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Glycolysis Biochemistry All organisms produce ATP by breaking down molecules and by releasing energy stored in glucose and other sugars. Aerobic respiration - the process by which a cell uses O2 to "burn" molecules and release energy The reaction: C6H12O6 + 6O2 >> 6CO2 + 6H2O Aerobic respiration - the process by which a cell uses O2 to "burn" molecules and release energy The reaction: C6H12O6 + 6O2 >> 6CO2 + 6H2O Note: this reaction is the opposite of photosynthesis three major reaction pathways •Glycolysis •The Kreb's Cycle •Electron Transport Phosphorylation (chemiosmosis) Glucose is metabolized to pyruvate by the pathway of glycolysis Aerobic tissues metabolize pyruvate to acetyl-CoA, which can enter the citric acid cycle for complete oxidation to CO2 and H2O, linked to the formation of ATP in the process of oxidative phosphorylation Glycolysis (glyco = sugar; lysis = breaking) •Goal: break glucose down to form two pyruvates •Who: all life on earth performs glycolysis •Where: the cytoplasm Glycolysis literally means "splitting sugars." glucose (a six carbon sugar) is split into two molecules of a threecarbon sugar. Glycolysis Is Regulated at Three Steps Involving Nonequilibrium Reactions Although most of the reactions of glycolysis are reversible, three are markedly exergonic and must therefore be considered physiologically irreversible. These reactions, catalyzed by 1. hexokinase (and glucokinase) 2. Phosphofructokinase 3. pyruvate kinase, are the major sites of regulation of glycolysis. The First Stage of Glycolysis •Glucose (6C) is broken down into 2 (3C) •This requires two ATP's The Second Stage of Glycolysis •2 (3C) are converted to 2 pyruvates •This creates 4 ATP's and 2 NADH's •The net ATP production of Glycolysis is 2 ATP's 10 Steps of Glycolysis Step 1 The enzyme hexokinase phosphorylates (adds a phosphate group to) glucose in the cell's cytoplasm. In the process, a phosphate group from ATP is transferred to glucose producing glucose 6-phosphate. Glucose (C6H12O6) + hexokinase + ATP → ADP + Glucose 6-phosphate (C6H11O6P1) Step 2 The enzyme phosphoglucoisomerase converts glucose 6phosphate into its isomer fructose 6-phosphate. Isomers have the same molecular formula, but the atoms of each molecule are arranged differently. Glucose 6-phosphate (C6H11O6P1) + Phosphoglucoisomerase → Fructose 6-phosphate (C6H11O6P1) Step 3 The enzyme phosphofructokinase uses another ATP molecule to transfer a phosphate group to fructose 6-phosphate to form fructose 1, 6diphosphate. Fructose 6-phosphate (C6H11O6P1) + phosphofructokinase + ATP → ADP + Fructose 1, 6-diphosphate (C6H10O6P2) Step 4 The enzyme aldolase splits fructose 1, 6bisphosphate into two sugars that are isomers of each other. These two sugars are dihydroxyacetone phosphate and glyceraldehyde phosphate. Fructose 1, 6-bisphosphate (C6H10O6P2) + aldolase → Dihydroxyacetone phosphate (C3H5O3P1) + Glyceraldehyde phosphate (C3H5O3P1) Step 5 The enzyme triose phosphate isomerase rapidly interconverts the molecules dihydroxyacetone phosphate and glyceraldehyde phosphate. Glyceraldehyde phosphate is removed as soon as it is formed to be used in the next step of glycolysis. Dihydroxyacetone phosphate (C3H5O3P1) → Glyceraldehyde phosphate (C3H5O3P1) Net result for steps 4 and 5: Fructose 1, 6-diphosphate (C6H10O6P2) ↔ 2 molecules of Glyceraldehyde phosphate (C3H5O3P1) Step 5 The enzyme triose phosphate isomerase rapidly interconverts the molecules dihydroxyacetone phosphate and glyceraldehyde phosphate. Glyceraldehyde phosphate is removed as soon as it is formed to be used in the next step of glycolysis. Dihydroxyacetone phosphate (C3H5O3P1) → Glyceraldehyde phosphate (C3H5O3P1) Net result for steps 4 and 5: Fructose 1, 6-diphosphate (C6H10O6P2) ↔ 2 molecules of Glyceraldehyde phosphate (C3H5O3P1) Step 6 The enzyme triose phosphate dehydrogenase serves two functions in this step. First the enzyme transfers a hydrogen (H-) from glyceraldehyde phosphate to the oxidizing agent nicotinamide adenine dinucleotide (NAD+) to form NADH. Next triose phosphate dehydrogenase adds a phosphate (P) from the cytosol to the oxidized glyceraldehyde phosphate to form 1, 3-bisphoshoglyceric acid. This occurs for both molecules of glyceraldehyde phosphate produced in step 5. A. Triose phosphate dehydrogenase + 2 H- + 2 NAD+ → 2 NADH + 2 H+ B. Triose phosphate dehydrogenase + 2 P + 2 glyceraldehyde phosphate (C3H5O3P1) → 2 molecules of 1,3-bisphoshoglyceric acid (C3H4O4P2) Step 7 The enzyme phosphoglycerokinase transfers a P from 1,3-diphoshoglyceric acid to a molecule of ADP to form ATP. This happens for each molecule of 1,3diphoshoglyceric acid. The process yields two 3phosphoglyceric acid molecules and two ATP molecules. 2 molecules of 1,3-diphoshoglyceric acid (C3H4O4P2) + phosphoglycerokinase + 2 ADP → 2 molecules of 3-phosphoglyceric acid (C3H5O4P1) + 2 ATP Step 8 The enzyme phosphoglyceromutase relocates the P from 3-phosphoglyceric acid from the third carbon to the second carbon to form 2phosphoglyceric acid. 2 molecules of 3-Phosphoglyceric acid (C3H5O4P1) + phosphoglyceromutase → 2 molecules of 2Phosphoglyceric acid (C3H5O4P1) Step 9 The enzyme enolase removes a molecule of water from 2-phosphoglyceric acid to form phosphoenolpyruvic acid (PEP). This happens for each molecule of 2-phosphoglyceric acid. 2 molecules of 2-Phosphoglyceric acid (C3H5O4P1) + enolase → 2 molecules of phosphoenolpyruvic acid (PEP) (C3H3O3P1) Step 10 The enzyme pyruvate kinase transfers a P from PEP to ADP to form pyruvic acid and ATP. This happens for each molecule of PEP. This reaction yields 2 molecules of pyruvic acid and 2 ATP molecules. 2 molecules of PEP (C3H3O3P1) + pyruvate kinase + 2 ADP → 2 molecules of pyruvic acid (C3H4O3) + 2 ATP 1 2 1 3 2 4 Glycolysis produces 4 ATP's and 2 NADH, but uses 2 ATP's in the process a net of 2 ATP and 2 NADH NOTE: this process does not require O2 and does not yield much energy 2 ATP are used in steps 1-3 2 ATP are generated in step 7 2 ATP are generated in step 10. 4 ATP molecules produced. - 2 ATP molecules used --------- 2 ATP molecules (Total) Summary of Glycolysis a single glucose molecule in glycolysis produces a total of 2 2 2 2 molecules molecules molecules molecules of of of of pyruvic acid ATP NADH water Kreb’s Cycle Citric Acid Cycle / Tricarboxylic Acid Cycle What is Krebs Cycle? Used to oxidize the pyruvate formed during the glycolytic breakdown of glucose into Carbon Dioxide (CO2) and Water (H2O). It also oxidizes acetyl CoA which arises from breakdown of carbohydrate, lipid, and protein. Metabolic pathways fall into three categories: 1) Anabolic pathways are those involved in the synthesis of compounds. Anabolic pathways are endergonic. (2) Catabolic pathways are involved in the breakdown of larger molecules, commonly involving oxidative reactions; they are exergonic, producing reducing equivalents and, mainly via the respiratory chain, ATP. (3) Amphibolic pathways occur at the “crossroads” of metabolism, acting as links between the anabolic and catabolic pathways, eg, the citric acid cycle. GLUCOSE GLYCOLYSIS PYRUVATE PYRUVATE KREB’S CYCLE CO2 & H20 CO2 & H20 It begins when acetyl –CoA enters into a reaction to form citric Acid. This cycle was discovered by British biochemist Sir Hans Krebs. The first product of Krebs cycle is