Carbohydrate Metabolism PDF

CARBOHYDRATE METABOLISM Glucose degradation: Glycolysis and pentose phosphate pathway. Fermentations. Gluconeogenesis. Synthesis and degradation of glycogen. Use of other carbohydrates. Coordination in the control of glucose and...

CARBOHYDRATE METABOLISM Glucose degradation: Glycolysis and pentose phosphate pathway. Fermentations. Gluconeogenesis. Synthesis and degradation of glycogen. Use of other carbohydrates. Coordination in the control of glucose and glycogen metabolism: importance of tissue metabolic specialization. M 1  CENTRAL IMPORTANCE OF GLUCOSE Glucose is an excellent fuel ✓ Yields good amount of energy upon oxidation ✓ Can be efficiently stored in the polymeric form ✓ Many organisms and tissues can meet their energy needs on glucose only Glucose is a versatile biochemical precursor ✓ Bacteria can use glucose to build the carbon skeletons of: ▪ All the amino acids ▪ Membrane lipids ▪ Nucleotides in DNA and RNA ▪ Cofactors needed for the metabolism M 2  FOUR MAJOR PATHWAYS OF GLUCOSE UTILIZATION Storage Can be stored in the polymeric form (starch, glycogen) When there’s plenty of excess energy Glycolysis Generates energy via oxidation of glucose Short-term energy needs Pentose Phosphate Pathway Generates NADPH via oxidation of glucose For detoxification and the biosynthesis of lipids and nucleotides Synthesis of Structural Polysaccharides For example, in cell walls of bacteria, fungi, and plants M 3  I- GLYCOLYSIS IMPORTANCE Sequence of enzyme-catalyzed reactions by which glucose is converted into pyruvate ✓ Pyruvate can be further aerobically oxidized ✓ Pyruvate can be used as a precursor in biosynthesis Some of the oxidation-free energy is captured by the synthesis of ATP and NADH M 4  I- GLYCOLYSIS OVERVIEW In the evolution of life, glycolysis probably was one of the earliest energy-yielding pathways It developed before photosynthesis, when the atmosphere was still anaerobic Thus, the task upon early organisms was: ✓ How to extract free energy from glucose anaerobically? ✓ The solution: ▪ First: Activate it by phosphorylation ▪ Second: Collect energy from the high-energy metabolites M 5  THE TWO PHASES OF GLYCOLYSIS In the preparatory phase two molecules of glyceraldehyde 3-phosphate are formed and 2 molecules of ATP consumed. In the payoff phase 2 glyceraldehyde 3-phosphate are oxidized to pyruvate and 2 NAD+ reduced. 4 ATPs are formed. M 6  FIRST PHASE OF GLYCOLYSIS M 7  FIRST PHASE OF GLYCOLYSIS STEP 1: PHOSPHORYLATION OF GLUCOSE Traps glucose inside the cell This process uses the energy of ATP ATP-bound Mg++ facilitates this process by shielding the negative charges on ATP Highly thermodynamically favorable/irreversible ✓ Regulated mainly by substrate inhibition REGULATION OF HEXOKINASE IV (GLUCOKINASE) BY SEQUESTRATION IN THE NUCLEUS The protein inhibitor of hexokinase IV is a nuclear binding protein that draws hexokinase IV into the nucleus when the fructose 6-phosphate concentration in liver is high and releases it to the cytosol when the glucose concentration is high. M 8  FIRST PHASE OF GLYCOLYSIS STEP 2: PHOSPHOHEXOSE ISOMERASE An aldose (glucose) can isomerize into a ketose (fructose) Slightly thermodynamically unfavorable/reversible ✓ Product concentration kept low to drive forward M 9  FIRST PHASE OF GLYCOLYSIS STEP 3: PHOSPHOFRUCTOKINASE 1 (PFK-1) Further activation of glucose by the use of the energy of ATP Allows for 1 phosphate/3-carbon sugar after step 4 First Committed Step of Glycolysis REGULATION OF PHOSPHOFRUCTOKINASE 1 (PFK-1) Phosphofructokinase-1 is highly regulated: ✓ By ATP, fructose-2,6-bisphosphate, and other metabolites M ✓ Do not burn glucose if there is plenty of ATP 10  FIRST