Protein lipoylation

Stable Identifier
Homo sapiens
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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 (Arribas-Carreira et al., 2023).
Literature References
PubMed ID Title Journal Year
36190515 Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined nonketotic hyperglycinemia and lipoate deficiency

Karstensen, HG, Lund, AM, Stence, NV, Lawrence Merritt Ii, J, Van Hove, JLK, Santer, R, Hempel, M, Achleitner, MT, Kronquist, K, Spector, EB, Swanson, MA, Julve, N, Grunewald, S, Feichtinger, RG, Koutsoukos, S, Christensen, M, Farris, J, Pérez, B, Østergaard, E, Aquaviva-Bourdain, C, Mayr, JA, Dallabona, C, Rodríguez-Pombo, P, Magistrati, M, Ugarte, M, Arribas-Carreira, L, Riela, AR, Arnoux, JB, Tsiakas, K, Donnini, C, Haldar, K

Hum Mol Genet 2023
29339506 Development and retention of a primordial moonlighting pathway of protein modification in the absence of selection presents a puzzle

Zhu, L, Cao, X, Hong, Y, Hu, Y, Cronan, JE

Proc Natl Acad Sci U S A 2018
19570983 Lipoic acid synthesis and attachment in yeast mitochondria

Dieckmann, CL, Kursu, VA, Schonauer, MS, Hiltunen, JK, Kastaniotis, AJ

J. Biol. Chem. 2009
32508887 Progress in the Enzymology of the Mitochondrial Diseases of Lipoic Acid Requiring Enzymes

Cronan, JE

Front Genet 2020
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