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Overview of Carbohydrate Metabolism Glycogen Glycogen Synthesis UDP-Glucose Glycogen Degradation Glucose-1-P Glucose Glucose-6-P Pentose Phosphate Pathway Glycolysis Gluconeogenesis Triose Phosphates 2 Pyruvate 2 Lactate 2 Acetyl-CoA Oxaloacetate Citrate Citric Acid Cycle C02, H20, 12 ~P Overview of Carbohydrate Metabolism Glycogen Glycogen Synthesis UDP-Glucose Insulin Glycogen Degradation Fed State Glucose-1-P Glucose Glucose-6-P Pentose Phosphate Pathway Glycolysis Gluconeogenesis Triose Phosphates Insulin 2 Pyruvate 2 Lactate 2 Acetyl-CoA Oxaloacetate Citrate Citric Acid Cycle C02, H20, 12 ~P Overview of Carbohydrate Metabolism Glycogen Glucagon/ Epinephrine Glycogen Synthesis UDP-Glucose Glycogen Degradation Glucose-1-P Glucose Glucose-6-P Glucagon/ Epinephrine Gluconeogenesis Glucagon/ Epinephrine Fasted State/ Starvation Pentose Phosphate Pathway Glycolysis Triose Phosphates 2 Pyruvate 2 Lactate 2 Acetyl-CoA Oxaloacetate Citrate Citric Acid Cycle C02, H20, 12 ~P 1 Hexokinase/ * Glucokinase * Phosphofructokinase-1 Pyruvate * kinase HEXOKINASE inhibited by Glu 6-P * * GLUCOKINASE USED IN LIVER Fructose 6-P reduces activity by causing enzyme to translocate to nucleus * * Phosphofructokinase-1 * + Fructose 2,6- bisP AMP - ATP, citrate - Glucagon & Epinephrine in Liver * 2 * * Pyruvate Kinase + fructose-1,6-bisP - ATP, alanine * - glucagon & epinephrine Glucokinase Liver: Insulin Increases Transcription Of Genes Encoding These Enzymes PFK-1 * Pyruvate Kinase * Liver: * PFK-2/ PFK-1 Glucagon Epinephrine Pyruvate Kinase * 3 * PFK-2/ PFK-1 Heart: * Epinephrine * Pyruvate Dehydrogenase (PDH) Lactate PDH Pyruvate + CoASH+ NAD+ -------> Alanine Acetyl-CoA+ CO2 + NADH+ H+ PDH Gene Deficiency: Lactic Acidosis Neurological Defects PDH Activity Low Thiamine Deficiency Arsenic Poisoning Treatment – ketogenic diet 4 Galactosemia Galactokinase Deficiency Elevated galactitol Cataracts Classical Galactosemia Galactose 1-P UridylTransferase Deficiency Elevated galactitol Cataracts Galactosemia Galactosemia Galactosuria Galactosuria Treatment: Eliminate galactose/ Lactose MILK Elevated Galactose 1-P Hepatic Dysfunction Brain Dysfunction (Retardation) Cataracts Autosomal recessive HEREDITARY FRUCTOSE INTOLERANCE A Deficiencyof AldolaseB Symptoms Hypoglycemia Vomiting Jaundice Hepatic failure Treatment: Decrease fructose/sucrose Glucose Homeostasis is Required for Survival Glucose Glycogen Pi Glucose 6-Phosphatase Glucose 6-Phosphate Glycogen Degradation Glycogen Phosphorylase Phosphorylase Kinase Glucose 1-Phosphate Gluconeogenesis Pyruvate 5 Glucose Glucose 6-phosphatase Glucose 6-phosphaate Triacylglycerol Fructose 6-phosphate Fructose 1,6-bisphosphatase -F-2,6-bisP -AMP Fructose 1,6-bisphosphate Glyceraldehyde 3-phosphate 1,3 Bisphosphoglycerate Glycerol Dihydroxyacetone phosphate 3, Phosphoglycerate Glycolysis In other Tissues Muscle Protein Phosphoenolpyruvate Phosphoenolpyruvate Carboxykinase *** Oxaloacetate Some