3-Methylcrotonyl-CoA carboxylase deficiency

Stable Identifier
R-HSA-9909438
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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3-Methylcrotonyl-CoA carboxylase deficiency
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3-methylcrotonyl-CoA carboxylase catalyzes the reversible conversion of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA, the fourth step in the catabolism of leucine (Chu et al, 2007; Son et al, 2020). MCCC is composed of two subunits encoded by MCCC1 and MCCC2. MCCC1 protein is covalently attached to a biotin moiety that is essential for the ATP dependent carboxylation activity, while MCCC2 contributes carboxyltransferase activity (Holzinger et al, 2001; Lau et al, 1979; Gallardo et al, 2001; Baumgartner et al, 2001). Mutations in either subunit of the enzyme, MCCC1 and MCCC2, are associated with 3-methylcrotonyl-CoA carboxylase deficiency (MCCD), also known as 3-methylcrotonylglycinuria, an autosomal recessive inborn error of metabolism characterized by accumulation and excretion of 3-hydroxyvaleric acid and 3-methylcrotonylglycine (Bannwart et al, 1992; Lehnert et al, 1996; Baumgartner et al, 2005). MCCD is the most prevalent organic aciduria with frequencies ~ 1:50,000 but has variable clinical phenotypes. 1-2% of affected individuals are at risk of a severe adverse effect that manifests during the neonatal period with severe neurological impairment while ~10% of affected individuals develop only minor symptoms (Baumgartner et al, 2001; Gallardo et al, 2001; Gruenert et al, 2012). Mutations in MCCC1 and MCCC2 have been identified that affect the stability or activity of the alpha or beta subunit, occasionally by compromising the essential biotinylation of the protein (Gallardo et al, 2001; Grunert et al, 2012; Fonseca et al, 2016; Dantas et al, 2005 ; Steen et al, 1999; Morscher et al, 2012 ; Baumgartner et al, 2001; 2004; Uematsu et al, 2007; Holzinger et al, 2001).
Literature References
PubMed ID Title Journal Year
15359379 Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy

Baumgartner, MR, Dantas, MF, Suormala, T, Almashanu, S, Giunta, C, Friebel, D, Gebhardt, B, Fowler, B, Hoffmann, GF, Baumgartner, ER, Valle, D

Am J Hum Genet 2004
1293382 Isolated biotin-resistant deficiency of 3-methylcrotonyl-CoA carboxylase presenting as a clinically severe form in a newborn with fatal outcome

Bannwart, C, Wermuth, B, Baumgartner, R, Suormala, T, Weismann, UN

J Inherit Metab Dis 1992
11181649 The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.

Baumgartner, MR, Almashanu, S, Suormala, T, Obie, C, Cole, RN, Packman, S, Baumgartner, ER, Valle, D

J Clin Invest 2001
22642865 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals

Grünert, SC, Stucki, M, Morscher, RJ, Suormala, T, Bürer, C, Burda, P, Christensen, E, Ficicioglu, C, Herwig, J, Kölker, S, Möslinger, D, Pasquini, E, Santer, R, Schwab, KO, Wilcken, B, Fowler, B, Yue, WW, Baumgartner, MR

Orphanet J Rare Dis 2012
32561715 Leucine regulates autophagy via acetylation of the mTORC1 component raptor

Son, SM, Park, SJ, Stamatakou, E, Vicinanza, M, Menzies, FM, Rubinsztein, DC

Nat Commun 2020
11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism

Gallardo, ME, Desviat, LR, Rodríguez, JM, Esparza-Gordillo, J, Pérez-Cerdá, C, Pérez, B, Rodríguez-Pombo, P, Criado, O, Sanz, R, Morton, DH, Gibson, KM, Le, TP, Ribes, A, de Córdoba, SR, Ugarte, M, Peñalva, MA

Am J Hum Genet 2001
15868465 Molecular mechanism of dominant expression in 3-methylcrotonyl-CoA carboxylase deficiency

Baumgartner, MR

J Inherit Metab Dis 2005
17360195 Expression, purification, characterization of human 3-methylcrotonyl-CoA carboxylase (MCCC)

Chu, CH, Cheng, D

Protein Expr Purif 2007
8831079 Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency: long-term outcome in a case with neonatal onset

Lehnert, W, Niederhoff, H, Suormala, T, Baumgartner, ER

Eur J Pediatr 1996
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Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-05-13)
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