8-Pathways of Hexose Metabolism..pdf

Pathways of Other Hexose Metabolism Objectives:- After studying this topic, you should be able to:- 1. Describe the uronic acid pathway and its importance for synthesis of glucuronic acid for conjugation reactions and vitamin C. 2. Describe and explain the consequences of large intakes of...

Pathways of Other Hexose Metabolism Objectives:- After studying this topic, you should be able to:- 1. Describe the uronic acid pathway and its importance for synthesis of glucuronic acid for conjugation reactions and vitamin C. 2. Describe and explain the consequences of large intakes of fructose. 3. Describe the synthesis and physiological importance of galactose. 4. Explain the consequences of genetic defects of the uronic acid pathway (essential pentosuria), and fructose and galactose metabolism  Uronic acid pathway  I t is an alternative oxidative pathway for glucose that, like PPP, does not lead to the formation of ATP.  It occurs in liver,  Catalyzes the conversion of glucose to glucuronic , acid, ascorbic acid (vit C -except in human beings) and pentoses. Glucose-6-phosphate is isomerized to glucose-1-phosphate, which then reacts with uridine triphosphate (UTP) to form uridine diphosphate glucose (UDPGlc) in a reaction catalyzed by UDPGlc pyrophosphorylase. UDPGlc is oxidized by NAD-dependent UDPGlc dehydrogenase to yield UDP- glucuronate(active form). Glucuronate is a highly polar molecule. UDP-glucuronate is the source of glucuronate for : 1. Proteoglycans synthesis. 2. Conjugation reaction (steroid hormones, bilirubin, some drugs that are excreted in urine or bile as glucuronide conjugates which is more soluble). Glucuronate is reduced to L- gulonate, the direct precursor of ascorbate (vit C) in animals. In human beings and other species , ascorbic acid cannot be synthesized because of the absence of L- gulonolactone oxidase. Clinical aspect ; Disruption of the uronic acid pathway is caused by enzyme defects & some drugs; Essential pentosuria, is rare benign hereditary condition because of a lack of xylulose reductase. Considerable quantities of xylulose appear in the urine.  drugs activate the uronic acid pathway: 1. Barbital 2. Chlorobutanol 3. Aminopyrine 4. Antipyrine.  Fructose Metabolism Source: Sucrose or high-fructose syrups (HFS).  Fructose undergoes more rapid glycolysis in the liver than glucose because it bypasses the regulatory step catalyzed by phosphofructokinase. Leading to increased : 1. Fatty acid synthesis and esterification, 2. Serum triacylglycerols. 3. LDL cholesterol concentrations. Fructose is converted to fructose-1- phosphate by Fructokinase in liver, kidney, and intestine. This enzyme, its activity is not affected by fasting or by insulin, and this explain why fructose is cleared from the blood of diabetic patients at a normal rate.  Fructose-1-phosphate is cleaved to D- glyceraldehyde and dihydroxyacetone phosphate by aldolase B, an enzyme found in the liver.  D-Glyceraldehyde enters glycolysis via phosphorylation to glyceraldehyde-3-phosphate catalyzed by triokinase.  The two triose phosphates, dihydroxyacetone phosphate, and glyceraldehyde-3-phosphate, may either be degraded by glycolysis or may be substrates for aldolase and hence gluconeogenesis.  Conversion of glucose to fructose (polyol pathway)  D-glucose is converted to D-sorbitol by aldose reductase.  The presence of sorbitol dehydrogenase in the liver, is responsible for the conversion of sorbitol into fructose.  This two reactions important in the seminal vesicles for sperm cells, which use fructose as major carbohydrate energy source. Clinical aspect ; Loading of the liver with fructose may potentiate; 1. Hypertriacylglycerolemia. 2. Hypercholesterolemia. 3. Hyperuricemia. Depletion of inorganic phosphate, fructose1- P accumulate, and ATP level fall, then adenine converted to uric acid, causing hyperuricemia. Decreased availability of hepatic ATP affects gluconeogensis ( hypoglycemia). If the fructose is not removed from the diet, liver failure and death can occur. Essential fructosuria :  Benign and asymptomatic condition due to lack of hepatic fructokinase.  Since fructose is absorbed from the small intestine by passive diffusion, high oral doses may lead to osmotic diarrhea. Hereditary fructose intolerance:  Due to aldolase B deficiency  The effect of hyperglycemia on sorbitol metabolism This pathway increases in activity as the glucose concentration rises in those tissues that are not insulin-sensitive ; the lens, peripheral nerves, and renal glomeruli. If sorbitol dehydrogenase is deficient, sorbitol accumulates. It does not diffuse through cell membranes, causing osmotic damage which can be attribute in part to cataract formation, peripheral neuropathy and vascular problems leading to nephropathy and retinopathy.  Galactose metabolism  From lactose  Galactose is converted in the liver to glucose.  Galactose is synthesized from glucose in the lactating mammary gland.  Galactose is required for the synthesis of glycolipids, proteoglycans, and glycoproteins.  Galactokinase converts galactose to Galactose 1- phosphate which reacts with UDPGlc to form uridine diphosphate galactose (UDPGal) and glucose 1- phosphate catalyzed by galactose-1-phosphate uridyl transferase.  The conversion of UDPGal to UDPGlc is catalyzed by UDPGal 4-epimerase ( freely reversible, so glucose can be converted to galactose, and galactose is not a dietary essential).  The UDPGlc is then incorporated into glycogen.  In the synthesis of lactose in the mammary gland, UDPGal condenses with glucose to yield lactose, catalyzed by lactose synthase.  Clinical aspects Enzyme deficiencies in the galactose pathway cause galactosemia Galactosemias:  Inherited defects of galactokinase, galactose-1- phosphate uridyl transferase. or 4-epimerase.  Galactose which increase in concentration in blood, is reduced by aldose reductase in the eye to the corresponding polyol (galactitol) which accumulate causing cataract.  Accumulation of galactose1-P and galactitol in nerve, liver, and kidney causes liver damage, jundice, vomiting, diarrhea, severe mental retardation, and cataract.  Treatment: remove of galactose and lactose from the diet. The end