The Citric Acid Cycle and Cellular Respiration

The Citric Acid Cycle

• A cyclical metabolic pathway that plays a crucial role in cellular respiration
• It's a key process for energy production and an important intermediary in various metabolic pathways
• The citric acid cycle is a central metabolic hub, converting acetyl CoA to CO2 with concomitant electron transfer
• Converging catabolism generates intermediates for energy or biosynthesis
• Diverging anabolism provides the starting materials for biosynthesis

Cellular Respiration and Energy Production

• Aerobic catabolism involving three key stages
• Stage 1: Organic fuels (e.g., glucose) are oxidized to acetyl CoA
• Stage 2: Acetyl CoA is oxidized to CO2 and reduces electron carriers (NADH and FADH2)
• Stage 3: Electron carriers are oxidized by O2, producing ATP through oxidative phosphorylation

Cellular Respiration in Mitochondria

• Mitochondria are the sites of cellular respiration
• The outer membrane is freely permeable to small molecules
• The inner membrane is impermeable and contains respiratory electron carriers, ATP synthase, and other transporters
• The matrix contains the enzymes for pyruvate oxidation, the citric acid cycle, and fatty acid oxidation

Oxidation of Pyruvate to Acetyl CoA

• Catalyzed by the pyruvate dehydrogenase complex (PDH)
• An irreversible oxidative decarboxylation process
• Converts pyruvate (3 carbons) to acetyl CoA (2 carbons) and releases CO2
• The complex includes three enzymes and five cofactors (TPP, lipoic acid, NAD+, FAD, and CoA)

Coenzyme A and Acetyl CoA

• Coenzyme A (CoA) is a crucial component of acetyl CoA, a key intermediate in metabolism
• Acetyl CoA has a higher energy content than ATP

Lipoic Acid

• Lipoic acid is a key cofactor in the PDH complex
• It undergoes reversible redox reactions, facilitating the transfer of acetyl groups

Oxidation of Pyruvate to Acetyl CoA (Further Details)

• A five-step process catalyzed by the PDH complex
• Involves the participation of enzymes E1, E2, and E3, and several cofactors
• The PDH complex can be regulated by phosphorylation/dephosphorylation

Oxidation of Pyruvate to Acetyl CoA (Complex Structure)

• The PDH complex is a supramolecular complex with three distinct enzymes (E1, E2, and E3) arranged to facilitate efficient catalysis
• E2 includes a swinging lipoyl arm that transfers intermediates between the active sites of E1 and E3. The enzymes are mechanically coupled.

Step 1: Decarboxylation of Pyruvate

• Thiamine pyrophosphate (TPP) plays a crucial role in this decarboxylation step

Step 2: Oxidation of Activated Acetaldehyde to Acetate

• The acetaldehyde on TPP is transferred to the lipoyl group of the E2 enzyme
• Acetaldehyde is oxidized, and CoA is attached, forming acetyl CoA

Steps 3, 4: Reoxidation of Reduced Lipoyl Group; Electron Harvesting

• The reduced lipoyl group (from the E2 enzyme) is reoxidized by E3, generating reduced electron carriers (FADH2)
• FADH2 is then reoxidized, generating NADH (a key electron carrier in cellular respiration)

Citric Acid Cycle: Steps

• A series of enzyme-catalyzed reactions completing the oxidation of acetyl CoA
• Intermediates are critical in anabolic pathways and maintaining steady state

Citric Acid Cycle: Steps (Further Details)

• The cycle involves the generation of ATP, NADH, and FADH2 and forms a cycle
• Citrate is isomerized to isocitrate
• Isocitrate is oxidatively decarboxylated to α-ketoglutarate
• a-ketoglutarate is oxidatively decarboxylated to succinyl CoA
• Succinyl CoA is converted to succinate with GTP production
• Succinate is oxidized to fumarate
• Fumarate is hydrated to malate
• Malate is oxidized to oxaloacetate

Citric Acid Cycle: Summary

• The citric acid cycle is a central metabolic pathway, crucial for energy production and the formation of biosynthetic precursors.
• In this cycle, two-carbon acetyl CoA molecules are completely oxidized to CO2, generating reduced electron carriers (NADH and FADH2) and GTP (which can be converted to ATP).
• The cycle is also significant for the generation of intermediates used in other metabolic pathways.

Citric Acid Cycle: Regulation

• The regulation of the citric acid cycle occurs at the level of the various highly exothermic steps

Fate of Citrate

• Citrate has metabolic fates beyond energy generation.
• Citrate can be exported to the cytoplasm, providing reducing equivalents for biosynthetic processes.

Sources and Fate of Succinate

• Succinate arises from the citric acid cycle's operations and plays a role in various metabolic pathways,including heme synthesis.

Goals and Objectives

• Topics covered include cellular respiration, mitochondrial structure, pyruvate oxidation, the citric acid cycle, and metabolic regulation, including anaplerotic reactions.

Drugs and Diseases

• Several vitamins (e.g., thiamine, riboflavin, niacin) and lipoic acid are critical for the reactions in the citric acid cycle. Deficiencies can lead to diseases like Beri-Beri.

Anaplerotic Reactions

• These reactions replenish the citric acid cycle's intermediates, ensuring constant intermediate concentrations

Biological Tethers

• Lipoic acid, biotin, and CoA act to shuttle groups between enzymes during metabolic pathways, allowing for transfer of intermediates.