Carbohydrate Metabolism Lecture #2 PDF

Carbohydrate Metabolism Dr NN Mhlongo Medical Biochemistry [email protected]  Objectives Discuss HMP pathway and its importance Highlight some disorders associated with carbohydrate metabolism  Hexose Monophosphate Pathway Alternative route...

Carbohydrate Metabolism Dr NN Mhlongo Medical Biochemistry [email protected]  Objectives Discuss HMP pathway and its importance Highlight some disorders associated with carbohydrate metabolism  Hexose Monophosphate Pathway Alternative route for glucose oxidation, not for energy production. Occurs cytosol of liver, adipose tissue, ovaries, testes, RBCs & retina. Oxidative irreversible phase: Glucose 6-phosphate undergoes dehydrogenation and decarboxylation to yield ribulose 5-phosphate. Nonoxidative reversible phase: Six molecules of ribulose 5-P are converted to 5 molecules of glucose 6-P by two enzymes: transketolase and transaldolase Pentose Phosphate Pathway HMP pathway continued  Importance of HMP pathway Provides ribose 5-phosphate required for synthesis of nucleotides and nucleic acids. Main source of NADPH, required for: o Reductases: 1. Glutathione reductase 2. Folate, retinal reductase 3. Reductases of FA, steroid synthesis o Hydroxylases: Steroids hydroxylase o NADPH Oxidase: Phagocytosis Defective glucose-6-phosphate dehydrogenase Mutations in G6PD Oxidative stress Causative agents of oxidative stress: Fava beans, certain drugs Consequence of oxidative stress: Hemolytic crisis on exposure to above factors G6PD and oxidative stress: G6PD deficiency → HMP inhibition →↓NADPH→ glutathione reductase inhibition, resulting in ↓reduced GSH → failure to protect cells from oxidative damage. Leads to lysis of red blood cells, haemolytic anemia and jaundice. Haemolytic anemia  Favism Vicine causes oxidative stress and hemolytic anaemia in people with defective G6PD enzyme. RBC have denatured hemoglobin Copyright WW Norton & Company, Inc., Miesfeld & McEvoy Biochemistry, 2021 presenting as Heinz bodies.  Uronic acid Pathway An alternative route for glucose oxidation Occurs in cytosol of liver Importance of Uronic acid pathway: o Main function is formation of UDP-glucuronate: 1. Glycosaminoglycans (GAGs) synthesis 2. Synthesis of L-ascorbic acid (not in human) 3. Conjugation reactions: with bilirubin, steroids to make them more soluble, easily excreted Galactose metabolism Galactose metabolism Galactose metabolism  Galactose metabolism: inherent disorder Impaired metabolism of galactose - Galactosaemia All three enzymes may be defective Deficiency of galactose-1-phosphate uridylyltransferase (GALT) Galactokinase and UDP-galactose epimerase deficiencies may Galactose disrupt the normal galactose metabolism. Levels of galactose-1-phosphate reach toxic levels & galactose is alternatively reduced to galactitol. Galactitol → direct damage to tissues → hepatomegaly, cirrhosis, renal failure, feeding intolerance, vomiting, hypoglycemia, seizure, lethargy, intellectual & behavioural impairment, cataracts, speech difficulties, low bone mineral density, tremors & primary ovarian insufficiency.  Fructose metabolism: inherent disorders Deficiency of aldolase B which splits fructose-1,6- bisphosphate → dihydroxyacetone phosphate & glyceraldehyde and converts the triphosphates → glucose & lactate. Accumulation of fructose-1,6-bisphosphate inhibits both hepatic glycogenolysis & gluconeogenesis, hence inducing hypoglycaemia & result in ATP depletion. Causes inhibition of protein synthesis, ultrastructural lesions, hepatic & renal dysfunction.  