk & milk products • Some galactose can also be obtained by lysosomal degradation of complex CHOs, such as glycoproteins & glycolipids, which are important memb components • Galactose enters glycolysis by its conversion to glucose-1-phosphate (G1P).This occurs through a series of steps • Like fructose, entry of galactose into cells is not insulin dependent

  22. Galactose metabolism 1. Phosphorylation of galactose • Like fruc, galactose must be phosphorylated before it can be further metabolized • Most tissues have a specific enzyme for this purpose, galactokinase, which produces galactose 1-P ATP is the P donor 2. Formation of UDP-galactose There is no direct oxidative pathway for galactose-1-P It has to be converted to UDP-galac. toenterglucose metabolism

  23. 3. Use of UDP-galactose as a carbon source for glycolysis or gluconeogenesis • to enter the mainstream of gluc metabolismUDP-galactose, must be converted to its C-4 epimer, UDP-gluc, by UDP-hexose 4-epimerase

  24. Role of UDP-galactose in biosynthetic reactions UDP-galactose has role in: • Synth.of lactose, glycoproteins, glycolipids, glycosaminoglycans • if no galactose in diet; all tissueUDP-galactose needs can be met by the action of UDP-hexose 4-epimerase on UDP-glucose

  25. Disorders of galactose metabolism:

  26. classic galactosemia • Galactose 1-phosphate uridyltransferasedeficiency • galactose 1-P &galactose, accumulates in cells • genetic disease (AR, 1/25 000-60 000) • hepatomegaly, jaundice, cataracts, mental retargation, death • symptoms starts in 1st week with breast feeding , glycoprot, GAG, lactose

  27. classic galactosemia • The accumulated galactose is shunted into side pathways such as that of galactitol production • This reaction is catalyzed by aldose reductase, the same enzyme that converts glucose to sorbitol Baby has cataracts within days or weeks

  28. Metabolism of galactose

  29. Lactose synthesis

  30. Lactose synthesis • a disaccharide : β-galactose attached by β(1→4) linkage to glucose • So lactose is galactosyl β(1→4)-glucose • known as “milk sugar”, milk & other dairy products are the dietary sources of lactose synthesized in the ER by lactose synthase(UDP-galactose:glucose galactosyltransferase), which transfers galactose from UDP-galactose to glucose, releasing UDP

  31. The enzyme has two subunits: • protein A (β-D galactosyltransferase) found in most cells where it synthesizes N-acetyllactosamine • protein B (α-lactalbumin) found only in the lactating mammary glditssynthesis is stimulated by the peptide hormone, prolactin • When both subunits are present, the transferase produces lactose

  32. protein A: β-D-galactosyltransferase • In tissues other than the lactating mammary gland, this enzyme transfers galactose from UDP-galactose to N-acetyl-D-glucoasamine, • forming the same β(1→4) linkage found in lactose, • producing N-acetyllactosamine, a component of the structurally important N-linked glycoproteins

  33. Figure 12.8. Key concept map for metabolism of fructose and galactose.

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