propionylCoA

Propionyl-CoA is the thioester formed by the activation of propionic acid with coenzyme A. It is a key metabolic intermediate in the breakdown of odd-chain fatty acids, certain amino acids (valine, isoleucine, methionine, threonine), and dietary propionate, linking lipid and amino acid metabolism to the tricarboxylic acid cycle.

Formation and transformation: Propionate is activated to propionyl-CoA by a propionyl-CoA synthetase–type enzyme in an ATP-dependent reaction. Propionyl-CoA is then converted to methylmalonyl-CoA through a biotin-dependent carboxylation by propionyl-CoA carboxylase. Methylmalonyl-CoA is subsequently rearranged by methylmalonyl-CoA mutase, which requires vitamin B12, to yield succinyl-CoA. Succinyl-CoA can enter the TCA cycle, providing an anaplerotic input to energy metabolism.

Sources and connections: Propionyl-CoA can originate from the catabolism of propionate produced by gut microbiota, as well as from the breakdown of the above-mentioned amino acids and odd-chain fatty acids. The pathway thus serves as a bridge between dietary intakes, microbial metabolism, and central energy production.

Clinical significance: Defects in propionyl-CoA metabolism, particularly deficiency of propionyl-CoA carboxylase, cause propionic acidemia. This disorder leads to accumulation of propionyl-CoA and propionic acids, with presentations including metabolic acidosis, hyperammonemia, and failure to thrive in infancy. Management involves dietary restriction of propionate-precursor amino acids, monitoring of organic acids, and metabolic crisis support; some cases may require carnitine supplementation or other interventions. Proper function of this pathway depends on adequate biotin and vitamin B12 status.