MUT isomerises L-MM-CoA to SUCC-CoA

Stable Identifier
Reaction [transition]
Homo sapiens
L-methylmalonyl-CoA <=> succinyl-CoA
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Methylmalonyl CoA mutase (MUT aka MCM) (Jansen et al. 1989) utilises adenosylcobalamin (AdoCbl) as a cofactor and catalyzes interchange of a carbonyl-CoA group and a hydrogen atom in conversion of methylmalonyl CoA to form succinyl CoA, a precursor for the citric acid cycle. MUT has a homodimeric structure and is located in the mitochondrial matrix. Defects in MUT cause methylmalonic aciduria, mut type (MMAM; MIM:251000), an often fatal disorder of organic acid metabolism (Worgan et al. 2006).

Methylmalonic aciduria type A protein (MMAA) is thought to act as a chaperone to MUT, the enzyme which utilises adenosylcobalamin (AdoCbl) as a cofactor. MMAA is suggested to play a dual role with regards to MUT protection and reactivation. Some AdoCbl-dependent enzymes undergo suicide inactivation after catalysis due to the oxidative inactivation of Cbl. MMAA is thought to play a protective role to prevent MUT being inactivated in this way. After the catalytic cycle when MUT is inactive, MMAA increases the enzymatic activity of MUT through exchange of the damaged cofactor. Whether this happens via GTP-mediated hydrolysis is unknown at present (Takahashi-Iniguez et al. 2011, Froese et al. 2010). Bacterial AdoCbl-containing enzymes possess reactivating factors which release the inactivated cofactor to allow the resulting apoenzyme to reconstitute into an active form. A bacterial orthologue of MMAA, MeaB, forms a stable complex with MUT and plays a role in its protection and reactivation (Padovani & Banerjee 2006).

Defects in MMAA cause methylmalonic aciduria type cblA (cblA aka methylmalonic aciduria type A or vitamin B12-responsive methylmalonicaciduria of cblA complementation type; MIM:251100). Affected individuals accumulate methylmalonic acid in the blood and urine and are prone to potentially life threatening acidotic crises in infancy or early childhood (Dobson et al. 2002, Lerner-Ellis et al. 2004).

Literature References
PubMed ID Title Journal Year
21138732 Protection and reactivation of human methylmalonyl-CoA mutase by MMAA protein

Flores, ME, García-Arellano, H, Takahashi-Íñiguez, T, Trujillo-Roldán, MA

Biochem. Biophys. Res. Commun. 2011
20876572 Structures of the human GTPase MMAA and vitamin B12-dependent methylmalonyl-CoA mutase and insight into their complex formation

Froese, DS, Gravel, RA, Wu, X, Ugochukwu, E, Oppermann, U, Muniz, JR, Kochan, G, Krysztofinska, E, Yue, WW, Gileadi, C

J. Biol. Chem. 2010
12438653 Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements

Dobson, CM, Hudson, T, Doré, C, Gravel, RA, Rosenblatt, DS, Wu, X, Leclerc, D, Wai, T, Wilson, A

Proc. Natl. Acad. Sci. U.S.A. 2002
16866376 Assembly and protection of the radical enzyme, methylmalonyl-CoA mutase, by its chaperone

Padovani, D, Banerjee, R

Biochemistry 2006
16281286 Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype

Niles, K, Worgan, LC, Rosenblatt, DS, Lepage, P, Hofmann, A, Kucic, T, Tirone, JC, Sammak, A, Verner, A

Hum. Mutat. 2006
15523652 Mutations in the MMAA gene in patients with the cblA disorder of vitamin B12 metabolism

Dobson, CM, Doré, C, Gravel, RA, Rosenblatt, DS, Lepage, P, Leclerc, D, Watkins, D, Wai, T, Tirone, JC, Lerner-Ellis, JP

Hum. Mutat. 2004
2567699 Cloning of full-length methylmalonyl-CoA mutase from a cDNA library using the polymerase chain reaction

Jansen, R, Rosenberg, LE, Kalousek, F, Ledley, FD, Fenton, WA

Genomics 1989
Catalyst Activity

methylmalonyl-CoA mutase activity of 2xMMAA:2xMUT:AdoCbl [mitochondrial matrix]

Orthologous Events
Cross References
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