krebs cycle

The Citric Acid Cycle - Overview

The citric acid cycle, also known as the Krebs cycle, is a vital metabolic pathway that plays a crucial role in cellular respiration, where energy is produced from the breakdown of carbohydrates, fats, and proteins. This series of enzymatic reactions occurs in the mitochondria and utilizes acetyl-CoA derived from pyruvate.

Fate of Pyruvate

Upon glycolysis, phosphoenolpyruvate is converted to pyruvate, which can follow various metabolic pathways depending on cellular conditions. In bacterial cells, pyruvate is directly converted to acetyl CoA in the cytosol, whereas in eukaryotic cells, this conversion occurs in the mitochondria through the pyruvate dehydrogenase complex (PDC).

Mitochondrial Import of Pyruvate

For pyruvate to serve as a substrate in the PDC reactions, it must be imported from the cytoplasm to the mitochondria via a specialized pyruvate transporter embedded in the inner mitochondrial membrane. Once inside, pyruvate engages with cofactors and undergoes decarboxylation to form acetyl CoA, a key substrate for the citric acid cycle.

The Citric Acid Cycle: Key Features

The citric acid cycle proceeds through a series of reactions resulting in the complete oxidation of acetyl CoA.

Main Steps of the Cycle

  1. Condensation of Acetyl CoA and Oxaloacetate: The cycle begins with the reaction of acetyl CoA and oxaloacetate to form citrate, catalyzed by citrate synthase, representing the cycle's key regulatory step.

  2. Isomerization: Citrate is then converted to isocitrate via aconitase, a reversible reaction that involves hydration and dehydration steps.

  3. Oxidative Decarboxylation: Isocitrate is oxidatively decarboxylated to form α-ketoglutarate through the action of isocitrate dehydrogenase, which also reduces NAD+ to NADH.

  4. Decarboxylation of α-Ketoglutarate: This step, catalyzed by α-ketoglutarate dehydrogenase, closely resembles the conversion of pyruvate to acetyl CoA and results in the release of CO2 and the formation of succinyl CoA.

  5. Conversion to Succinate: Succinyl CoA synthetase catalyzes the hydrolysis of succinyl CoA to succinate, generating GTP or ATP in the process.

  6. Oxidation to Fumarate: Succinate undergoes oxidation to fumarate mediated by succinate dehydrogenase, with FAD functioning as a bound cofactor.

  7. Hydration of Fumarate: Fumarate is then converted to malate by fumarase in a hydration reaction.

  8. Final Oxidation to Regenerate Oxaloacetate: The cycle completes with the oxidation of malate to oxaloacetate, producing another molecule of NADH.

Products of One Cycle

In each turn of the cycle, two molecules of CO2 are released, along with three NADH, one FADH2, and one GTP (or ATP). This cycle is pivotal, not only for energy production but also for providing intermediates necessary for various biosynthetic pathways.

Pyruvate Dehydrogenase Complex (PDC)

The PDC, consisting of three major enzymes (E1, E2, E3), is responsible for the oxidative decarboxylation of pyruvate, with five coenzymes playing critical roles in electron transfer and substrate transformation. These include thiamine pyrophosphate (TPP) and coenzyme A.

Regulation of the PDC

The activity of E1 (pyruvate dehydrogenase) is modulated by covalent modifications. It can be inhibited by phosphorylation and activated by dephosphorylation, with pyruvate acting as a potent inhibitor of the kinase that phosphorylates E1. Calcium ions also enhance E1 activity, particularly in muscles during contraction.

Deficiency and Dysfunctions

The inability to convert pyruvate to acetyl CoA can lead to lactic acidosis due to rerouting pyruvate to lactate. Wernicke-Korsakoff syndrome, associated with thiamine deficiency, leads to neurological and cognitive impairments due to disrupted ATP production. Pyruvate dehydrogenase deficiency results from mutations affecting E1 and is often X-linked dominant, prompting symptoms that necessitate dietary management.

Citric Acid Cycle’s Historical Note

The discovery of citric acid is credited to Abu Musa Jabir ibn Hayyan, who isolated it from citrus fruits. The cycle itself illustrates the complex interplay of metabolic pathways integral to energy production in aerobic organisms.