Defective HLCS does not biotinylate 6xMCCC1:6xMCCC2

Stable Identifier
Reaction [transition]
Homo sapiens
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Biotin (Btn) acts as a coenzyme for 5 carboxylases that exist in their inactive apo forms. In the cytosol and mitochondrion, these apo carboxylases (apo-CBXs) are biotinylated to their active holo forms by the activity of biotin protein ligase (HCLS) (Ingaramo & Beckett 2012, Bailey et al. 2010, Hiratsuka et al. 1998). Methylcrotonoyl-CoA carboxylase, most likely functional as a dodecamer, composed of 6 Btn-containing alpha subunits (MCCC1) and six beta subunits (MCCC2), is shown here. Defects in HLCS causes holocarboxylase synthetase deficiency (HLCS deficiency aka early-onset multiple carboxylase deficiency; MIM:253270). HLCS deficiency is an autosomal recessive disorder whereby deficient HLCS activity results in reduced activity of all 5 carboxylases. Symptoms include metabolic acidosis, organic aciduria, lethargy, hypotonia, convulsions and dermatitis. Mutations in HCLS associated with HLCS deficiency include the compound heterozygote G261Vfs*20/L237P, D571N, R508W, G581S, V550M and L216R (Suzuki et al. 1994, Yang et al. 2000, Dupuis et al. 1996, Aoki et al, 1999, Yang et al. 2001, Morrone et al. 2002).
Literature References
PubMed ID Title Journal Year
20153287 Holocarboxylase synthetase: correlation of protein localisation with biological function

Polyak, SW, Bailey, LM, Wallace, JC

Arch. Biochem. Biophys. 2010
8817339 Clustering of mutations in the biotin-binding region of holocarboxylase synthetase in biotin-responsive multiple carboxylase deficiency

Gravel, RA, Leon-Del-Rio, A, Gibson, KM, Sweetman, L, Leclerc, D, Campeau, E, Dupuis, L, Saudubray, JM, Herman, G

Hum. Mol. Genet. 1996
9630604 Identification of holocarboxylase synthetase (HCS) proteins in human placenta

Suzuki, Y, Li, X, Narisawa, K, Sakamoto, O, Hiratsuka, M, Aoki, Y

Biochim. Biophys. Acta 1998
22123817 Selectivity in post-translational biotin addition to five human carboxylases

Ingaramo, M, Beckett, D

J. Biol. Chem. 2012
10190325 Identification and characterization of mutations in patients with holocarboxylase synthetase deficiency

Suzuki, Y, Li, X, Baumgartner, ER, Narisawa, K, Sakamoto, O, Suormala, T, Hiratsuka, M, Aoki, Y, Akaishi, H, Briones, P, Xu, L

Hum. Genet. 1999
11185745 Haplotype analysis suggests that the two predominant mutations in Japanese patients with holocarboxylase synthetase deficiency are founder mutations

Suzuki, Y, Li, X, Kure, S, Gibson, KM, Matsubara, Y, Narisawa, K, Sakamoto, O, Hiratsuka, M, Aoki, Y, Yang, X

J. Hum. Genet. 2000
12124727 Clinical findings and biochemical and molecular analysis of four patients with holocarboxylase synthetase deficiency

Pela, I, Boneh, A, Zammarchi, E, Morrone, A, Funghini, S, Pasquini, E, Donati, MA, Ciani, F, Peters, H, Malvagia, S

Am. J. Med. Genet. 2002
11735028 Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency

Ohki, M, Suzuki, Y, Kubota, M, Li, X, Kure, S, Matsubara, Y, Asakawa, S, Minoshima, S, Kudoh, J, Sakamoto, O, Inui, K, Taheri, S, Aoki, Y, Christensen, E, Ohira, M, Shimizu, N, Narisawa, K, Kawasaki, K, Hiratsuka, M, Shintani, A, Yang, X, Shibuya, K

Hum. Genet. 2001
7842009 Isolation and characterization of mutations in the human holocarboxylase synthetase cDNA

Suzuki, Y, Ishida, Y, Kishino, T, Matsubara, Y, Narisawa, K, Chiba, Y, Aoki, Y, Iwamatsu, A, Niikawa, N

Nat. Genet. 1994
Catalyst Activity

biotin-protein ligase activity of HLCS mutants [cytosol]

Normal reaction
Functional status

Loss of function of HLCS mutants [cytosol]

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