1 12.4 Glycolysis From Hydrolysis Products to Common Metabolites The Chemical Reactions in Glycolysis In the body, energy must be transferred in small amounts to minimize the heat released in the process. Reactions that produce energy are coupled with reactions that require energy, thereby helping to maintain a constant body temperature. In glycolysis, energy is transferred through phosphate groups undergoing condensation and hydrolysis reactions. There are 10 chemical reactions in glycolysis that result in the formation of two molecules of pyruvate from one molecule of glucose.
2 12.4 Glycolysis From Hydrolysis Products to Common Metabolites The Chemical Reactions in Glycolysis The first five reactions require an energy investment of two molecules of ATP, which are used to add two phosphate groups to the sugar molecule. This molecule is split into two sugar phosphates. Reactions 6 through 10 generate two high-energy NADH molecules during the addition of two more phosphates and four ATP molecules when the four phosphates are removed from the sugar phosphates.
3 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
4 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
5 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
6 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
7 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
8 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
9 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
10 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
11 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
12 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
13 12.4 Glycolysis From Hydrolysis Products to Common Metabolites Regulation of Glycolysis The main step of regulation in glycolysis is step 3. The enzyme phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate, is heavily regulated by the cells. ATP acts as an inhibitor of phosphofructokinase. If cells have plenty of ATP, glycolysis slows down.
14 12.4 Glycolysis From Hydrolysis Products to Common Metabolites The Fates of Pyruvate Aerobic conditions: pyruvate produces more energy for the cell when the carboxylate functional group of pyruvate is liberated as CO 2 during oxidative decarboxylation. The acetyl group binds to coenzyme A during the oxidation through a sulfur atom, creating a thioester functional group and acetyl CoA. This reaction occurs in the mitochondria.
15 12.4 Glycolysis From Hydrolysis Products to Common Metabolites The Fates of Pyruvate Anaerobic conditions: the middle carbonyl in pyruvate is reduced (hydrogen added) to an alcohol group, and lactate is formed. The hydrogen (and energy) required for this reaction is supplied by NADH and H +, producing NAD +. The NAD + produced funnels back into glycolysis to oxidize more glyceraldehyde-3-phosphate (step 6), providing a small amount of ATP. This reaction occurs in the cytosol.
16 12.4 Glycolysis From Hydrolysis Products to Common Metabolites
17 12.4 Glycolysis From Hydrolysis Products to Common Metabolites Yeast converts pyruvate to ethanol under anaerobic conditions. This process is called fermentation. In the preparation of alcoholic beverages, yeast produces pyruvate from glucose in grape juices and under low-oxygen conditions transforms pyruvate into ethanol.
18 12.4 Glycolysis From Hydrolysis Products to Common Metabolites Fructose and Glycolysis Fructose is readily taken up in the muscle and liver. In the muscles, it is converted to fructose-6-phosphate, entering glycolysis at step 3. In the liver, it is converted to the trioses used in step 5. Fructose that enters a cell flows from reaction 5 to 10. Fructose uptake by the cells is not regulated by insulin: all fructose in the bloodstream is forced into catabolism. Glycolysis is regulated at step 3. The triose products created in the liver provide an excess of reactants that create excess pyruvate and acetyl CoA that, if not required for energy by the cells, is converted to fat.
19 12.5 The Citric Acid Cycle Central Processing During aerobic catabolism, glucose, amino acids, and fatty acids funnel into and out of the citric acid cycle. The citric acid cycle degrades two-carbon acetyl groups from acetyl CoA into CO 2 and generates the high-energy molecules NADH and FADH 2. The initial reaction is a condensation reaction between acetyl CoA and the four-carbon molecule oxaloacetate. The six-carbon citrate loses first one and then a second carbon as CO 2, forming the four-carbon succinyl CoA. These carbon carbon bond-breaking reactions transfer energy and produce NADH from the coenzyme NAD +. Succinyl CoA then runs through a set of reactions regenerating oxaloacetate, and the cycle begins again.
20 12.5 The Citric Acid Cycle Central Processing Reactions of the Citric Acid Cycle Reaction 1, Formation of Citrate: The acetyl group from acetyl CoA (two carbons) combines with oxaloacetate (four carbons), forming citrate (six carbons) and CoA. Reaction 2, Isomerization to Isocitrate: The OH and one of the H atoms are swapped in citrate to form isocitrate. This rearrangement is necessary because isocitrate is oxidized in the next reaction. Reaction 3, First Oxidative Decarboxylation (Release of CO 2 ): An alcohol undergoes oxidation (two hydrogens removed) to a ketone called α-ketoglutarate, and NAD + is reduced to NADH, accepting the proton and electrons removed during the oxidation. The six-carbon isocitrate is decarboxylated to the five-carbon α-ketoglutarate.