PHASE OF GLYCOLYSIS STEP 4: ALDOLASE Aldolase creates two triose phosphates: ✓ Dihydroxyacetone Phosphate (DHAP) ✓ Glyceraldehyde-3-Phosphate (GAP) Cleavage of a six-carbon sugar into two three-carbon sugars High-energy phosphate sugars are three-carbon sugars ✓ GAP concentration kept low to pull reaction forward M 11  FIRST PHASE OF GLYCOLYSIS STEP 5: TRIOSE PHOSPHATE ISOMERASE Allows glycolysis to proceed by one pathway Only GAP is the substrate for the next enzyme DHAP must be converted to GAP Completes preparatory phase Thermodynamically unfavorable/reversible ▪ GAP concentration kept low to pull reaction forward M 12  THE 2nd PHASE OF GLYCOLYSIS M 13  THE SECOND PHASE OF GLYCOLYSIS STEP 6: GLYCERALDEHYDE 3-PHOSPHATE DEHYDROGENASE Generation of a high-energy phosphate compound Incorporates inorganic phosphate First energy-yielding step in glycolysis Oxidation of aldehyde with NAD+ gives NADH Thermodynamically unfavorable/reversible ✓ Coupled to next reaction to pull forward M 14  THE SECOND PHASE OF GLYCOLYSIS STEP 7: Phosphoglycerate kinase Phosphoglicerat kinase Mg+2 Substrate-level phosphorylation to make ATP 1,3-bisphosphoglycerate is a high-energy compound ✓ can donate the phosphate group to ADP to make ATP Highly thermodynamically favorable/reversible M ✓ Is reversible because of coupling to GAPDH reaction 15  THE SECOND PHASE OF GLYCOLYSIS STEP 8: PHOSPHOGLYCERATE MUTASE Be able to form high-energy phosphate compound Mutases catalyze the (apparent) migration of functional groups Thermodynamically unfavorable/reversible ✓ Reactant concentration kept high by PGK to push forward M 16  THE SECOND PHASE OF GLYCOLYSIS Bisphosphoglicerate mutase Pi 2,3-Bisphosphoglicerate phosphatase A bypass in glycolysis allows synthesis of 2, 3-BPG a regulator of oxygen binding to Hb M 17  THE SECOND PHASE OF GLYCOLYSIS STEP 9: ENOLASE Generate a high-energy phosphate compound 2-Phosphoglycerate is not a good enough phosphate donor Two negative charges in 2-PG are fairly close But loss of phosphate from 2-PG would give a secondary alcohol with no further stabilization Slightly thermodynamically unfavorable/reversible Product concentration kept low to pull forward M 18  THE SECOND PHASE OF GLYCOLYSIS STEP 10: PYRUVATE KINASE Piruvat kinase Mg+2, K+ Substrate-level phosphorylation to make ATP Pyruvate kinase requires K+ and divalent metals (Mg++ or Mn++) for activity The reaction Highly thermodynamically favorable/irreversible REGULATION OF PYRUVATE KINASE ✓ Regulated by ATP, divalent metals, and other metabolites M 19  1x Balance 2 1a FASE 2 1x 4 Ahora me 2x 2a FASE faltan 2 NAD+ y ¿de donde los saco? Porque sinó…. M 2x Pyruvate 20  REGULATED STEPS IN GLYCOLYSIS: Hexokinase PFK-1 Pyruvate kinase M 21  SUMMARY OF GLYCOLYSIS Glucose + 2 NAD+ + 2 ADP + 2 Pi → 2 Pyruvate + 2 NADH + 2 H+ + 2 ATP The sum of the formation of ATP from ADP + Pi (endergonic) and the conversion of glucose to pyruvate (exergonic) gives the overall ΔG’os of glycolysis: 2ADP + 2Pi → 2ATP + 2H2O Glucose + 2NAD+ → 2pyruvate + 2NADH + 2H+ G’º2 = 61 kJ/mol G’º1 = -146 kJ/mol The energy extracted by the cell from a glucose molecule in glycolysis: G’ºs = G’º1 + G’º2 = -146 kJ/mol + 61 kJ/mol = -85 kJ/mol Total available energy of the glucose molecule: Glucose → 6CO2 + 6H2O ΔG’o= -2840 kJ/mol Then Glycolysis releases only a small fraction of the (146/2840)·100 = 5,2% total available energy of the glucose molecule Made: 2 pyruvates with various different fates ▪ 2 ATP Used for energy-requiring processes within the cell ▪ 2 NADH Must be reoxidized to NAD+ in order for glycolysis to continue Glycolysis is heavily regulated ▪ Ensure proper use of nutrients M ▪ Ensure production of ATP only when needed 22