Metabolism of Monosaccharides and Disaccharides

Question 1

Glucose & Fructose

Answer 1

1. Glucose is absorbed into the blood more quickly than fructose and has a longer half-life in the blood. Glucose raises insulin levels, but fructose does NOT.
2. It is suspected that the optimal human diet should NOT contain excess amounts of fructose. The reason is that fructokinase has a lower Km and a higher Vmax than adolase B, a metabolic disparity which can lead to the intracellular accumulation of fructose-1-phosphate. This accumulation might possibly result in the Pi and ATP’s being unavailable for other metabolic needs because it is taking everything away.
3. The major energy source for sperm in the seminal fluid i fructose, as it appears to help maintain the acrosome; while inide the female reproductive tract, the sperm utilize glucose

Question 2

Glucose & Galactose

Answer 2

1. Glucose and galactose are epimers
2. The intracellular accumulation of galactose-1-phosphate can result in the unavailability of Pi and ATP
3. Galactitol accumulation in the lens can result in cataract formation as a result of its osmotic activity.
4. Human milk has the highest lactose content of any mammalian species. This might be linke to the energy needs associated with a rapidly growing human brain.

Question 3

Overview

Answer 3

1. Two other monosaccharides–fructose and galactose–occur in significant amounts in diet (primarily in disaccharides), and make important contributions to energy metabolism.
2. Galactose, especially, is an important component of cell structural carbohydrates.

Question 4

Fructose Metabolism

Answer 4

1. The major source of fructose is the disaccharide sucrose, which when cleaved, releases equimolar amounts of fructose and glucose; also found as a free monosaccharide in many fruits, in honey, etc.
2. Entry of fructose into cells is NOT insulin-dependent
3. Fructose does NOT promote the secretion of insulin.

Question 5

Phosphorylation of Fructose

Answer 5

1. Fructose must first be phosphorylated in order to enter the pathways of intermediry metabolism, accomplished by either hexokinase or fructokinse.
2. Hexokinase phosphorylates glucose and other hexoses but has a low affinity (HIGH Km) for fructose, meaning little fructose is converted to fructose 6-P by hexokinase.
3. Fructokinase is the primary enzyme for fructose phosphorylation, found in liver (mostly), kidney, and small intestinal mucosa. Product: Fructose 1-phosphate.

Question 6

Disorders of Fructose Metabolism

Answer 6

1. A deficiency of one of the key enzymes required for the entry of fructose into intermediary metabolic pathways can result in either:
   
   1. A benign condition as a result of fructokinase deficiency (essential fructosuria)
   2. A severe disturbance of liver and kidney metabolism as a result of aldolase B deficiency (hereditary fructose intolerance, HFI).
2. HFI is estimated to occur in 1:20,000 live births
3. First symptoms are noticed when baby begins to be fed food containing sucrose or fructose
4. Fructose 1-P accumulates, resulting in a drop in the level of P and ATP.
5. In the absence of Pi, AMP is degraded causing hyperuricemia (and lactic acidosis)
6. Decreased hepatic ATP affects gluconeogenesis and protein synthesis (and kidney function)
7. Diagnosis of HFI made on the basis of fructose in the urine, enayme eassay or by DNA-based testing
8. Sucrose and sorbitol as well as fructose must be removed from the diet to prevent liver failure and possible death
9. Individuals with HFI display aversion to sweets and have an absence of dental caries in general.

Question 7

Cleavage of Fructose 1-Phosphate

Answer 7

1. Fructose 1-P is not phosphorylated to Fructose 1,6-bisphosphate as is fructose 6-P, but is cleaved by aldolase B to dihydroxyacetone phosphate (DHAP) and glyceraldehyde.
   
   1. All of aldolases A, B, and C cleaves fructose 1,6-bisphosphate but only aldolase B can cleave fructose 1-P.
2. DHAP can directly enter glycolysis or gluconeogenesis, whereas glyceraldehyde can be metabolized by a number of pathways.
3. The rate of fructose metabolism is more rapid than that of glucose because it bypasses phosphofructokinase-1 (PFK-1), the major rate-limiting step in glycolysis.

Question 8

Mannose to F 6-P

Answer 8

1. Mannose, the C-2 epimer of glucose, is an important component of glycoproteins
2. Hexokinase phosphorylates mannose, producing mannose 6-phosphate, which in turn is isomerized to F 6-P by phosphomannose isomerase.

