acetyldihydrolipoamide

Acetyldihydrolipoamide is a transient thioester intermediate in the oxidative decarboxylation of pyruvate within the pyruvate dehydrogenase complex (PDH). It consists of an acetyl group bound to the reduced lipoamide moiety (dihydrolipoamide) attached to the E2 component, dihydrolipoamide acetyltransferase, of PDH. The acetyl group is subsequently transferred from acetyldihydrolipoamide to coenzyme A, forming acetyl-CoA and regenerating the oxidized lipoamide for reuse in the catalytic cycle.

In the PDH catalytic cycle, pyruvate is decarboxylated by E1, and the resulting hydroxyethyl group is transferred to the lipoamide arm on E2 to form acetyl-dihydrolipoamide. The E2 component then transfers the acetyl group to CoA, producing acetyl-CoA and the reduced form of lipoamide. The dihydrolipoamide is reoxidized by the E3 component, lipoamide dehydrogenase, with FAD and NAD+ serving as electron acceptors. This cycling is essential for the production of acetyl-CoA, a key substrate for the citric acid cycle and other biosynthetic pathways.

Acetyldihydrolipoamide is typically a bound, transient intermediate and is not usually isolated under physiological conditions. The concept extends to related multienzyme complexes that employ lipoamide prosthetic groups, such as other α-keto acid dehydrogenase complexes, where analogous acyl-dihydrolipoamide intermediates participate in substrate transfer.

Dysfunction or regulation of PDH and its lipoamide cycle can impact cellular energy metabolism, underlining the biological importance of acetyldihydrolipoamide as part of aerobic respiration.