lipoyl

Lipoyl refers to the lipoyl group, the prosthetic moiety derived from lipoic acid that is covalently bound to specific lysine residues on certain mitochondrial enzyme complexes. The lipoyl moiety functions as a flexible “swinging arm” that shuttles substrates and intermediates between catalytic centers in multienzyme complexes such as the pyruvate dehydrogenase complex (PDH), the α-ketoglutarate dehydrogenase complex, and the branched-chain α-ketoacid dehydrogenase complex.

Chemistry and structure: The lipoyl group is formed when lipoic acid is covalently attached to a lysine residue on the E2 subunit, creating lipoyllysine. The lipoyl group contains a disulfide bond in its oxidized form and reversibly becomes dihydrolipoyl (reduced) during catalysis. This redox-active disulfide enables the transfer of acyl groups between active sites during the catalytic cycle.

Biological role and biosynthesis: In bacteria and mitochondria, lipoylation begins with the transfer of an octanoyl unit to the E2 subunit, followed by sulfur insertion to generate the mature lipoyl disulfide. Enzymes such as lipoyl transferases and lipoyl synthase mediate these steps. In eukaryotes, specialized lipoylation enzymes attach the lipoyl moiety to E2 subunits, enabling proper function of PDH, OGDH (α-ketoglutarate dehydrogenase), and branched-chain dehydrogenase complexes.

Clinical and research relevance: Proper lipoylation is essential for aerobic energy metabolism. Defects in lipoylation pathways can impair mitochondrial enzyme function and are explored in the context of metabolic and mitochondrial disorders. Lipoyl-containing proteins are also studied as models for understanding prosthetic-group dynamics in complex enzyme mechanisms.