lipoylated

Lipoylated refers to a protein that has covalently attached lipoic acid, forming a lipoyllysine residue. This post-translational modification is essential for the activity of several mitochondrial multienzyme complexes and certain glycine cleavage system components. The lipoyl group serves as a flexible, swinging arm that shuttles substrates and intermediates between catalytic centers within these complexes, while also participating in redox chemistry during catalysis.

The lipoyl moiety is derived from lipoic acid and is attached to specific lysine residues in designated protein subunits, most notably the E2 subunits of the pyruvate dehydrogenase complex (PDH), alpha-ketoglutarate dehydrogenase complex (OGDH), and branched-chain α-ketoacid dehydrogenase complex (BCKDH), as well as the H protein of the glycine cleavage system in mitochondria. The lipoyl group cycles between reduced and oxidized states as it orchestrates transfer of acyl groups and electrons during the catalytic cycle.

Biosynthesis and attachment pathways vary across organisms. In bacteria, separate enzymes install the lipoyl group: an octanoyltransferase transfers an octanoyl chain, and a lipoyl synthase introduces sulfur atoms to generate the mature lipoyl moiety; subsequent transfer enzymes can attach it to target proteins. In eukaryotes, mitochondrial machinery, including lipoyl synthase activity and transfer factors, accomplishes lipoylation of the relevant protein subunits.

Defects in lipoylation or in enzymes that supply or transfer the lipoyl moiety can impair central metabolism, leading to metabolic disorders and energetic deficiencies. Lipoylation remains a key example of how a small cofactor modification enables complex, multi-subunit enzyme systems to function cohesively.