Citric Acid Cycle

Functions

Production of energy 

• Direct production of guanosine triphosphate (GTP) (equivalent to adenosine triphosphate [ATP])
• NADH + H⁺ and FADH₂ then produce ATP within the respiratory chain. 

Amphibolic center

The citric acid cycle provides precursors for many catabolic and anabolic processes.

• Precursors for amino acids: 
  • Alpha-ketoglutarate for glutamate
  • Oxaloacetate for aspartate
• Succinyl-CoA is crucial for the synthesis of porphyrins or heme.
• Citrate is needed for the synthesis of fatty acids and cholesterol.
• Oxaloacetate is a substrate for gluconeogenesis.

Reactions, Yield, and Energy Balance

Two main substrates: acetyl-CoA and oxaloacetate

• Acetyl-CoA from the beta-oxidation of fatty acids and glycolysis 
  • Pyruvate dehydrogenase produces acetyl-CoA from pyruvate.
• Oxaloacetate from regeneration within the Krebs cycle or from pyruvate
  • Pyruvate carboxylase produces oxaloacetate from pyruvate and CO₂.

Steps:
Acetyl-CoA (C2) + oxaloacetate (C4) → Citrate (C6) → Isocitrate (C6) → α-Ketoglutarate (C5) → Succinyl-CoA (C4) → Succinate (C4) → Fumarate (C4) → Malate (C4) → Oxaloacetate (C4)
Mnemonic device: Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate

Notable reactions:

• Irreversible:
  • Acetyl-CoA + oxaloacetate → citrate via citrate synthase
  • Isocitrate → α-ketoglutarate via isocitrate dehydrogenase
  • α-ketoglutarate → succinyl-CoA via α-ketoglutarate dehydrogenase
• Succinate dehydrogenase: only enzyme of the Krebs cycle that is anchored to the inner membrane of the mitochondrion
• α-ketoglutarate dehydrogenase: requires 5 cofactors (thiamine pyrophosphate, lipoic acid, coenzyme A, FAD, and NAD⁺)

Yield:
3 NADH + H⁺ + 1 FADH₂ + 1 GTP + 2 CO₂ per acetyl-CoA (x 2 per glucose)

Energy balance:
7,5 ATP (3 NADH + H⁺) + 1,5 ATP (1 FADH₂) + 1 ATP (1 GTP) = 10 ATP per acetyl-CoA (x 2 per glucose)

Regulation

Clinical Relevance

The following process is stimulated by the tricarboxylic acid (TCA) cycle:

• Ketogenesis: the synthesis of ketone bodies from acetyl-CoA. Ketogenesis is caused by prolonged starvation, diabetic ketoacidosis, and alcoholism. The inhibition of the TCA cycle leads to a rise in acetyl-CoA levels, which directly stimulates ketogenesis.

The following conditions inhibit the TCA cycle:

• Hyperammonemia: a condition defined by an excess of ammonia in the blood. It may be acquired (liver disease) or hereditary (urea cycle enzyme deficiencies). In hyperammonemia, the level of α-ketoglutarate rises, inhibiting the TCA cycle. It presents as asterixis, slurring of speech, somnolence, vomiting, cerebral edema, and blurry vision. 
• Thiamine deficiency: a condition that occurs due to malnutrition and/or alcoholism, which inhibits the enzyme α-ketoglutarate dehydrogenase via a lack of 1 of its cofactors (thiamine). This leads to the accumulation of glutamate, leading to Wernicke’s encephalopathy. It presents as a triad of confusion, ophthalmoplegia, and ataxia.
• Diabetic ketoacidosis: a condition primarily seen in patients with type I diabetes mellitus, which is caused by insufficient insulin levels. It presents with hyperglycemia, polyuria, polydipsia, nausea, vomiting, and volume depletion. It can inhibit the TCA cycle by lowering the levels of oxaloacetate.
• Alcohol use disorder: Alcoholism is a level of alcohol consumption that exceeds the sociocultural standard. The condition is marked by mental and physical addiction with an irresistible desire for alcohol and tolerance of the drug. It can inhibit the TCA cycle by causing a rise in the NADH/NAD⁺ ratio.