amino acids +AcCoA requires biotin Pyruvate carboxylase Lactate Some amino acids Pyruvate Ethanol metabolism can cause hypoglycemia; the high NADH opposes gluconeogenesis Ethanol metabolism increases NADH Increased NADH promotes the conversion of two glucogenic precursors (pyruvate and oxaloacetate) to lactate and malate. This removes pyruvate and oxaloacetate from the pool of glucogenic precursors. Glycogen Synthesis and Degradation (Overview of key enzymes in pathway) Glucose Pi Glycogen ATP hexokinase glucokinase ADP glycogen phosphorylase glycogen synthase glucose 6-phosphatase Glucose 6-P Glucose 1-P UDP-glucose UTP PPi 6 Pentose Phosphate Pathway (Hexose Monophosphate Shunt) Generates: NADPH – Lipid Biosynthesis Ribose 5-Phosphate – Purine Biosynthesis – e.g., DNA, RNA, CoA A Genetic Deficiency of Glucose 6-Phosphate Dehydrogenase is Associated with Drug-Induced Hemolytic Anemia. 7 Malaria Glucose 6- Phosphate Dehydrogenase Deficiency Shaded Countries: > 1/200 men with deficiency 5-25% in Tropical Africa, Middle East, Tropical Asia, Mediterranean THE RATE-LIMITING ENZYMES IN LIPID METABOLISM Bile Acids 7-α-hydroxylase Dietary Fatty Acids ACAT Cholesterol Cholesterol Ester Fatty Acyl-CoA’s HMG-CoA Reductase CPT-1/ CAT-1 Glycerol Glycerol 3-P or Acetyl-CoA Carboxylase 2-Monoacyl glycerol (intestines) Glucose HSTL ACETYL-CoA Succinyl-CoA Transferase (absent in liver) HMG-CoA Synthase (present only in liver mitochondria) Triacylglycerols OAA Citrate Ketone Bodies CO2, H2O 12 ~P/cycle THE RATE-LIMITING ENZYMES IN LIPID METABOLISM Bile Acids 7-α-hydroxylase Dietary Fatty Acids ACAT Cholesterol Fed State Cholesterol Ester Fatty Acyl-CoA’s HMG-CoA Reductase CPT-1/ CAT-1 Insulin Glycerol Glycerol 3-P or Dietary Glucose Acetyl-CoA Carboxylase 2-Monoacyl glycerol (intestines) Insulin Glucose HSTL ACETYL-CoA Succinyl-CoA Transferase (absent in liver) HMG-CoA Synthase (present only in liver mitochondria) Triacylglycerols OAA Citrate Ketone Bodies CO2, H2O 12 ~P/cycle 8 THE RATE-LIMITING ENZYMES IN LIPID METABOLISM Bile Acids Dietary Fat 7-α-hydroxylase Dietary Fatty Acids ACAT Cholesterol Cholesterol Ester Fatty Acyl-CoA’s HMG-CoA Reductase CPT-1/ CAT-1 Glycerol Glycerol 3-P or Acetyl-CoA Carboxylase 2-Monoacyl glycerol (intestines) Glucose HSTL ACETYL-CoA Succinyl-CoA Transferase (absent in liver) HMG-CoA Synthase (present only in liver mitochondria) Triacylglycerols OAA Citrate Ketone Bodies CO2, H2O 12 ~P/cycle THE RATE-LIMITING ENZYMES IN LIPID METABOLISM Bile Acids 7-α-hydroxylase Dietary Fatty Acids ACAT Cholesterol Cholesterol Ester Fatty Acyl-CoA’s HMG-CoA Reductase CPT-1/ CAT-1 Glycerol Glycerol 3-P or Acetyl-CoA Carboxylase Glucose 2-Monoacyl glycerol (intestines) EpinephrineHSTL ACETYL-CoA Succinyl-CoA Transferase (absent in liver) HMG-CoA Synthase (present only in liver mitochondria) Triacylglycerols OAA Citrate Ketone Bodies Epinephrine CO2, H2O 12 ~P/cycle Acetyl CoA Carboxylase Citrate, Insulin + - Biotin Long Chain Fatty Acids Glucagon, Epinephrine 