21 12.5 The Citric Acid Cycle Central Processing Reactions of the Citric Acid Cycle Reaction 4, Second Oxidative Decarboxylation: The thiol group of CoA is oxidized (loses a hydrogen), and another NAD + is reduced to NADH. Alpha-ketoglutarate (five carbons) is decarboxylated into a succinyl group (four carbons). The CoA is bonded to the succinyl group, thus producing succinyl CoA. Reaction 5, Hydrolysis of Succinyl CoA: Succinyl CoA undergoes hydrolysis to succinate and coenzyme A. The energy produced produces the high-energy nucleotide guanosine triphosphate or GTP from GDP and P i. GTP is converted to ATP in the cell.
22 12.5 The Citric Acid Cycle Central Processing Reactions of the Citric Acid Cycle Reaction 6, Dehydrogenation of Succinate: One hydrogen is eliminated from each of the two central carbons of succinate, forming a trans C=C bond, thus producing fumarate. These two hydrogens reduce the coenzyme FAD to FADH 2. Reaction 7, Hydration of Fumarate: Water adds to the trans double bond of fumarate as H and OH forming malate. Reaction 8, Oxidation of Malate: As in reaction 3, the secondary alcohol of malate is oxidized to a ketone forming oxaloacetate, providing protons and electrons to reduce the coenzyme NAD + to NADH.
23 12.5 The Citric Acid Cycle Central Processing One turn of the citric acid cycle produces a net energy output of three NADH, one FADH 2, and one GTP (which forms ATP). Two CO 2 and one CoA also are produced. The net reaction for one turn of this eight-step cycle is
24 12.5 The Citric Acid Cycle Central Processing
25 12.6 Electron Transport and Oxidative Phosphorylation Two ATP are produced in glycolysis and two ATP in the citric acid cycle. Where is all the energy? NADH and FADH 2 are produced in glycolysis (two NADH per glucose), from pyruvate oxidation to acetyl CoA (two NADH per glucose), and in the citric acid cycle (six NADH and two FADH 2 per glucose). High-energy reduced forms of the nucleotides transfer electrons and hydrogens through the inner mitochondrial membrane and to form H 2 O. The energy generated as a result of this process is used to drive the reaction of ADP to form ATP. This is called oxidative phosphorylation.
26 12.6 Electron Transport and Oxidative Phosphorylation Mitochondria are the ATP factories of the cell. Reduced nucleotides from the citric acid cycle are produced here, and their energy upon oxidation is used to generate ATP. The reactions of the citric acid cycle occur in the matrix of the mitochondria. The reduced nucleotides, NADH and FADH 2, begin their journey through the inner membrane here. Enzyme complexes I through V are embedded in the inner membrane of the mitochondria and electron carriers that transport the electrons and protons of NADH and FADH 2 through the inner mitochondrial membrane. Two of the electron carriers, coenzyme Q and cytochrome c, are not firmly attached to any one complex and shuttle electrons between the complexes.
27 12.6 Electron Transport and Oxidative Phosphorylation
28 12.6 Electron Transport and Oxidative Phosphorylation Complex I, NADH Dehydrogenase: At complex I, NADH enters electron transport. During its oxidation, two electrons and two protons are transferred to the electron transporter coenzyme Q, reducing its two ketone groups to alcohols (see figure at left). NAD + is regenerated and returns to a catabolic pathway as in the citric acid cycle. The overall reaction at complex I is NADH + H + + Q NAD + + QH 2
29 12.6 Electron Transport and Oxidative Phosphorylation Complex II, Succinate Dehydrogenase: FADH 2 enters electron transport after the reduced nucleotide is produced in the conversion of succinate to fumarate in the citric acid cycle. Two electrons and two protons from FADH 2 are also transferred to coenzyme Q to yield QH 2. FADH 2 + Q FAD + QH 2 Complex III, Coenzyme Q Cytochrome c Reductase: At complex III, the reduced coenzyme Q (QH 2 ) molecules are reoxidized to ubiquinone (Q), and the electrons pass through a series of electron acceptors until they arrive at cytochrome c, which moves the electron from complex III to complex IV.
30 12.6 Electron Transport and Oxidative Phosphorylation Complex IV, Cytochrome c Oxidase: At complex IV, single electrons are transferred from cytochrome c through another set of electron acceptors to combine with hydrogen ions and oxygen (O 2 ) to form water. This is the final stop for the electrons: 4H + + 4e + O 2 2H 2 O
31 12.6 Electron Transport and Oxidative Phosphorylation Oxidative phosphorylation: The chemiosmotic model links electron transport to the generation of a proton (H + ) gradient across the inner membrane. In this model, three of the complexes (I, III, and IV) span the inner membrane and pump (relocate) protons out of the matrix and into the intermembrane space as electrons are shuttled through the complexes. The formation of the proton gradient across the inner mitochondrial membrane provides the energy for ATP synthesis. Protons move back into the matrix through a protein complex, called complex V, or ATP synthase. As protons flow back into the matrix through complex V, the resulting release of energy drives the synthesis of ATP.
