Chemistry 2100 Lecture 13

Metabolism

Stages of Catabolism • digestion: hydrolysis • degradation: nutrients acetyl CoA • TCA Cycle: acetyl CoA CO2 + NADH / FADH2 • oxidative phosphorylation: NADH / FADH2 ATP

Catabolic Pathways Two principal types of compounds participating in the common catabolic pathway are: AMP, ADP, and ATP: agents for the storage and transfer of phosphate groups. NAD+/NADH and FAD/FADH2: agents for the transfer of electrons in biological oxidation-reduction reactions

Adenosine Triphosphate

H 2 O 31.4 kJ/mol P Ad +

Coupled Reactions (and why we need them)

+ R C O H R' 16.7 kJ/mol 2

R C O H + 10.5 kJ/mol P Ad

R C O Ad P + 25.1 kJ/mol H R'

R C O R' H + ATP AMP PP 14.6 kJ/mol

NAD+/NADH NAD+ is a two-electron oxidizing agent, and is reduced to NADH. NADH is a two-electron reducing agent, and is oxidized to NAD+. The structures shown here are the nicotinamide portions of NAD+ and NADH. NADH is an electron and hydrogen ion transporting molecule.

FAD/FADH2 FAD is a two-electron oxidizing agent, and is reduced to FADH2. FADH2 is a two-electron reducing agent, and is oxidized to FAD. Only the flavin moiety is shown in the structures below.

Carbohydrate Catabolism • glycolysis: glucose pyruvate acetyl CoA • TCA Cycle: acetyl CoA CO2 + NADH / FADH2 • oxidative phosphorylation: NADH / FADH2 ATP

Glycolysis

• H phosphofructokinase •

• H •

• H •

• H • • H •

• H • • H •

• H • • H •

• H • • H •

• H • • H •

AD AD O H H O C C NH H OH + N CH O PO O O PO O H H C C NH H OH + N CH 2 HPO -2 H OH + 4 dehydrogenase N CH O PO -2 2 3 AD -2 glyceraldehyde O O PO O 3 H H 3-phosphate NAD C + C NH 2 H OH + N • • -2 CH O PO 2 3 AD 1,3-bisphospho glycerate NADH

1,3 bisphospho glycerate

1,3 bisphospho glycerate

1,3 bisphospho glycerate 3-phospho glycerate

1,3 bisphospho glycerate 2-phospho glycerate 3-phospho glycerate

H O 2-phospho glycerate

H O 2-phospho glycerate

pyruvate

Anaerobic Glycolysis pyruvate pyruvic acid (–)-lactic acid lactic acid

Fermentation pyruvate pyruvic acid acetaldehyde acetaldehyde ethanol

TriCarboxylic Acid Cycle Prep pyruvate

Acetyl-CoA production FIGURE 16-1 (part 1) Catabolism of proteins, fats, and carbohydrates in the three stages of cellular respiration. Stage 1: oxidation of fatty acids, glucose, and some amino acids yields acetyl-CoA. Stage 2: oxidation of acetyl groups in the citric acid cycle includes four steps in which electrons are abstracted. Stage 3: electrons carried by NADH and FADH2 are funneled into a chain of mitochondrial (or, in bacteria, plasma membrane-bound) electron carriers—the respiratory chain—ultimately reducing O2 to H2O.This electron flow drives the production of ATP. 53

Acetyl-CoA Oxidation FIGURE 16-1 (part 2) Catabolism of proteins, fats, and carbohydrates in the three stages of cellular respiration. Stage 1: oxidation of fatty acids, glucose, and some amino acids yields acetyl-CoA. Stage 2: oxidation of acetyl groups in the citric acid cycle includes four steps in which electrons are abstracted. Stage 3: electrons carried by NADH and FADH2 are funneled into a chain of mitochondrial (or, in bacteria, plasma membrane-bound) electron carriers—the respiratory chain—ultimately reducing O2 to H2O.This electron flow drives the production of ATP. 54

