Enzymes
UniProtKB help_outline | 1,193 proteins |
Reaction participants Show >> << Hide
- Name help_outline 2-oxoadipate Identifier CHEBI:57499 Charge -2 Formula C6H6O5 InChIKeyhelp_outline FGSBNBBHOZHUBO-UHFFFAOYSA-L SMILEShelp_outline [O-]C(=O)CCCC(=O)C([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 11 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H+ Identifier CHEBI:15378 Charge 1 Formula H InChIKeyhelp_outline GPRLSGONYQIRFK-UHFFFAOYSA-N SMILEShelp_outline [H+] 2D coordinates Mol file for the small molecule Search links Involved in 9,176 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
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Namehelp_outline
N6-[(R)-lipoyl]-L-lysyl-[dihydrolipoyllysine-residue succinyltransferase]
Identifier
RHEA-COMP:10483
Reactive part
help_outline
- Name help_outline N6-[(R)-lipoyl]-L-lysine residue Identifier CHEBI:83099 Charge 0 Formula C14H24N2O2S2 SMILEShelp_outline *-N[C@@H](CCCCNC(=O)CCCC[C@@H]1CCSS1)C(-*)=O 2D coordinates Mol file for the small molecule Search links Involved in 12 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline CO2 Identifier CHEBI:16526 (Beilstein: 1900390; CAS: 124-38-9) help_outline Charge 0 Formula CO2 InChIKeyhelp_outline CURLTUGMZLYLDI-UHFFFAOYSA-N SMILEShelp_outline O=C=O 2D coordinates Mol file for the small molecule Search links Involved in 980 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
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Namehelp_outline
N6-[(R)-S8-glutaryldihydrolipoyl]-L-lysyl-[dihydrolipoyllysine-residue succinyltransferase]
Identifier
RHEA-COMP:17726
Reactive part
help_outline
- Name help_outline N6-[(R)-S8-glutaryldihydrolipoyl]-L-lysine residue Identifier CHEBI:184385 Charge -1 Formula C19H31N2O5S2 SMILEShelp_outline C([C@@H](C(*)=O)N*)CCCNC(CCCC[C@H](CCSC(CCCC([O-])=O)=O)S)=O 2D coordinates Mol file for the small molecule Search links Involved in 1 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
RHEA:69576 | RHEA:69577 | RHEA:69578 | RHEA:69579 | |
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Reaction direction help_outline | undefined | left-to-right | right-to-left | bidirectional |
UniProtKB help_outline |
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Publications
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The human Krebs cycle 2-oxoglutarate dehydrogenase complex creates an additional source of superoxide/hydrogen peroxide from 2-oxoadipate as alternative substrate.
Nemeria N.S., Gerfen G., Guevara E., Nareddy P.R., Szostak M., Jordan F.
Recently, we reported that the human 2-oxoglutarate dehydrogenase (hE1o) component of the 2-oxoglutarate dehydrogenase complex (OGDHc) could produce the reactive oxygen species superoxide and hydrogen peroxide (detected by chemical means) from its substrate 2-oxoglutarate (OG), most likely concurr ... >> More
Recently, we reported that the human 2-oxoglutarate dehydrogenase (hE1o) component of the 2-oxoglutarate dehydrogenase complex (OGDHc) could produce the reactive oxygen species superoxide and hydrogen peroxide (detected by chemical means) from its substrate 2-oxoglutarate (OG), most likely concurrently with one-electron oxidation by dioxygen of the thiamin diphosphate (ThDP)-derived enamine intermediate to a C2α-centered radical (detected by Electron Paramagnetic Resonance) [Nemeria et al., 2014 [17]; Ambrus et al. 2015 [18]]. We here report that hE1o can also utilize the next higher homologue of OG, 2-oxoadipate (OA) as a substrate according to multiple criteria in our toolbox: (i) Both E1o-specific and overall complex activities (NADH production) were detected using OA as a substrate; (ii) Two post-decarboxylation intermediates were formed by hE1o from OA, the ThDP-enamine and the C2α-hydroxyalkyl-ThDP, with nearly identical rates for OG and OA; (iii) Both OG and OA could reductively acylate lipoyl domain created from dihydrolipoyl succinyltransferase (E2o); (iv) Both OG and OA gave α-ketol carboligaton products with glyoxylate, but with opposite chirality; a finding that could be of utility in chiral synthesis; (v) Dioxygen could oxidize the ThDP-derived enamine from both OG and OA, leading to ThDP-enamine radical and generation of superoxide and H<sub>2</sub>O<sub>2</sub>. While the observed oxidation-reduction with dioxygen is only a side reaction of the predominant physiological product glutaryl-CoA, the efficiency of superoxide/ H<sub>2</sub>O<sub>2</sub> production was 7-times larger from OA than from OG, making the reaction of OGDHc with OA one of the important superoxide/ H<sub>2</sub>O<sub>2</sub> producers among 2-oxo acid dehydrogenase complexes in mitochondria. << Less
Free Radic. Biol. Med. 108:644-654(2017) [PubMed] [EuropePMC]
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Evidence for functional and regulatory cross-talk between the tricarboxylic acid cycle 2-oxoglutarate dehydrogenase complex and 2-oxoadipate dehydrogenase on the l-lysine, l-hydroxylysine and l-tryptophan degradation pathways from studies in vitro.
