Carbohydrates Metabolism TOPICS Minor pathways for glucose metabolism

Carbohydrates Metabolism

TOPICS • Minor pathways for glucose metabolism. 1. Hexose mono-phosphate (HMP) pathway. 2. Uronic acid pathway. 3. Polyol pathway. • Metabolism of other hexoses (i. e. fructose and galactose 2

Uronic acid pathway of Glucose Ø Synthesis of acidic sugars • D-Glucuronic acid, whose structure is that of glucose with an oxidized carbon 6 (–CH 2 OH → –COOH) I. Glucuronic acid is essential components for synthesis of glycosaminoglycans (GAGs) as Heparin, Hyalouronic acid, and Keratan. ü GAGs are large complexes of negatively charged heteropolysaccharide chains composed of repeating disaccharide unit [acidic sugar–amino sugar]n II. D-Glucuronic acid is also required in detoxification reactions of a number of insoluble compounds , such as bilirubin, steroids, and many drugs.

Uronic acid pathway of Glucose • The active form of glucuronic acid that donates the sugar in GAG synthesis and other glucuronidation reactions is UDP-glucuronic acid, which is produced by oxidation of UDP-glucose. • The end product of glucuronic acid metabolism in humans is D- xylulose 5 -phosphate , which can enter the pentose phosphate pathway. • Deficiency of xylulose reductase→ L-xylulose excreted in urine (Essential Pentosuria is one of Garrod’s tetrad [alkaptonuria, albinism, pentosuria, cystinuria- inborn error of metabolism] • In lower animals, glucuronic acid serves as a precursor of ascorbic acid (vitamin C).

URONIC ACID PATHWAY G-6 -P Phosphoglucomutase G-1 -P + UTP [UDPG Phosphorylase] (enters Uronic acid pathway)

1) Glucuronic acid can be obtained : a) from the diet but in small amounts. b) from the lysosomal degradation of GAGs. c) from glucose 6 -phosphate via the uronic acid pathway. d) A and B e) C and B f) All of the above.

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, in honey • Fructose transport into cells is not insulin dependent and, in contrast to glucose, fructose does not promote the secretion of insulin.

Fructose metabolism Principally in the liver (small intestine, kidney) Essential fructosuria Hereditary fructose intolerance

Fructose Metabolism Ø Disorders of fructose metabolism • A deficiency of fructokinase can result in a benign condition (Essential fructosuria ). • While aldolase B deficiency results of a severe disturbance of liver, small intestine and kidney metabolism (hereditary fructose intolerance [HFI]). • Sucrose should be removed from diet of Patient with HFI

The Polyol Pathway (Sorbitol- Aldose reductase Pathway) • An alternate mechanism for metabolizing a monosacharide to convert it to a polyol (sugar alcohol) by the reduction of an aldehyde group by aldose reductase, thereby producing Sorbitol from Glucose. This reaction oxidizes NADPH to NADP+. • Sorbitol dehydrogenase can then oxidize sorbitol to fructose, which produces NADH from NAD+. • Fructose can enter glycolysis or gluconeogenesis.

The Polyol Pathway(Sorbitol- Aldose reductase Pathway) KEY ENZYMES 1 - Aldose reductase Glucose to Sorbitol Lens, retina, Schwann cell of peripheral nerves, kidney, placenta, RBC, cells of ovaries and seminal vesicles. 2 - Sorbitol dehydrogenase Sorbitol to Fructose In the cells of liver, ovaries, and seminal vesicles Glucose to Sorbitol to Fructose: in seminal vesicles for sperm cell [fructose is preferred carbohydrate energy source] 11

The Polyol Pathway (Sorbitol- Aldose reductase Pathway) • In uncontrolled diabetics that have high blood glucose(Hyperglycemia) - more than the glycolysis pathway can handle the reaction's mass balance ultimately favors the production of sorbitol. • Sorbitol cannot cross cell membranes, and, when it accumulates, it produces osmotic stresses on cells by drawing water into the tissues. • which causes cataract formation, peripheral neuropathy, vascular problems leading to nephropathy and retinopathy In Lenses, Nerves, Kidneys

The Polyol Pathway (Sorbitol- Aldose reductase Pathway) • Activation of the polyol pathway results in a decrease of reduced NADPH and oxidized NAD+; these are necessary cofactors in redox reactions throughout the body, and under normal conditions they are not interchangeable. • The decreased concentration of these NADPH leads to decreased synthesis of reduced glutathione (antioxidant) and nitric oxide • Sorbitol may also glycate nitrogens on proteins, such as collagen, and the products of these glycations are referred-to as AGEs - advanced glycation endproducts. AGEs are thought to cause disease in the human body. 13

Galactose Metabolism • The major dietary source of galactose is lactose obtained from milk and its products, which, when cleaved in the intestine by lactase enzyme, releases equimolar amounts of galactose and glucose. • Galactose transport into cells is not insulin dependent. An Exchange Reaction

Galactose Metabolism Galactose metabolism: Galactitol Aldolase reductase (GALT) 15

Galactose Metabolism ØClinical correlations: A newborn: failure to grow, vomiting and diarrhea after milk • galactosemia (Galactose 1 -phosphate uridylyltransferase (GALT) deficiency) • genetic disease (AR, 1/60 000) • accumulation of galactose and galactitol production • Causes hepatomegaly, jaundice, cataracts, mental retardation, death Management: early diagnose, elimination of galactose from the diet (artificial milk from soybean hydrolysate) 16

A nursing female with classic galactosemia is on a galactose-free diet. She is able to produce lactose in breast milk because : A. galactose can be produced from fructose by isomerization. B. galactose can be produced from a glucose metabolite by epimerization. C. hexokinase can efficiently phosphorylate galactose to galactose 1 phosphate. D. the enzyme affected in galactosemia is activated by a hormone produced in the mammary gland.

2 - The -------- utilize fructose but not glucose. (a) Ovum (b) Spermatozoa (c) Adipose tissue (d) Mammary gland