Branched-chain ketoacid dehydrogenase kinase deficiency

Stable Identifier
R-HSA-9912481
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Branched-chain ketoacid dehydrogenase kinase deficiency
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Branched-chain ketoacid dehydrogenase kinase deficiency (BCKDKD) is a neurological disorder that arises due to mutations in branched-chain ketoacid dehydrogenase kinase (BCKDK) (Joshi et al 2006; Novarino et al, 2012; Garcia-Cazorla et al, 2014; Tangeraas et al, 2023). BCKDK is a negative regulator of the branched-chain ketoacid dehydrogenase complex (BCKDH), the enzyme responsible for oxidative decarboxylation of branched-chain amino acid derivatives. BCKDK-dependent phosphorylation of serine residues in the E1 alpha subunit of the enzyme BCKDHA inactivates the BCKDH (Popov et al, 1992; Li et al, 2004; Wynn et al, 2004).
Inactivating mutations of BCKDK are associated with impaired intellectual development, microencephaly and autism (Joshi et al 2006; Novarino et al, 2012; Garcia-Cazorla et al, 2014; Tangeraas et al, 2023). Consistent with the role of BCKDK in inhibiting BCKDH activity, inactivating mutations in BCKDK result in higher levels of BCKDH activity and reduced BCAAs in plasma, tissues and urine in mouse models, patients and cell lines (Joshi et al, 2006; Novarino et al, 2012). Symptoms of BCKDK deficiency are alleviated in mouse models by dietary supplementation with a BCAA-enriched diet (Joshi et al, 2006; Novarino et al, 2012).
Literature References
PubMed ID Title Journal Year
15166214 Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase

Li, J, Wynn, RM, Machius, M, Chuang, JL, Karthikeyan, S, Tomchick, DR, Chuang, DT

J. Biol. Chem. 2004
1377677 Branched-chain alpha-ketoacid dehydrogenase kinase. Molecular cloning, expression, and sequence similarity with histidine protein kinases

Popov, KM, Zhao, Y, Shimomura, Y, Kuntz, MJ, Harris, RA

J Biol Chem 1992
15576032 Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation

Wynn, RM, Kato, M, Machius, M, Chuang, JL, Li, J, Tomchick, DR, Chuang, DT

Structure 2004
24449431 Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients

Garcia-Cazorla, A, Oyarzabal, A, Fort, J, Robles, C, Castejón, E, Ruiz-Sala, P, Bodoy, S, Merinero, B, Lopez-Sala, A, Dopazo, J, Nunes, V, Ugarte, M, Artuch, R, Palacin, M, Rodríguez-Pombo, P, Alcaide, P, Navarrete, R, Sanz, P, Font-Llitjós, M, Vilaseca, MA, Ormaizabal, A, Pristoupilova, A, Agulló, SB

Hum. Mutat. 2014
36729635 BCKDK deficiency: a treatable neurodevelopmental disease amenable to newborn screening

Tangeraas, T, Constante, JR, Backe, PH, Oyarzabal, A, Neugebauer, J, Weinhold, N, Boemer, F, Debray, FG, Ozturk-Hism, B, Evren, G, Tuba, EF, Ummuhan, O, Footitt, E, Davison, J, Martinez, C, Bueno, C, Machado, I, Rodríguez-Pombo, P, Al-Sannaa, N, De Los Santos, M, López, JM, Ozturkmen-Akay, H, Karaca, M, Tekin, M, Pajares, S, Ormazabal, A, Stoway, SD, Artuch, R, Dixon, M, Mørkrid, L, García-Cazorla, A

Brain 2023
16875466 Impaired growth and neurological abnormalities in branched-chain alpha-keto acid dehydrogenase kinase-deficient mice

Joshi, MA, Jeoung, NH, Obayashi, M, Hattab, EM, Brocken, EG, Liechty, EA, Kubek, MJ, Vattem, KM, Wek, RC, Harris, RA

Biochem J 2006
22956686 Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy

Novarino, G, El-Fishawy, P, Kayserili, H, Meguid, NA, Scott, EM, Schroth, J, Silhavy, JL, Kara, M, Khalil, RO, Ben-Omran, T, Ercan-Sencicek, AG, Hashish, AF, Sanders, SJ, Gupta, AR, Hashem, HS, Matern, D, Gabriel, S, Sweetman, L, Rahimi, Y, Harris, RA, State, MW, Gleeson, JG

Science 2012
Participants
Events
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as an event of
Disease
Name Identifier Synonyms
amino acid metabolic disorder DOID:9252 inborn errors of amino acid metabolism
branched-chain keto acid dehydrogenase kinase deficiency DOID:0090126 BCKDKD, BCKDK deficiency, autism-epilepsy syndrome due to branched chain ketoacid dehydrogenase kinase deficiency
Cross References
Mondo
Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-06-08)
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