Pentose phosphate pathway A.Functions 1. NADPH for reductive biosyntheses. 2. ribose-5-phosphate for nucleic acid biosynthesis. 3. a route for the conversion of pentoses to F6P and G3P. 4. Erythrocytes depend on the HMP for NADPH, which is required to maintain glutathione in the reduced state. Reduced glutathione is needed to maintain the integrity of the red blood cell membrane.

PENTOSE PHOSPHATE PATHWAY A.location 1. The pentose phosphate pathway is most active in the erythrocytes, liver, mammary glands, adipose tissue, and the adrenal cortex. 2. Within the cell, the enzymes of this pathway are located in the cytoplasm.

PENTOSE PHOSPHATE PATHWAY  G6PD deficiency can cause hemolytic anemia because in erythrocytes, flux through the HMP is not sufficiently high to maintain reduced glutathione levels. (1)genetic defects. (2)In people with low G6PD activity, certain drugs and chemicals that act as oxidizing substances (e.g., aspirin, primaquine, sulfonamides, and nitrofurans) can causes increased free radical oxidative damage to fatty acid in membranes lead to hemolytic anemia. These compounds reoxidize reduced glutathione and increase the demand for flux through the HMP.

PENTOSE PHOSPHATE PATHWAY  Wernicke-Korsakoff syndrome This syndrome results from chronic thiamine deficiency. Patients with this disorder have been shown to have defective transketolase. It's sometimes seen in patients with chronic alcoholism because of their poor nutrition coupled with impaired absorption of the vitamin. Clinical manifestations of the syndrome include weakness or paralysis and impaired mental function.

PENTOSE PHOSPHATE PATHWAY Regulation. The cellular concentration of NADP+ is the major factor in regulating flux through the pathway. Its availability regulates the rate-limiting G6PD reaction.

II. METABOLISM OF FRUCTOSE  Sources 1. Fructose is a product of the hydrolysis of sucrose, a glucose-fructose disaccharide. 2. Fructose is the major sugar present in plants, diet like fruits and honey.

METABOLISM OF FRUCTOSE  Fructose metabolism in spermatozoa 1. Fructose is the major energy source for spermatozoa and is formed from glucose in the seminal vesicle. The fructose concentration of semen may reach 10 mM, most of which is available for the spermatozoa because fructose is used sparingly by the other tissues that come in contact with the seminal fluid.

METABOLISM OF FRUCTOSE 2. Formation. Glucose is reduced to the sugar alcohol sorbitol, which is then oxidized to fructose. a.Aldose reductase catalyzes the conversion of glucose to sorbitol. Glucose + NADPH + H + →Sorbitol + NADP + a.Sorbitol dehydrogenase catalyzes the conversion of sorbitol to fructose. Sorbitol + NADP→ Fructose +NADPH + H +

METABOLISM OF FRUCTOSE  Regulation of metabolism 1. Unlike glucose, fructose uptake by cells is not regulated by insulin. 2. Because fructose enters the glycolytic pathway as G3P, it bypasses the major regulatory step in glycolysis, which is catalyzed by phosphofructokinase.

SORBITOL METABOLISM IN DIABETES The formation of sorbitol from glucose proceeds rapidly in the lens of the eye and in the Schwann cells of the nervous system. Sorbitol cannot pass through the cell membrane, and in people with diabetes, sorbitol levels build up in these cells because the rate of oxidation of sorbitol to fructose is decreased. The elevated sorbitol causes an increase in osmotic pressure, which may be a cause development of the lens cataracts and the neural dysfunction that occur.

METABOLISM OF GALACTOSE

Galactokinase deficiency leads to an accumulation of galactose in blood and tissues. In the lens of the eye, galactose is reduced by aldose reductase to galacitol, which cannot escape from the cells. This causes an osmotic imbalance, which contributes to the development of cataracts.

METABOLISM OF GALACTOSE Galactose-l-phosphate uridyl transferase deficiency (classic galactosemia) leads to the accumulation of both galactose and galactose-l-phosphate in tissues. Cataracts develop. If not treated, mental retardation and liver cirrhosis may occur because of increased cellular levels of galactose-1-phosphate in neural tissues and liver cells. It's treated by removal of galactose (lactose) from the diet.

METABOLISM OF GALACTOSE  Biosynthesis of lactose 1. In humans, this occurs only in the mammary glands. 2. Lactose is formed from UDP-galactose and glucose in a reaction catalyzed by galactosyl transferase. This enzyme does not use glucose as a substrate in tissues other than the mammary gland.  a-lactalbumin is a protein that binds to galactosyl transferase and modifies its specificity so that it catalyzes lactose formation. The complex of a- lactalbumin and galactosyl transferase is called lactose synthase.  Prolactin increases the rate of synthesis of galactosyl transferase and of a-lactalbumin.

ETHANOL METABOLISM  Oxidation to acetate in the liver 1. Ethanol is oxidized in the liver by a cytosolic alcohol dehydrogenase to acetaldehyde. CH 3 CH 2 O + NAD +  CH 3 CHO + NADH + 2H + 2. The acetaldehyde is further oxidized to acetate by a mitochondrial aldehyde dehydrogenase. CH 3 CHO + NAD + + H2O  CH 3 COO - + NADH + 2H +

ETHANOL METABOLISM Mechanism of methanol and ethylene glycol poisoning. Alcohol dehydrogenase is not a very specific enzyme and also converts methanol to formaldehyde and ethylene glycol to oxalate, both of which are very toxic. Aldehyde dehydrogenase is the enzyme that is inhibited by the drug disulfiram, which is given to alcoholics to discourage drinking. It causes acetaldehyde to accumulate, which leads to severe nausea. However, if alcohol consumption is not discouraged, aldehyde levels may become lethal.