9 Glucose (From the liver) VLDL (From the liver) Glucose Fatty Acids Glycerol 3-phosphate Insulin PGs - Chylomicron-TAG (from intestines) Fatty Acyl-CoA Triacylgylcerols HSTL: HormoneSensitive Triacylglycerol Lipase Glycerol + Epinephrine Fatty Acids Glycerol (To the liver) Fatty acid-albumin complex (To the liver) Triacylglycerol Epinephrine Glycerol (used by liver for gluconeogenesis) Fatty Acids a) inhibits X Fatty Acid Biosynthesis (b) increases Beta-Oxidation of Fatty Acids (c) increases Ketone Body Formation X increased ATP e) facilitates (d) inhibits Glycolysis Gluconeogenesis Carnitine transports fatty acids into the mitochondrial matrix. CPT –1 Only Inhibitor Is Malonyl-CoA 10 Ketone bodies: Beta-hydroxybutyrate Acetoacetate acetone LDL Metabolism “Statins” Inhibit HMC-CoA Reductase 11 Two Pathways of LDL Clearance HDL2 Oxidized LDL HDL is involved with reverse cholesterol transport * treatment * treatment * treatment 12 From Lippincott 13 Type 1 Collagen Triple-stranded Gly-X-Y repeat Glycine – smallest aa Proline – polyproline helix OH-pro, OH-lys H-bonding Lysine aldehydes cross-linking Disorder Selected Collagen Disorders Collagen synthesis Clinical Manifestations Osteogenesis Imperfecta 1 Decreased synthesis of type 1 collagen Autosomal Dominant – may act like dominant negative Osteogenesis Imperfecta 2 Point mutations & rearrangement of exons in triple helical regions Autosomal Dominant EhlersDanlos susceptibility to fractures sometimes confused with child abuse blue sclerae - translucent connective tissue over choroid Perinatal death; soft, fragile & malformed bones Faulty collagen synthesis Hyperextensive skin, hypermobility of joints, tendency to bleed Fibrillin is essential to the integrity of elastin Marfan’s Syndrome mutation in the fibrillin gene 14 Glycogen Glycogen Synthase Phosphorylase Kinase Glycogen Phosphorylase UDP-Glucose •Pentose Phosphate Pathway (NADPH ribose 5-P, glycolytic intermediates) Glucose 1-P Glucose Hexokinase/Glucokinase Glucose-6-P Glucose 6-Phosphatase Phosphofructokinase-1 (PFK1) Fructose-1,6-Bisphosphatase Triose Phosphates (Glyceraldehyde 3-P Dehydrogenase) Pyruvate Kinase PEP Carboxykinase Lactate Dehydrogenase 2 Pyruvate Pyruvate Carboxylase 2 Lactate Pyruvate Dehydrogenase Acetyl-CoA Oxaloacetate Precursor of Lipids Citrate Formed from Fatty Acid and Ketone Metabolism CO2, H2O, 12 ~ P THE RATE-LIMITING ENZYMES IN LIPID METABOLISM Bile Acids 7-α-hydroxylase Dietary Fatty Acids ACAT Cholesterol Cholesterol Ester Fatty Acyl-CoA’s HMG-CoA Reductase CPT-1/ CAT-1 Glycerol Glycerol 3-P or Acetyl-CoA Carboxylase 2-Monoacyl glycerol (intestines) Glucose HSTL ACETYL-CoA Succinyl-CoA Transferase (absent in liver) HMG-CoA Synthase (present only in liver mitochondria) Triacylglycerols Ketone Bodies OAA Citrate CO2, H2O 12 ~P/cycle ABBREVIATIONS: ACAT: acyl-CoA acyltransferase HSTL: hormone sensitive triacylglycerol lipase (adipose tissue) CPT-1: carnitine palmitoyl transferase-1 CAT-1: carnitine acyl transerfase-1 15 16