Pyruvate Metabolism Overview

Study Notes

The citric acid cycle (TCA cycle, or Krebs cycle) is the primary energy-producing pathway in the body.
It occurs in the mitochondria, a specialized organelle within cells.
The cycle is a series of interconnected reactions that involve oxidation-reduction and other transformations.
It is the final common pathway for the breakdown (catabolism) of carbohydrates, fats, and proteins.
Acetyl-CoA derived from glucose, fatty acids, and some amino acids enters the cycle by combining with oxaloacetic acid (OAA) to form citrate.
Through a series of steps involving dehydrogenations and carbon dioxide (CO2) release, the cycle regenerates OAA, which can then accept another acetyl group from acetyl-CoA.
All TCA cycle enzymes are found in the mitochondrial matrix except succinate dehydrogenase, which is located in the inner mitochondrial membrane.
Electrons are transferred to NAD+ and FAD during the cycle.
These reduced coenzymes (NADH and FADH2) subsequently donate their electrons to the electron transport chain, leading to ATP generation through oxidative phosphorylation.
One GTP molecule is generated per cycle through substrate-level phosphorylation.
The entire process is aerobic, requiring oxygen as the final electron acceptor.
The TCA cycle is crucial for energy production.

Citrate synthase: Catalyzes the initial condensation of acetyl-CoA with OAA to form citrate.
Isocitrate dehydrogenase (ICD): Catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, generating NADH.
α-ketoglutarate dehydrogenase: Catalyzes the oxidative decarboxylation of α-ketoglutarate to succinyl-CoA, generating NADH and CO2.

It is the final common pathway for the catabolism of carbohydrates, proteins, and fats, with acetyl-CoA serving as the central molecule.
It plays a major role in energy production by oxidizing acetyl-CoA to CO2 and H2O, yielding ATP.
It provides intermediates for anabolic pathways such as heme synthesis, non-essential amino acid synthesis, fatty acid synthesis, cholesterol synthesis, and steroid synthesis.

The oxidation of one molecule of acetyl-CoA generates 12 ATP molecules.
This includes 9 ATP from NADH oxidation, 2 ATP from FADH2 oxidation, and 1 ATP from GTP production.

The electron transport chain (ETC) is the final pathway for electron transfer in aerobic cells, transferring electrons from various substrates to oxygen.
It is located in the mitochondrial inner membrane and consists of a series of organized redox enzymes.
The ETC is crucial for energy production as it utilizes energy released from electron transfer to pump protons across the inner mitochondrial membrane.
This proton gradient creates an electrochemical potential that drives ATP synthesis.

Complex I (NADH-CoQ reductase): Transfers electrons from NADH to CoQ, pumping protons across the membrane.
Complex II (Succinate-CoQ reductase): Transfers electrons from succinate to CoQ via FADH2.
Complex III (CoQ-Cyt.C reductase): Transfers electrons from CoQ to cytochrome c, also pumping protons.
Complex IV (Cyt.C oxidase): Transfers electrons from cytochrome c to oxygen, generating water and pumping protons.

Energy from electron transport is used to pump protons across the inner mitochondrial membrane, creating an electrochemical gradient.
Protons flow back into the matrix through ATP synthase, driving the phosphorylation of ADP to ATP.
ATP is then transported from the matrix to the cytosol in exchange for ADP.

Cyanide poisoning: Cyanide binds to cytochrome aa3, blocking electron transport and ATP production, leading to rapid death.
Acute myocardial infarction: Blockage of coronary arteries can lead to oxygen deprivation in heart muscle, inhibiting electron transport and ATP production.
This results in energy depletion and damage to heart muscle cells, potentially causing heart failure.