Defective HLCS does not biotinylate PC:Mn2+

Stable Identifier
R-HSA-9035988
Type
Reaction [transition]
Species
Homo sapiens
Compartment
cytosol
ReviewStatus
5/5
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Defective HLCS does not biotinylate PC:Mn2+
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The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout
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). Homotetrameric pyruvate carboxylase (PC) with its manganese cofactor (4xPC:Mn2+) 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

Bailey, LM, Wallace, JC, Polyak, SW

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Nat. Genet. 1994
Participants
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as an event of
Catalyst Activity

biotin--[biotin carboxyl-carrier protein] ligase activity of HLCS mutants [cytosol]

Physical Entity
HLCS mutants [cytosol] (Homo sapiens)
Activity
biotin--[biotin carboxyl-carrier protein] ligase activity (GO:0004077)
Normal reaction
HLCS biotinylates PC:Mn2+ (Homo sapiens)
Functional status

Loss of function of HLCS mutants [cytosol]

Normal Entity
Disease Entity
Status
Disease
Cross References
Mondo
Authored
Jassal, B  (2013-05-09)
Reviewed
Polyak, SW  (2013-08-15)
Created
Jassal, B  (2013-05-09)
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