citric acid (citrate).Therefore, it is also known as citric acid cycle. Pyruvate dehydrogenase 6C 4C THE OXIDATION OF PYRUVATE TO ACETYL-CoA IS THE IRREVERSIBLE ROUTE FROM GLYCOLYSIS TO THE CITRIC ACID CYCLE Pyruvate Dehydrogenase Is Regulated by End-Product Inhibition & Covalent Modification Pyruvate dehydrogenase is inhibited by its products 1. acetyl-CoA 2. NADH All the products of digestion are metabolized to a common product, acetyl- CoA, which is then oxidized by the citric acid cycle Steps of Krebs cycle cyclic oxidation process nine steps occur in overall Krebs cycle: 1. Condensation 2. Isomerisation 3. Dehydrogenation 4. Decarboxylation 5. Oxidative Decarboxylation 6. Substrate level ATP/GTP synthesis. 7. Dehydrogenation (oxidation) of Succinate 8. Hydration 9. Dehydrogenation (Oxidation) of Malate Step 1: Condensation In first step of Krebs cycle, Acetyl CoA combines with oxaloacetate in the presence of condensing enzymes citrate synthetase. CoA is released out. The product of condensation is citrate which is a tricarboxylic 6-carbon compound. CATALYTIC ROLE Step 2: Isomerisation Citrate formed in first step is converted into its isomer isocitrate in a two – step reaction in the presence of iron containing enzyme aconitase. (i) Dehydration : A molecule of water is released and citric acid is changed into cis-aconitate. Step 2: Isomerisation Citrate formed in first step is converted into its isomer isocitrate in a two – step reaction in the presence of iron containing enzyme aconitase. (i) Dehydration : A molecule of water is released and citric acid is changed into cis-aconitate. (ii) Rehydration : Cis – aconitate combines with a molecule of water and form isocitrate. Step 2: Isomerisation Citrate formed in first step is converted into its isomer isocitrate in a two – step reaction in the presence of iron containing enzyme aconitase. (i) Dehydration : A molecule of water is released and citric acid is changed into cis-aconitate. (ii) Rehydration : Cis – aconitate combines with a molecule of water and form isocitrate. Step 3: Dehydrogenation Now isocitrate undergoes dehydrogenation in the presence of an enzyme isocitrate dehydrogenase. Mn2+ ion is required for the functioning of enzyme. Hydrogen given out by isocitrate is picked up by NAD+ (Nicotinamide adenine dinucleotide) to form NADH2. After losing hydrogen, isocitrate is changed into oxalosuccinate (6C). Step 4: Decarboxylation Oxalosuccinate in Step 4 undergoes decarboxylation. In the presence of oxalosuccinate decarboxylase enzyme, oxalosuccinate is changed into α-ketoglutarate. Step 5: Oxidative Decarboxylation In this step 5-carbon compound, α – Ketoglutarate undergoes simultaneous dehydrogenation and decarboxylation in the presence of enzyme α – ketoglutarate dehydrogenase complex. This enzyme complex contain Thiamine Pyrophosphate (TPP), Lipoic Acid , Mg2+ and trans – succinylase. NAD+ and CoA are required. The products formed are 4 – carbon compound succinyl CoA, NADH2 and CO2. Step 6: Substrate level ATP/GTP Synthesis In the presence of enzyme succinyl thiokinase, succinyl CoA is hydrolyzed. CoA and Succinate are formed. The energy liberated during the process is used in synthesis of ATP in Plants and GTP (Guanosine triphosphate) or ITP (Inosine triphosphate) in animals. CoA is released out. Step 7: Dehydrogenation (Oxidation) 4 – Carbon compound Succinate is oxidized to another 4-carbon compound fumarate with the help of enzyme succinate dehydrogenase and hydrogen acceptor FAD (Flavin Adenine Dinucleotide). The enzyme is attached to inner mitochondrial membrane. It contains non haem iron (Fe–S) protein. This enables the enzyme to get directly linked to