Biochemistry Glycolysis PDF

1A BIOCHEMISTRY GLYCOLYSIS DR. BRENDO JANDOC I. OVERVIEW  Glycolysis  initial step in the metabolism of glucose  glucose...

1A BIOCHEMISTRY GLYCOLYSIS DR. BRENDO JANDOC I. OVERVIEW  Glycolysis  initial step in the metabolism of glucose  glucose  2 pyruvate  results in the net ATP production  SOURCES of CARBON and ENERGY for GLYCOLYSIS Carbon Sources  Starch- major nutrient derived from ingested plant cells  Lactose- disaccharide of glucose and galactose - major carbohydrate component of milk  Fructose- ketose isomer of glucose - important carbohydrate source when sucrose (glucose-fructose disaccharide) intake is high Glucose  product of starch digestion  major form in which carbohydrate is presented to the cells of the body Glycogen  major form of carbohydrate storage in animals  highly branched polymer of glucose  REACTIONS of GLYCOLYSIS  2 molecules of NADH are formed when pyruvate is produced  Pyruvate is the end product of glycolysis in cells with  NADH is reconverted to NAD+ when lactate is mitochondria and an adequate supply of oxygen the end product  Aerobic Glycolysis 1. Phosphorylation of Glucose  oxygen is required to reoxidize the NADH  irreversible formed during the oxidation of glyceraldehyde 3-  effectively trapping glucose as glucose phosphate 6-phosphate (too polar  does not  sets the stage for the oxidative decarboxylation of diffuse out of the cell) pyruvate to acetyl CoA  lack of specific carriers   produces 6 moles ATP / mole of glucose phosphorylated sugar molecules do not  Stages of Glycolysis readily penetrate cell membranes 1. Conversion of Hexose to Triose Phosphate A. Hexokinase I  6 carbon sugar is split to 2 three-carbon sugar  catalyzes phosphorylation of  requires 2 moles ATP/mole of hexose that is split glucose in most tissue 2. Conversion of Triose Phosphate to Pyruvate  phosphorylate several  2 three-carbon sugars metabolized to 2 molecules hexoses other than glucose of pyruvate  low Km (easily saturable)  produces 2 moles ATP/mole of triose phosphate high affinity to glucose converted to pyruvate ( 4 moles ATP  low Vmax for glucose cannot phosphorylate large produced/mole of hexose) quantities of glucose B. Glucokinase (Hexokinase D or Type IV)  1A BIOCHEMISTRY GLYCOLYSIS DR. BRENDO JANDOC  in liver parenchymal cells  catalyzed by glyceraldehyde 3- and β cells of pancreas phosphate dehydrogenase  predominant enzyme for 7. ATP Formation from 1,3-Biphosphoglycerate glucose phosphorylation (1,3-BPG) and ADP (very specific for glucose)  converts 1,3-BPG  3-  glucose sensor in the β cells phosphoglycerate (3-PG) of pancreas  1st glycolytic step that generates ATP  determine threshold for  catalyzed by phosphoglycerate kinase insulin secretion 8. Phosphate Group Shift from Carbon 3 to  levels increased by insulin Carbon 2 and carbohydrate-rich diet  catalyzed by phosphoglycerate  higher Km (not easily mutase saturable) 9. 2-Phosphoglycerate Dehydration  requires higher [glucose] for  catalyzed by enolase half-saturation 10. Pyruvate Formation  functions only with elevated  3rd irreversible reaction of glycolysis hepatocyte [glucose]  catalyzed by pyruvate kinase  high Vmax  allows liver to effectively remove glucose from the portal blood  minimizes hyperglycemia during absorptive period  GLUT-2 insures that blood glucose equilibrates rapidly across the hepatocyte membrane  Regulated by Fructose-6- phosphate, Glucose and Insulin 2. Glucose 6-Phosphate Isomerization  catalyzed by phosphoglucose isomerase  reversible 3. Fructose 6-Phosphate Phosphorylation  irreversible  catalyzed by phosphofructokinase 1 (PFK-1) which is the major regulatory enzyme of glycolysis  most important control point of glycolysis  rate-limiting step of glycolysis  controlled by ATP, fructose 6-  ALTERNATE FATES of PYRUVATE phosphate and regulatory substances 1. Oxidative Decarboxylation of Pyruvate (effectors or modulators)  important pathway in tissues with high 4. Fructose 1,6-Biphosphate Cleavage oxidative capacity (cardiac muscle)  catalyzed by aldolase A  irreversibly converts pyruvate to acetyl CoA  unregulated reversible reaction  acetyl CoA is the major fuel for the TCA  aldolase operates via Schiff base and cycle and the building block for fatty acid enamine intermediates in animals and synthesis plants  catalyzed by pyruvate dehydrogenase  Aldolase B functions in the metabolism complex of dietary fructose 2. Carboxylation of Pyruvate to Oxaloacetate (OAA) 5. DHAP Isomerization  catalyzed by pyruvate carboxylase (biotin  interconversion of DHAP and dependent) glyceraldehyde 3-phosphate  net  replenishes TCA cycle intermediate production of 2 molecules of  provides substrates for gluconeogenesis glyceraldehyde 3-phosphate 3. Reduction of Pyruvate to Ethanol (Yeast, Certain  catalyzed by triose phosphate Microorganisms) isomerase through an enediolate  2 Step Process intermediate - Pyruvate Decarboxylase Reaction 6. Glyceraldehyde 3-Phosphate Oxidation - Alcohol Dehydrogenase Reaction  to 1,3-biphosphoglycerate 4. Pyruvate to Alanine  1st redox reaction of glycolysis  links carbohydrate and amino acid  require NAD+ as electron carrier metabolism  1A BIOCHEMISTRY GLYCOLYSIS DR. BRENDO JANDOC  catalyzed by alanine aminotransferase 5. Reduction of Pyruvate to Lactate  Lactate is the final product of anaerobic glycolysis  ENERGY YIELD of GLYCOLYSIS  Anaerobic Glycolysis- anaerobic catabolism of glucose can be 100 times faster than the catabolism of glucose in the presence of oxygen Glucose + 2Pi + 2ADP  2Lactate + 2ATP + 2H2O  Aerobic Glycolysis Inherited Enzyme Deficiencies of Glycolysis Glucose + 2Pi + 2NAD+ + 2ADP  1. Pyruvate Kinase Deficiency 2 Pyruvate + 2ATP + 2NADH + 2H+ + o 2nd most common (95%) cause (after H2O glucose 6-phosphate dehydrogenase deficiency) of enzyme deficiency- related hemolytic anemia o restricted to the erythrocytes o produces mild to severe chronic hemolytic anemia 2. Glucose Phosphate Isomerase Deficiency 3. Triose Phosphate Isomerase Deficiency  LACTIC ACIDOSIS  Anaerobic Glycolysis as an Emergency Source of ATP  Blood Lactate Normal Levels is 1.2 Mm  Lactic Acidosis when the blood lactate is 5 mM or more  due to increased formation or reduced utilization, lowered blood pH, decreased bicarbonate levels  excess oxygen required in order to recover from a period when oxygen availability has been inadequate  HORMONAL REGULATION of GLYCOLYSIS Short-Term Regulation  allosteric activation or inhibition  phosphorylation or dephosphorylation of rate-limiting enzymes  minutes to hours effect Hormonal Influences  slower  more profound effects  10-20 fold increase in enzyme activity  occur over hours to days  GLYCOLYSIS and RBC METABOLISM  Mature RBCs contain no mitochondria, they totally dependent on glycolysis for ATP production