Reactome | Protein lipoylation

Protein lipoylation

Stable Identifier

R-HSA-9857492

DOI

10.3180/R-HSA-9857492.1

Type

Pathway

Species

Homo sapiens

Compartment

mitochondrial inner membrane, mitochondrial matrix

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Click the image above or here to open this pathway in the Pathway Browser

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