CARBOHYDRATE METABOLISM-Fructose & galactose

Lecture 8

Dr. Stanley Mukanganyama Department of Biochemistry University of Zimbabwe MBChB and BDS1 2005

Fructose Metabolism
Diets containing large amounts of sucrose (a disaccharide of glucose and fructose) can utilize the fructose as a major source of energy. Pathway to utilization of fructose differs in muscle and liver. Muscle which contains only hexokinase can phosphorylate fructose to F6P which is a direct glycolytic intermediate. In the liver which contains mostly glucokinase, which is specific for glucose as its substrate, requires the function of additional enzymes to utilize fructose in glycolysis. Hepatic fructose is phosphorylated on C-1 by fructokinase yielding fructose-1-phosphate (F1P).

Fructose Metabolism
In liver aldolase B that predominates can utilize both F-1,6-BP and F1P as substrates When presented with F-1-P the enzyme generates DHAP and glyceraldehyde. DHAP converted, by triose phosphate isomerase, to G3P and enters glycolysis. Glyceraldehyde phosphorylated to G3P by glyceraldehyde kinase or converted to DHAP through the concerted actions of alcohol dehydrogenase, glycerol kinase and glycerol phosphate dehydrogenase.

Entry of fructose carbon atoms into the glycolytic pathway in hepatocytes

Clinical Significances of Fructose Metabolism

Hereditary fructose intolerance is a potentially lethal disorder resulting from a lack of aldolase B which is normally present in the liver, small intestine and kidney cortex. characterized by severe hypoglycaemia and vomiting following fructose intake. Prolonged intake of fructose by infants with this defect leads to vomiting, poor feeding, jaundice, hepatomegaly, haemorrhage and eventually hepatic failure and death. Hypoglycemia that result following fructose uptake is caused by fructose-1-phosphate inhibition of glycogenolysis, by interfering with the phosphorylase reaction, and inhibition of gluconeogenesis at the deficient aldolase step. between 1 in 10,000 to 1 in 50,000 persons exhibit fructose intolerance Patients remain symptom free on a diet devoid of fructose and sucrose.

Hereditary fructose-1,6bisphosphatase deficiency

results in severely impaired hepatic gluconeogenesis and leads to episodes of hypoglycemia, apnea, apnea hyperventillation, ketosis and lactic acidosis. Symptoms can take on a lethal course in neonates. Later in life episodes are triggered by fasting and febrile infections.

fructose such a strong signal for release of glucokinase If fructose comes to the liver, it will be taken up and very quickly metabolized Rapid entry of fructose into glycolysis leads to fatty acid synthesis in the liver. Because fructose metabolism "fills" glycolysis with substrate at a very high rate, frequent use of sucrose (dimer of fructose and glucose) or fructose promotes fat production. Plasma triglyceride levels are increased by the ingestion of large amounts of sugar. There is a correlation between sugar consumption, high plasma lipid levels and atherosclerosis.

Fructose Metabolism and its Influence on Glucose Metabolism

The new sweetener, high fructose corn syrup (HFCS)

contains either 42 % or 55 % fructose. from corn through hydrolysis of starch. Resulting glucose syrup is then isomerized to the sweeter high fructose syrup enzymatically. widely used today in commercial production of soft drinks, breakfast cereals, baked goods and condiments. Total sugar consumption has increased in the USA during the past 30 years despite a real fall in sucrose consumption. Decreased use of sucrose is more than balanced by substituting fructose for sugar in commercial food production. The global distribution of soft drinks, breakfast cereals and fast food is leading to similar increases in sugar consumption in many areas. Fructose does not cause insulin release from beta cells, as these lack fructokinase. One of the results of this is that fructose consumption does not dampen appetite. This may lead to increased caloric intake with obesity and the metabolic syndrome as a result.

Galactose Metabolism
metabolized from the milk sugar, lactose (glucose + galactose), enters glycolysis by its conversion to glucose-1-phosphate (G1P). phosphorylated by galactokinase to yield galactose-1phosphate. Epimerization of galactose-1-phosphate to G1P requires the transfer of UDP from uridine diphosphoglucose (UDP-glucose) catalyzed by galactose-1-phosphate uridyl transferase. Generates UDP-galactose and G-1-P. UDP-galactose epimerized to UDP-glucose by UDPgalactose-4 epimerase. UDP portion is exchanged for phosphate generating glucose-1-phosphate which then is converted to G6P by phosphoglucose mutase.

Entry of galactose carbon atoms into the glycolytic pathway. The full name for the enzyme UDP-Glc pyrophos. is UDP-glucose pyrophosphorylase, that of UDP-Glc:Gal-1-P uridylyltransferase is UDPglucose:-D-galactose-1-phosphate uridylyltransferase.

Clinical Significances of Galactose Metabolism

Classic galactosemia a major symptom of two enzyme defects: One results from loss of the enzyme galactose-1-phosphate uridyl transferase. The second form of galactosemia results from a loss of galactokinase. These two defects are manifest by a failure of neonates to thrive. Vomiting and diarrhoea occur following ingestion of milk, hence individuals are termed lactose intolerant.

Clinical Significances of Galactose Metabolism

impaired liver function (which if left untreated leads to severe cirrhosis), elevated blood galactose, hypergalactosemia, hyperchloremic metabolic acidosis, urinary galactitol excretion and hyperaminoaciduria. Unless controlled by exclusion of galactose from the diet, these galactosemias can go on to produce blindness and fatal liver damage. Even on a galactose-restricted diet, transferase-deficient individuals exhibit urinary galacitol excretion and persistently elevated erythrocyte galactose-1-phosphate levels.

Clinical Significances of Galactose Metabolism

Blindness is due to the conversion of circulating galactose to the sugar alcohol galactitol, by an NADPH-dependent galactose reductase that is present in neural tissue and in the lens of the eye. At normal circulating levels of galactose this enzyme activity causes no pathological effects. a high concentration of galactitol in the lens causes osmotic swelling, with the resultant formation of cataracts and other symptoms. Principal treatment of these disorders eliminate lactose from the diet.

Glycogenesis