Lecture 9: Metabolism of fructose, galactose, alcohol and its clinical relevance

Objectives: · Metabolism of fructose · Metabolism of galactose · Pathway of alcohol metabolism · Explain the metabolic defects (fructosuria , hereditary fructose intolerance (fructose poisoning) Explain the metabolic defects of galactose (galactosemia) Learning outcomes: At the end of the lecture, students should be able to: · Describe the pathway of fructose metabolism · Describe the pathway of galactose metabolism · Outline the pathway of alcohol metabolism Explain the metabolic defect and clinical symptoms of fructosuria hereditary fructose intolerance (fructose poisoning) Explain the metabolic defect and clinical symptoms of galactosemia

Introduction Genetically determined biochemical disorders. Due to the deficiency or absence of enzymes catalyzing the particular biochemical step. Results in the accumulation of the metabolites in the body fluids Metabolites excreted in urine. Inborn errors of carbohydrate metabolism

Fructose Metabolism Metabolism of Fructose : Different pathways in muscle and liver. Latter involves fructokinase and fructose 1-phosphate aldolase B

Disorders of Fructose Metabolism Metabolism of Fructose : Different pathways in muscle and liver. Involves the enzymes fructokinase and fructose 1-phosphate aldolase B. Fructosuria In normal individuals,  80% of the ingested fructose is converted to glucose, while the rest is broken down to form lactic acid. Fructosuria is due to the deficiency of fructokinase, required for the conversion of fructose to fructose 1-phosphate → accumulation of fructose in blood Fructose is excreted in urine. Benign, asymptomatic condition. Heredity Fructose Intolerance (Fructose Poisoning) • Absence of fructose 1-phosphate aldolase B leads to intracellular trapping of fructose 1-phosphate • Causes severe hypoglycemia, vomiting, jaundice, and hemorrhage • Can cause severe hepatic failure Therapy: rapid detection and removal of fructose and sucrose from the diet

Fructosuria (fructokinase deficiency) 2. Fructose intolerance (fructose 1 P aldolase B)

Metabolism of galactose

Galactosaemia Autosomal recessive inborn error of galactose metabolism. Due to the deficiency of galactose 1-phosphate uridyl transferase which metabolizes galactose to glucose in the liver (→ severe disease) Occasionally due to galactokinase deficiency → disorder mild. Deficiency of uridyl transferase → Accumulation of galactose 1-phosphate in blood and erythrocytes and excreted in urine.

Galactosaemia - symptoms Clinically - vomiting, diarrhea and jaundice, the child fails to grow, develops enlargement of liver. If the infant should survive, the child will be mentally retarded and have cirrhosis of the liver and cataracts. Galactose reduced to galactitol, initiator of cataract formation in the lens and plays role in central nervous system damage These patients often only achieve intelligence in the low normal range and have speech problems, growth failure and ovarian dysfunction. If the child is placed on a diet completely free from galactose and lactose (glucose-galactose) , it improves dramatically. The infant should receive a nutritionally complete lactose-free milk substitute and this should be used to replace normal milk thereafter. Prenatal diagnosis is by measurement galactose 1-phosphate in blood.

Metabolism of alcohol

1. Conversion of pyruvic acid to lactic acid - Increased lactic acid formation, reduced gluconeogenesis; 2. Excess NADH- Increased of lipid synthesis 3. Excess of NADH- Increased ATP-Inhbition of oxidation of fatty acid spiral and acetyl TCA cycle, fat accumulation in blood, Increased ketone body formation, incresed blood lipids.

Alcoholism Effects: A central role in the toxicity of alcohol may be played by acetaldehyde itself. Although the liver converts acetaldehyde into acetic acid, it reaches a saturation point where some of it escapes into the blood stream. The accumulated acetaldehyde exerts its toxic effects by inhibiting the mitochondria reactions and functions and causes further liver damage--hepatitis and cirrhosis. Recent investigations have suggested that acetaldehyde may be responsible for the development of alcohol addiction. Acetaldehyde in the brain may inhibit enzymes designed to convert certain nerve transmitters from aldehydes to acids. The nerve transmitters that accumulate may then react with the acetaldehyde to form compounds which are startlingly similar to certain morphine-type compounds.

References Benyon, S. Metabolism and Nutrition. Mosby (1998) Frayn, K.N. Metabolic Regulation. Portland Press (1996) Chapter 10. Garrow, J.S. & James, W.P.T. Human Nutrition and Dietetics. Churchill Livingstone (1993)  Guthrie, H. Human Nutrition. Mosby (1995) (For an American View!)  Vasudeva. Biochemistry for Medical Students. http://www.ucs.mun.ca/~skaur/3200/lecture.html http://www.ucs.mun.ca/~skaur/3200/alcohol.html