32 12.6 Electron Transport and Oxidative Phosphorylation
33 12.6 Electron Transport and Oxidative Phosphorylation Thermogenesis If ATP cannot be produced, the energy that would have been harnessed as ATP is released as heat. This is called thermogenesis. Some animals adapted to cold climates produce small organic molecules called uncouplers, which uncouple electron transport and oxidative phosphorylation and thereby assist in regulating their body temperature through thermogenesis. These animals have a higher amount of a tissue called brown fat, which appears brown due to the high concentrations of mitochondria present. The cytochrome molecules present in mitochondria contain an iron ion that is responsible for the brown color. Newborn babies have higher levels of brown fat than do adults because newborns do not have much stored fat. Brown fat deposits are located near major blood vessels that carry the warmed blood through the body, allowing a newborn to generate more heat to warm its body surface.
34 12.7 ATP Production Glycolysis: The oxidation of glucose produces two NADH molecules and two ATP molecules. Glycolysis occurs in the cytosol, and electron transport draws NADH from the matrix inside the mitochondria. The two NADH from glycolysis must be shuttled into the matrix to enter electron transport. This results in the production of five ATP. Oxidation of pyruvate: After glycolysis, the two pyruvates enter the mitochondria, where they are oxidized to produce two acetyl CoA, two CO 2, and two NADH. The oxidation of two pyruvates leads to the production of five ATP.
35 12.7 ATP Production
36 12.8 Other Fuel Choices If glycogen and glucose are not available, cells can oxidize fatty acids to acetyl CoA through beta oxidation (β oxidation). β oxidation includes four reactions that convert the CH 2 of the β carbon to a β ketone. Once this ketone is formed, the two-carbon acetyl group splits from the fatty acyl carbon chain. One cycle of β oxidation yields one FADH 2 and one NADH.
37 12.8 Other Fuel Choices
38 12.8 Other Fuel Choices Reaction 1, Oxidation (Dehydrogenation). The first reaction removes one hydrogen from the alpha and beta carbons, and a double bond is formed. These hydrogens are transferred to FAD to form FADH 2. Reaction 2, Hydration. In reaction 2, water is added to the α and β carbon double bond as H and OH, respectively. Reaction 3, Oxidation (Dehydrogenation). The alcohol formed on the β carbon is oxidized to a ketone. As we have seen before in the citric acid cycle, the hydrogen from the alcohol reduces NAD + to NADH. Reaction 4, Removal of Acetyl CoA. In the fourth reaction of the cycle, the bond between the α and β carbon is broken and a second CoA is added, forming an acetyl CoA and a fatty acyl CoA shortened by two carbons. The fatty acyl CoA can be run through the cycle again.
39 12.8 Other Fuel Choices Ketosis In the absence of carbohydrates, the body breaks down body fat through β oxidation to continue ATP production. The liver will produce glucose from pyruvate through gluconeogenesis for tissues like the brain. The oxidation of large amounts of fatty acids can cause acetyl CoA to accumulate in the liver. When accumulation occurs, the two carbon acetyl units condense in the liver, forming the four-carbon ketone molecules β-hydroxybutyrate and acetoacetate and the molecule acetone. These are collectively referred to as ketone bodies. Ketosis occurs when an excessive amount of ketone bodies is present in the body. Because two of the ketones are carboxylic acids, the excessive formation of ketone bodies can cause metabolic acidosis. Acetone vaporizes easily, giving someone suffering from ketosis an odd, sweet-smelling breath upon exhalation similar to that of someone who has been drinking alcohol.
40 12.8 Other Fuel Choices Energy from Amino Acids Amino acids produce nitrogen when metabolized in the body. When excess protein is ingested, amino acids must be degraded. The α-amino group of an amino acid is removed, yielding an α-keto acid through transamination. The α-keto acid can be converted into intermediates for other metabolic pathways. The ammonium ions produced in this process must be excreted from the body. The urea cycle converts ammonium ions (NH 4+ ) into urea, which can be excreted in the urine.
41 12.8 Other Fuel Choices Energy from Amino Acids Amino acids offer a way to replenish the intermediates in the citric acid cycle. Amino acids like alanine, containing three carbons, can enter the pathways as pyruvate. Amino acids with four carbons are converted to oxaloacetate. Five-carbon amino acids are converted to α-ketoglutarate. Some amino acids can enter at more than one point depending on cellular requirements. Amino acids provide only about 10% of the required energy under normal conditions.
42 12.8 Other Fuel Choices Putting It Together: Linking the Pathways Degradation of food biomolecules begins with digestion. When the cell requires energy and oxygen is plentiful, larger molecules are metabolized into smaller metabolites that ultimately funnel into the citric acid cycle, electron transport, and oxidative phosphorylation. Through anabolic pathways, larger molecules can be synthesized from the smaller metabolites when necessary.
43 12.8 Other Fuel Choices Putting It Together: Linking the Pathways The biological hydrolysis products can be shifted into anabolic or catabolic pathways depending on the requirements of the cell. Glucose can be degraded to acetyl CoA entering the citric acid cycle to produce energy or be converted to glycogen for storage in the cells. Amino acids provide nitrogen for anabolism of nitrogen compounds, but their carbons can enter the citric acid cycle as α-keto acids if necessary.
44 12.8 Other Fuel Choices