Glycogen Storage Diseases Inherent GSD – glycogen metabolism disorder associated with abnormal concentration and/or structure of glycogen in different tissues 12 different types of GSD are classified based on the deficient enzymes and affected tissues Liver and muscles Most common types with hepatic involvement are GSD I, III. Glycogen Storage Diseases Features of GSD  GSD I Glucose-6-phosphatase (G6Pase) deficiency Defect affects glycogenolysis and gluconeogenesis Two forms: GSDIa & GSDIb GSD Ia → mutations in a gene encoding for G6Pase GSD Ib → mutations in a glucose-6-phosphate translocase (G6PT) gene, which transports glucose-6- phosphate from cytoplasm to microsomes. G6Pase is expressed in liver, kidney and intestine G6Pase deficiency → excessive accumulation of glycogen and lipids in affected organs Endogenous glucose production by G6PT pathway is essential for normal neutrophil function  GSD II Alpha-1,4-glucosidase deficiency Alpha-1,4-glucosidase degrades smaller quantities of glycogen Deficiency → glycogen accumulation in the cells of numerous tissues, mostly in lysosomes, which transform into large vacuoles Abundant deposits - in cardiac and skeletal muscles Glycogenolysis is not impaired Some patients have a deficiency in precursor protein synthesis, while in others the amount of mature enzyme is insufficient or the enzyme has no catalytic activity  GSD III Deficiency of cytosolic glycogen debrancher enzyme, a monomer consisting of 2 catalytic units (amylo-1,6- glucosidase and oligo-1,4-1,4-glucanotransferase) The accumulated glycogen resembles dextrin, which is a product of glycogen degradation by phosphorylase Clinical presentation may be similar to type I GSD, with hypoglycaemia, hepatomegaly and hyperlipidaemia. Two forms of the disease exist: - GSD type IIIa - the liver, skeletal muscles, and cardiac muscle are involved. - GSD type IIIb - only the liver is involved.  GSD IV Accumulation of abnormally structured glycogen in the liver, heart, and neuromuscular system The abnormal glycogen has long external branches that resemble amylopectin. This form of glycogen is less soluble; liver cirrhosis probably arises as a reaction to this insoluble material. Associated with polyglucosan inclusions in myofibrils; inclusions are characteristic of brancher enzyme deficiency  GSD V The principal sources of energy are glycogen and anaerobic glycolysis. With further physical activity, glucose and FAs become irreplaceable energy sources for the skeletal muscles. Skeletal muscles use energy from endogenous glycogen (glycogenolysis by way of muscle phosphorylase) & signs of muscle fatigue occur after glycogen depletion. This is why patients with McArdle disease tolerate moderate physical activity relatively well, while intense physical exertion leads to disturbances & symptoms of the disease. Muscle glycogen concentrations increase, but its molecules are normal in structure.  GSD VI Deficiency of liver glycogen phosphorylase Rate-limiting enzyme that is necessary during glycogenolysis. Hepatic phosphorylase is activated in a series of reactions that requires adenylate cyclase, protein kinase A, & phosphorylase kinase. Glucagon stimulates a chain of reactions involved in the activation of phosphorylase  Insufficient G-6-Pase activity G-6-P cannot be converted into free glucose G-6-P is metabolized to lactic acid or incorporated into glycogen Large quantities of glycogen are formed & stored in the cytoplasm of hepatocytes (renal & intestinal mucosa cells-minimal) Metabolic effects: - hypoglycaemia Secondary abnormalities are: - hyperlactataemia, - metabolic acidosis, - hyperlipidaemia, - hyperuricaemia  Hypoglycaemia Glucose levels lower than normal in blood G-6-Pase deficiency blocks the process of glycogen degradation & gluconeogenesis in the liver, preventing the production of free glucose Patients with GSD type I have fasting hypoglycaemia Despite the metabolic block, the endogenous glucose formation is not fully inhibited Hypoglycaemia inhibits insulin secretion and stimulates glucagon and cortisol release  Hyperlactataemia Lactic acid production exceeds lactic acid clearance Undegraded G-6-P, galactose, fructose, and glycerol are metabolized via the G-6-P pathway to lactate Elevated blood lactate levels cause metabolic acidosis  Hyperuricaemia Blood uric acid levels are raised because of the increased endogenous production  Glycogen synthase deficiency Extremely rare Very little glucose is converted to glycogen Results in hyperglycaemia and hyperlactataemia