Lipoylation

Lipoylation is a post-translational modification in which lipoic acid is covalently attached to specific lysine residues in certain enzyme complexes. The best-known targets are the E2 subunits of the pyruvate dehydrogenase complex (PDC), the α-ketoglutarate dehydrogenase complex (OGDH), the branched-chain ketoacid dehydrogenase complex (BCKDC), and the H protein of the glycine cleavage system. The lipoyl moiety acts as a flexible swinging arm that shuttles intermediates between catalytic centers, enabling multi-step acetyl- and acyl-transfer reactions within these complexes.

In bacteria and some organelles, the lipoylation pathway begins with an octanoyl transfer from a carrier such as octanoyl-ACP to a conserved lysine on the target protein, a reaction catalyzed by the octanoyltransferase LipB. LipA then introduces sulfur atoms into the octanoyl moiety to form the functional lipoyl group. A salvage pathway uses lipoic acid ligases (LplA) that activate free lipoic acid with ATP and transfer it to the lysine residue.

In eukaryotes, lipoylation is initiated in mitochondria by LIAS (lipoyl synthase), which installs the lipoyl group on target proteins or carrier domains. Subsequent transfer to additional subunits is carried out by lipoyl transferases such as LIPT1 and LIPT2. Proper lipoylation is essential for the function of mitochondrial multienzyme complexes and, therefore, for cellular energy metabolism.

Clinical and research relevance: defects in lipoylation enzymes can impair energy production and cause metabolic disorders, including encephalopathy and lactic acidosis. Lipoylation status is often assessed by specialized biochemical methods such as mass spectrometry and lipoyl-lysine–specific antibodies.