Electron Transfer and Oxidative Phosphorylation FIGURE 16-1 (part 3) Catabolism of proteins, fats, and carbohydrates in the three stages of cellular respiration. Stage 1: oxidation of fatty acids, glucose, and some amino acids yields acetyl-CoA. Stage 2: oxidation of acetyl groups in the citric acid cycle includes four steps in which electrons are abstracted. Stage 3: electrons carried by NADH and FADH2 are funneled into a chain of mitochondrial (or, in bacteria, plasma membrane-bound) electron carriers—the respiratory chain—ultimately reducing O2 to H2O.This electron flow drives the production of ATP. 55

Where does this all happen? FIGURE 19-1 Biochemical anatomy of a mitochondrion. The convolutions (cristae) of the inner membrane provide a very large surface area. The inner membrane of a single liver mitochondrion may have more than 10,000 sets of electron-transfer systems (respiratory chains) and ATP synthase molecules, distributed over the membrane surface. The mitochondria of heart muscle, which have more profuse cristae and thus a much larger area of inner membrane, contain more than three times as many sets of electron-transfer systems as liver mitochondria. The mitochondrial pool of coenzymes and intermediates is functionally separate from the cytosolic pool. The mitochondria of invertebrates, plants, and microbial eukaryotes are similar to those shown here, but with much variation in size, shape, and degree of convolution of the inner membrane. 56

FIGURE 16-7 Reactions of the citric acid cycle FIGURE 16-7 Reactions of the citric acid cycle. The carbon atoms shaded in pink are those derived from the acetate of acetyl-CoA in the first turn of the cycle; these are not the carbons released as CO2 in the first turn. Note that in succinate and fumarate, the two-carbon group derived from acetate can no longer be specifically denoted; because succinate and fumarate are symmetric molecules, C-1 and C-2 are indistinguishable from C-4 and C-3. The number beside each reaction step corresponds to a numbered heading on pages 622–628. The red arrows show where energy is conserved by electron transfer to FAD or NAD+, forming FADH2 or NADH + H+. Steps 1, 3, and 4 are essentially irreversible in the cell; all other steps are reversible. The product of step 5 may be either ATP or GTP, depending on which succinyl-CoA synthetase isozyme is the catalyst. 57

Net Effect of the Citric Acid Cycle Acetyl-CoA + 3NAD+ + FAD + GDP + Pi + 2 H2O 2CO2 +3NADH + FADH2 + GTP + CoA + 3H+ carbons of acetyl groups in acetyl-CoA are oxidized to CO2 electrons from this process reduce NAD+ and FAD one GTP is formed per cycle, this can be converted to ATP intermediates in the cycle are not depleted

Energy Yield TABLE 16-1 Stoichiometry of Coenzyme Reduction and ATP Formation in the Aerobic Oxidation of Glucose via Glycolysis, the Pyruvate Dehydrogenase Complex Reaction, the Citric Acid Cycle, and Oxidative Phosphorylation 59

FIGURE 16-18 Regulation of metabolite flow from the PDH complex through the citric acid cycle in mammals. The PDH complex is allosterically inhibited when [ATP]/[ADP], [NADH]/[NAD+], and [acetyl-CoA]/[CoA] ratios are high, indicating an energy-sufficient metabolic state. When these ratios decrease, allosteric activation of pyruvate oxidation results. The rate of flow through the citric acid cycle can be limited by the availability of the citrate synthase substrates, oxaloacetate and acetyl-CoA, or of NAD+, which is depleted by its conversion to NADH, slowing the three NAD-dependent oxidation steps. Feedback inhibition by succinyl-CoA, citrate, and ATP also slows the cycle by inhibiting early steps. In muscle tissue, Ca2+ signals contraction and, as shown here, stimulates energy-yielding metabolism to replace the ATP consumed by contraction. 60

Oxidative Phosphorylation