electron transport chain. Step 8: Hydration Fumarate reacts with a molecule of water, in the presence of an enzyme fumarase forming another 4-carbon dicarboxylic acid called Malate. Step 9: Dehydrogenation (Oxidation) With the help of enzyme malate dehydrogenase, Malate formed in step 8 is oxidized to oxaloacetate. NAD+ reduced to NADH2. Malate + NAD+ N oxaloacetate + NADH2 An oxaloacetate formed in this reaction becomes available to combine with acetyl CoA to start a new cycle all over again. Back again to step 1 Note : The overall equation of oxidative catabolism of pyruvate can be written as follows:3 3 NADH2 & FADH2 are linked to electron transport system and formation of ATP by Oxidative Phosphorylation. The Conversion of Pyruvate to Acetyl CoA for Entry Into the Kreb's Cycle •2 NADH's are generated •2 CO2 are released The Kreb's Cycle •6 NADH's are generated •2 FADH2 is generated •2 ATP are generated •4 CO2's are released •Therefore, for each glucose molecule that enters into the Kreb's cycle (including the prepatory conversion to Acetyl CoA), the net production of products are: 8 NADH 2 FADH2 2 ATP 6 CO2 Stages of the TCA cycle The cycle can be divided into three stages according to the role of OAA: – Stage 1: • The attachment of acetyl CoA to oxaloacetate carrier (reaction1) – Stage 2: • Breaking of oxaloacetate carrier (reaction 2-5) – Stage 3: • Regeneration of the carrier (reaction 6-8) Functions of TCA cycle: Amphibolic Function: TCA cycle has both anabolic and catabolic functions a- Catabolic role: It is the final common pathway for oxidation of carbohydrate, lipids and proteins with energy production. B-Anabolic role: Source of the intermediates used in biosynthesis e.g. 1. Oxaloacetic acid is used in gluconeogenesis. 2. α- ketoglutarate is used for synthesis of some non essential amino a. 3. Succinyl CoA is used in heme synthesis Besides Glycolysis and kreb’s, Is there anything more? YES! E.T.P. Electron Transport Phosphorylation (Chemiosmosis) •Goal: to break down NADH and FADH2, pumping H+ into the outer compartment of the mitochondria •Where: mitochondria The figure is found at http://plaza.ufl.edu/tmullins/BCH3023/cell%20respiration.html (December 2006) The figure is found at http://academic.brooklyn.cuny.edu/biology/bio4fv/page/mito_ox.htm (December 2006) inner mitochondrial membrane ATP synthase The figure is found at http://plaza.ufl.edu/tmullins/BCH3023/cell%20respiration.html (December 2006) In this reaction, the ETS creates a gradient which is used to produce ATP, quite like in the chloroplast Electron Transport Phosphorylation typically produces 32 ATP's Net Energy Production from Aerobic Respiration •Glycolysis: •Kreb's Cycle: •Electron Transport Phosphorylation: •Net Energy Production: Net Energy Production from Aerobic Respiration •Glycolysis: LET’S COUNT THE ATP’S ONLY •Kreb's Cycle: AND EXCLUDE NADH & FADH •Electron Transport Phosphorylation: •Net Energy Production: Net Energy Production from Aerobic Respiration •Glycolysis: •Kreb's Cycle: •Electron Transport Phosphorylation: •Net Energy Production: Net Energy Production from Aerobic Respiration •Glycolysis: 2 ATP •Kreb's Cycle: •Electron Transport Phosphorylation: •Net Energy Production: Net Energy Production from Aerobic Respiration •Glycolysis: 2 ATP •Kreb's Cycle: 2 ATP •Electron Transport Phosphorylation: •Net Energy Production: Net Energy Production from Aerobic Respiration •Glycolysis: 2 ATP •Kreb's Cycle: 2 ATP •Electron Transport Phosphorylation: 32 ATP •Net Energy Production: Net Energy Production from Aerobic Respiration •Glycolysis: 2 ATP •Kreb's Cycle: 2 ATP •Electron Transport Phosphorylation: 32 ATP •Net Energy Production: 36 ATP!