Protein lipoylation

Lipoate is an essential cofactor for five redox reactions: four in oxoacid dehydrogenases (active in energy and amino acid metabolism) and one in the glycine cleavage system (GCS). Lipoate synthesis and transfer to target proteins in mitochondria requires three steps. Octanoyl carried by ACP from mitochondrial fatty acid synthesis is first transferred to GCSH. In the second step, two sulfur atoms of an iron-sulfur cluster are inserted on the side chain, synthesizing the lipoyl group in a highly complicated reaction. Finally, lipoyl is transferred onto the lipoyl domains of the E2 subunits (DLST, DLAT, DBT) of the target enzyme complexes (OGDH, OADH, PDH, BCKDH) (Schonauer et al., 2009; Cao et al., 2018; reviewed in Cronan, 2020). Defects in the enzymes catalyzing the three steps cause severe lactic acidosis and metabolic imbalances due to dehydrogenase deficiency. Mutations in the lipoyl carrier GCSH additionally cause hyperglycinemia, leading to epileptic encephalopathy, since GCSH moonlights in glycine catabolism.

Summary from Reactome (R-HSA-9857492), read 2026-09-23.