Question 9

Conversion of glucose to fructose via sorbitol

Answer 9

1. Most sugars are rapidly phosphorylated upon entry into cells therby trapped within the cells.
2. Also, monosaccharide is converted to a polyol (sugar alcohol) by the reduction of an aldehyde group, thereby producing an additional hydroxyl group.
3. Aldose reductase reduces glucose, producing sorbitol.
4. Sorbitol dehydrogenase, which can oxidize the sorbitol to produce fructose, is found in the cells of liver, ovaries, and seminal vesicles.
5. The two-reaction pathway from glucose to fructose in the seminal vesicles is for the benefit of sperm cells, which use fructose as a major carbohydrate energy source.
6. Sorbitol dehydrogenase in the liver provides a mechanism by which any available sorbitol is converted into a substarte that can enter glycolysis or gluconeogenesis.
7. Effect of hyperglycemia on sorbitol mechanism:
   
   1. Since insulin is not required for glucose in the aformentioned mechanism, additional glucose may enter the cells during times of hyperglycemia.
   2. Elevated intracellular glucose concentrations and an adequate supply of NADPH cause aldose reductase to produce a significant increase in the amount of sorbitol, which remains trapped inside the cells.
   3. Sorbitol accumulates in these cells, causing strong osmotic effects & thus swelling as a result.
   4. This may play part in cataract formation, peripheral neuropathy, and microvascular problems leading to nephropathy and retinopathy.

Question 10

Galactose Metabolism

Answer 10

1. The major dietary source of galactose is lactose obtained from milk and milk prodcuts, digested via beta-galactosidase (lactase).
2. It can also be obtained by lysosomal degradation of complex carbohydrates, such as glycoproteins & glycolipids, which are important membrane components.
3. Like fructose, the entry of galactose into cells is NOT insulin-dependent.
4. Phosphorylation of galactose:
   
   1. Like fructose, galactose must be phosphorylated before being metabolized; carried out by galactokinase, with ATp being phosphate donor.
5. Formation of UDP-galactose:
   
   1. Galactose 1-P can NOT enter the glycolytic pathway unless it is first converted to UDP-galactose.
   2. This occurs in an ‘exchange reaction’, where UDP-glucose reacts with galactose 1-P, producing UDP-galactose and glucose 1-P; this is done by enzyme galactose 1-phosphate uridyltransferase (GALT).
6. UDP-galactose as a carbon source
   
   1. UDP-galactose must first be converted to UDP-glucose by UDP-hexose 4-epimerase. This ‘new’ UDP-glucose can then participate in many biosynthetic reactions, as well as being used in the GALT reaction.

Question 11

Role of UDP-galactose in biosynthetic reactions

Answer 11

1. UDP-galactose can serve as the donor of galactose units in synthetic pathways including synthesis of lactose, glycoproteins, glycolipids, and glycosaminoglycans.
2. If galactose is not provided by the diet, all tissue requirements for UDP-galactose can be met by the action of UDP-hexose 4-epimerase on UDP-glucose.
3. GALT is deficient in individuals with classic galactosemia and galactose 1-P and therefore galactose accumulate in cells.
4. Physiological consequences are similar to those of hereditary fructose intolerance but broader spectrum affected.
5. The accumulated galactose is shunted into side pathways such as that of galactitol production, carried out by aldose reductase, the same enzyme that converts glucose to sorbitol.
6. Deficiency in galactokinase results in a less sever disorder.

Question 12

Lactose Synthesis

Answer 12

1. Lactose is galactosyl beta(1→4)-glucose
2. Mmilk and other dairy prodcuts are the dietary sources of lactose.
3. Lactose is synthesized in the Golgi by lactose synthase which transfers galactose from UDP-galactose to glucose, releasing UDP.
4. The enzyme is composed of two proteins, A and B:
   
   1. Protein A is a beta-D-galactosyltransferase and transfers galactose from UDP-galactose to N-acetyl-D-glucosamine producing N-acetyllactosamine–a component of N-linked glycoproteins.
   2. Protein B is found only in lactating mammary glands and is alpha-lactalbumin, and its synthesis is stimulated by the peptide hormone prolactin.
   3. Protein B forms a complex with Protein A, changing the specificity of that transferase so that lactose, rather than N-acetyllactosamine, is produced.