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Transcript
Metabolism of pentoses, glycogen, fructose and galactose Alice Skoumalová 1. The Pentose Phosphate Pathway An overview: The pentose phosphate pathway (PPP): occurs in the cytosol in all cells Two stages: 1) Oxidative (irreversible) • Products: → Ribulose 5-phosphate (nucleotide synthesis) → NADPH (fatty acid synthesis, detoxification, reduction of glutathion) 2) Nonoxidative (reversible) • Conversion of Ribulose 5-phosphate to intermediates of glycolysis • Production of Ribulose 5-phosphate from intermediates of glycolysis 1. The oxidative phase of PPP: Regulation: Glucose 6-phosphate dehydrogenase • inhibition - by NADPH • induction - by insulin/gluckagon ↑ 2. The nonoxidative phase of PPP: The role of PPP in maintenance of the erythrocyte membrane integrity: Clinical correlations: Treatment by certain drugs (i.e. sulfonamides) Increased production of free radicals People with glucose 6-phosphate dehydrogenase deficiency (7% of the world population) reduced protection of erythrocytes against FR hemolysis, hemoglobinuria, hemolytic anemia Pathways that require NADPH: Detoxification • Reduction of oxidized glutathione • Cytochrome P450 monooxygenases Reductive synthesis • Fatty acid synthesis • Fatty acid chain elongation • Cholesterol synthesis • Neurotransmitter synthesis • Deoxynucleotide synthesis •Superoxide synthesis Summary: The pentose phosphate pathway A shunt from glycolysis Production of NADPH (reductive syntheses, detoxifications), ribose 5-phospate Conversion to intermediates of glycolysis Isomerases, epimerases, transketolases, transaldolases Glucose 6-phosphate dehydrogenase deficiency 2. Metabolism of glycogen Glycogen α-D-Glucose, α-1,4 and α-1,6 link (branching every 8-10 units) source of energy in animals (liver, muscles) highly branched structure (rapid degradation and synthesis, better solubility) Nonreducing end glycogenin The role of glycogen in muscles and liver: Decrease in glucose in the blood High ATP demand → glycogen degradation → glycogen degradation → release of glucose to the blood → anaerobic glycolysis Glucose 6-phosphatase (only in liver) Glycogen metabolismoverview: Synthesis and degradation of glycogen: → different enzymes (regulation!) Glycogen synthesis: A glycogen primer - not degraded - synthesis (autophosphorylation of glycogenin) Transfer of 6-8 units Glycogen synthase (regulation) An energy-requiring pathway (UTP) Glycogen degradation: Chain cleavage (phosphorolysis) - to 4 units from a branch point - The debrancher enzyme (transfer of 3 units, hydrolysis of 1 glucose) Glycogen phosphorylase (regulation) Glycogen storage diseases: Type Enzyme affected Genetics I (Von Gierke´s Glucose 6phosphatase AR Liver (1/200 000) Hypoglycemia, lactate acidosis, hyperlipidemia, hyperuricemia. Enlarged liver and kidney. Lysosomal α-1,4glucosidase AR Organs with lysosomes Glycogen deposits in lysosomes. Hypotonia, cardiomegaly, cardiomyopathy (Infantile f.). Muscle weakness (Adult f.) The debrancher enzyme AR Liver, muscle, heart Hepatomegaly, hypoglycemia Muscle glycogen phosphorylase AR Muscle Exercise-induced muscular pain, cramps, muscle weakness disease) II (Pompe disease) III (Cori´s disease) V (McArdles disease) Organ involved Manifestations Clinical correlations: Maternal malnutrition in the last trimester of pregnancy (physiologically: glycogen formation and storage during the last 10 weeks of pregnancy by the fetus → reserve for first hours → prevention of hypoglycemia) reduced or no glycogen reserve in the fetus after birth → hypoglycemia, apathy, coma Regulation of liver and muscle glycogen metabolism: State Regulators Response Fasting Glucagon ↑, Insulin ↓ cAMP ↑ Glycogen degradation ↑ Glycogen synthesis ↓ Carbohydrate meal Glu ↑, Glucagon ↓, Insulin ↑ cAMP ↓ Glycogen degradation ↓ Glycogen synthesis ↑ Exercise and stress Adrenalin ↑ cAMP ↑, Ca2+-calmodulin ↑ Glycogen degradation ↑ Glycogen synthesis ↓ Fasting (rest) Insulin ↓ Glycogen synthesis ↓ Glucose transport ↓ Carbohydrate meal (rest) Insulin ↑ Glycogen synthesis ↑ Glucose transport ↑ Exercise Epinephrine ↑ AMP ↑, Ca2+-calmodulin ↑, cAMP ↑ Glycogen synthesis ↓ Glycogen degradation ↑ Glycolysis ↑ Liver Muscle Regulation of glycogenolysis in the liver by glucagon: cAMP → protein kinase A: 1. inactivates glycogen synthase 2. activates glycogen phosphorylase Regulation of glycogenolysis in muscle: Summary: Glycogen metabolism Different role of glycogen stores in the liver and muscles Glycogen synthesis and degradation are separate pathways (regulation) Glycogen storage diseases 3. Fructose and Galactose metabolism Fructose metabolism Essential fructosuria Hereditary fructose intolerance Principally in the liver (small intestine, kidney) Aldolase B: low affinity for fructose 1-phosphate (→ accumulation of fructose 1-phosphate in the liver ) The polyol pathway Seminal vesicles (spermatozoa use fructose) Accumulation of sorbitol in diabetic patients Lens (diabetic cataract) Muscles, nerves (periferal neuropathy) Galactose metabolism: Lens metabolism: Diabetic cataract : ↑glucose concentration in the lens → ↑aldose reductase activity → sorbitol accumulation → ↑osmolarity, structural changes of proteins Clinical correlations: A newborn: failure to thrive, vomiting and diarrhea after milk galactosemia (Galactose 1-phosphate uridylyltransferase deficiency) genetic disease (AR, 1/60 000) hepatomegaly, jaundice, cataracts, mental retargation, death Management: early diagnose, elimination of galactose from the diet (artificial milk from soybean hydrolysate) Summary: Fructose and Galactose metabolism Conversion to intermediates of glycolysis Genetic abnormalities, accumulation of intermediates, tissue damage Accumulation of sorbitol in diabetes Pictures used in the presentation: Marks´ Basic Medical Biochemistry A Clinical Approach, third edition, 2009 (M. Lieberman, A.D. Marks) Textbook of Biochemistry with Clinical Correlations, sixth edition, 2006 (T.M. Devlin)