Lipoamidarm

Lipoamidarm, also known as the lipoyl arm, refers to the flexible lipoylated domain that acts as a swinging cofactor within certain multienzyme complexes, most notably the pyruvate dehydrogenase complex (PDC). It contains a lysine residue covalently bound to a lipoic acid moiety and serves to shuttle acyl groups and electrons between catalytic centers during catalysis.

Structurally, the lipoamidarm is part of the E2 subunit (dihydrolipoamide transacetylase) of these complexes. A conserved lysine within the lipoyl domain becomes modified with the lipoic acid, forming the lipoyl group that can cycle between an oxidized dithiolane form and a reduced dihydrolipoamide form. The arm is connected to the protein by a flexible linker, allowing it to extend and reorient between the active sites of adjacent enzymes, such as E1 (decarboxylation) and E3 (reoxidation).

Functionally, the lipoamidarm acts as a transient carrier, physically transferring reaction intermediates from one active site to another within the complex. In the PDC and related complexes, pyruvate is decarboxylated by E1 and the resulting acyl group is transferred to the lipoyl group on the arm. The arm then delivers the acetyl group to CoA on E2, and the reduced lipoyl moiety is regenerated by E3 through redox chemistry involving FAD and NAD+. This mechanism enables substrate channeling and increases catalytic efficiency.

Physiological relevance includes its essential role in central metabolism. Proper lipoylation of the E2 subunit and the mobility of the lipoamidarm are critical for mitochondrial energy production; defects can contribute to metabolic disorders such as pyruvate dehydrogenase deficiency. The concept of the lipoamidarm extends to other multienzyme complexes that use the lipoyl strategy for substrate transfer.