Tricarboxylic acid cycle enzymes (anaplerotic succinyl-CoA pathway) (TCA cycle (anaplerosis))

The tricarboxylic acid (TCA) cycle enzymes involved in anaplerotic succinyl-CoA entry represent a critical metabolic target for treating disorders of energy metabolism. In conditions like long-chain fatty acid oxidation disorders (LC-FAOD), the inability to oxidize long-chain fats leads to a deficiency of acetyl-CoA and a subsequent depletion of TCA cycle intermediates, a state known as cataplerosis (Roe et al., 2002). By providing an alternative carbon source that enters the cycle at succinyl-CoA, such as through the administration of triheptanoin, the pool of catalytic intermediates is replenished. This anaplerotic effect allows the TCA cycle to continue functioning, facilitating the oxidation of both glucose and any available fatty acids to generate ATP (Vockley et al., 2015). This therapeutic approach is particularly vital for high-energy organs like the heart and skeletal muscle, which are severely impacted by metabolic fuel shortages (FDA, 2020). Consequently, this pathway serves as a vital target for pharmacological intervention to bypass enzymatic deficiencies in fatty acid or carbohydrate metabolism (Mochel, 2017).

Other names

Krebs cycleCitric acid cycleAnaplerotic pathwaySuccinyl-CoA entry pathwayHeptanoate metabolism pathway

Triheptanoin provides heptanoate, which is metabolized to propionyl-CoA and then to succinyl-CoA via propionyl-CoA carboxylase and methylmalonyl-CoA mutase; succinyl-CoA then enters the TCA cycle as an anaplerotic substrate to replenish intermediates and maintain ATP production (FDA, 2020; Vockley et al., 2015).