Reactome | DHTKD1 dimer decarboxylates 2-OA

DHTKD1 dimer decarboxylates 2-OA

Stable Identifier

R-HSA-9858321

Type

Reaction [transition]

Species

Homo sapiens

Compartment

mitochondrial matrix

Synonyms

2-oxoadipate + H(+) + N(6)-((R)-lipoyl)-L-lysyl-(dihydrolipoyllysine-residue succinyltransferase) => CO2 + N(6)-((R)-S(8)-glutaryldihydrolipoyl)-L-lysyl-(dihydrolipoyllysine-residue succinyltransferase)

ReviewStatus

5/5

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2-Oxoadipate dehydrogenase complex (OADC) component E1 (DHTKD1) catalyzes the decarboxylation of alpha-oxoadipate (2-OA), at the same time transferring the resulting glutaryl onto the lipoyl moiety of the E2 component (DLST) which gets reduced in the process. The enzyme is a homodimer, with each monomer binding one Mg2+ ion and one thiamin molecule (Nemeria et al., 2017; Bezerra et al., 2020; Leandro et al., 2020). Mutations in DHTKD1 can cause an axonal form of Charcot-Marie-Tooth disease (CMT2Q, MIM:615025; Xu et al., 2012) and a metabolic disorder characterized by increased levels of 2-oxoadipate and 2-hydroxyadipate (AAKAD, MIM:204750; Hagen et al., 2015). There are also reports of amyotrophic lateral sclerosis (ALS) associated with DHTKD1 polymorphisms (Osmanovic et al., 2021; Menon et al., 2023).

Literature References

PubMed ID	Title	Journal	Year
23141294	A nonsense mutation in DHTKD1 causes Charcot-Marie-Tooth disease type 2 in a large Chinese pedigree Wang, ZG, Sun, FT, Sun, LH, Chen, Y, Guo, WT, Wu, XL, Chen, SD, Gu, MM, Kuang, Y, Zhu, HB, Huang, W, Ji, BJ, Yuan, WT, Ma, JF, Xu, WY, Huang, L, Zhang, HX	Am J Hum Genet	2012
32633484	Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex Yu, C, Moustakim, M, Dodatko, T, Nemeria, NS, DeVita, RJ, Wilson, CG, Stauffer, B, Secor, C, Wang, H, Leandro, J, Jordan, F, Arkin, MR, Huynh, K, Khamrui, S, Wang, M, Suebsuwong, C, Houten, SM, Sanchez, R, Lazarus, MB	ACS Chem Biol	2020
29191460	The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species Zhang, X, Jordan, F, Yang, L, Nareddy, PR, Nemeria, NS, Gerfen, G, Szostak, M	Free Radic Biol Med	2018
35052424	Heterozygous DHTKD1 Variants in Two European Cohorts of Amyotrophic Lateral Sclerosis Patients Ludolph, AC, Brand, F, Müller, K, Martens, H, Weishaupt, JH, Schmidt, G, Petri, S, Feuerhake, F, Andersen, PM, Langhans, CD, Osmanovic, A, Schreiber-Katz, O, Weber, RG, Gogol, I, Widjaja, M	Genes (Basel)	2021
25860818	Genetic basis of alpha-aminoadipic and alpha-ketoadipic aciduria Ruijter, GJ, Knegt, AC, Wanders, RJ, Duran, M, Hagen, J, Oussoren, E, Hoogeboom, AJ, Te Brinke, H, Waterham, HR, Franke, I, Sass, JO, Becker, D, Schwab, KO, Houten, SM	J Inherit Metab Dis	2015
32695416	Crystal structure and interaction studies of human DHTKD1 provide insight into a mitochondrial megacomplex in lysine catabolism McCorvie, TJ, Kölker, S, Rutter, J, Foster, WR, Hicks, KG, Bailey, HJ, Okun, JG, Bezerra, GA, Sauer, SW, Yue, WW, Dimitrov, B	IUCrJ	2020
37880984	A novel DHTKD1 gene mutation with ALS like presentation: a case report Mk, F, Menon, D, Baskar, D, Arunachal, G, Vengalil, S, Kumar, V, Nashi, S, Mohanty, M, Thomas, A, Dubbal, R, Nalini, A	Amyotroph Lateral Scler Frontotemporal Degener	2023