Nemeria N.S., Gerfen G., Yang L., Zhang X., Jordan F.
Herein are reported findings in vitro suggesting both functional and regulatory cross-talk between the human 2-oxoglutarate dehydrogenase complex (hOGDHc), a key regulatory enzyme within the tricarboxylic acid cycle (TCA cycle), and a novel 2-oxoadipate dehydrogenase complex (hOADHc) from the fina ... >> More
Herein are reported findings in vitro suggesting both functional and regulatory cross-talk between the human 2-oxoglutarate dehydrogenase complex (hOGDHc), a key regulatory enzyme within the tricarboxylic acid cycle (TCA cycle), and a novel 2-oxoadipate dehydrogenase complex (hOADHc) from the final degradation pathway of l-lysine, l-hydroxylysine and l-tryptophan. The following could be concluded from our studies by using hOGDHc and hOADHc assembled from their individually expressed components in vitro: (i) Different substrate preferences (k<sub>cat</sub>/K<sub>m</sub>) were displayed by the two complexes even though they share the same dihydrolipoyl succinyltransferase (hE2o) and dihydrolipoyl dehydrogenase (hE3) components; (ii) Different binding modes were in evidence for the binary hE1o-hE2o and hE1a-hE2o subcomplexes according to fluorescence titrations using site-specifically labeled hE2o-derived proteins; (iii) Similarly to hE1o, the hE1a also forms the ThDP-enamine radical from 2-oxoadipate (electron paramagnetic resonance detection) in the oxidative half reaction; (iv) Both complexes produced superoxide/H<sub>2</sub>O<sub>2</sub> from O<sub>2</sub> in the reductive half reaction suggesting that hE1o, and hE1a (within their complexes) could both be sources of reactive oxygen species generation in mitochondria from 2-oxoglutarate and 2-oxoadipate, respectively; (v) Based on our findings, we speculate that hE2o can serve as a trans-glutarylase, in addition to being a trans-succinylase, a role suggested by others; (vi) The glutaryl-CoA produced by hOADHc inhibits hE1o, as does succinyl-CoA, suggesting a regulatory cross-talk between the two complexes on the different metabolic pathways. << Less
Biochim. Biophys. Acta 1859:932-939(2018) [PubMed] [EuropePMC]
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Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex.
Leandro J., Khamrui S., Wang H., Suebsuwong C., Nemeria N.S., Huynh K., Moustakim M., Secor C., Wang M., Dodatko T., Stauffer B., Wilson C.G., Yu C., Arkin M.R., Jordan F., Sanchez R., DeVita R.J., Lazarus M.B., Houten S.M.
DHTKD1 is the E1 component of the 2-oxoadipate dehydrogenase complex, which is an enzyme involved in the catabolism of (hydroxy-)lysine and tryptophan. Mutations in DHTKD1 have been associated with 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease type 2Q and eosinophilic esophag ... >> More
DHTKD1 is the E1 component of the 2-oxoadipate dehydrogenase complex, which is an enzyme involved in the catabolism of (hydroxy-)lysine and tryptophan. Mutations in DHTKD1 have been associated with 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease type 2Q and eosinophilic esophagitis, but the pathophysiology of these clinically distinct disorders remains elusive. Here, we report the identification of adipoylphosphonic acid and tenatoprazole as DHTKD1 inhibitors using targeted and high throughput screening, respectively. We furthermore elucidate the DHTKD1 crystal structure with thiamin diphosphate bound at 2.25 Å. We also report the impact of 10 disease-associated missense mutations on DHTKD1. Whereas the majority of the DHTKD1 variants displayed impaired folding or reduced thermal stability in combination with absent or reduced enzyme activity, three variants showed no abnormalities. Our work provides chemical and structural tools for further understanding of the function of DHTKD1 and its role in several human pathologies. << Less
Comments
RHEA:69576 part of RHEA:30795, RHEA:69576 is the first step in the overall reaction RHEA:30795 catalyzed by the 2-oxoadipate dehydrogenase complex