2-oxoadipate dehydrogenase complex
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The 2-oxoadipate dehydrogenase complex (OADHC, OADHc) or α-ketoadipate dehydrogenase complex is a mitochondrial, multienzyme complex, most commonly known for its role in the degradation of lysine, tryptophan and hydroxylysine. It belongs to the 2-oxoacid dehydrogenase complex family.
Reaction
[edit]The enzymatic activity of the 2-oxoadipate dehydrogenase complex can be summarized by the following reaction:[1] 2-oxoadipate + CoA + NAD+ → glutaryl-CoA + CO2 + NADH + H+
The OADHC can also process 2-oxopimelate, a non-native substrate, but does so over 100 times less efficiently than its natural substrate, 2-oxoadipate.[2]
Components
[edit]The OADHC consists of three distinct enzymatic components:
| Component | EC number | Name | Gene | Cofactor |
|---|---|---|---|---|
| E1a | 2-oxoadipate dehydrogenase | DHTKD1 | Thiamine pyrophosphate (TPP) | |
| E2o | EC 2.3.1.61 | Dihydrolipoyl succinyltransferase | DLST | Lipoic acid, coenzyme A |
| E3 | EC 1.8.1.4 | Dihydrolipoyl dehydrogenase | DLD | FAD, NAD |
E1a is the E1 enzyme specific to 2-oxoadipate (“a”), while E2o is the E2 subunit shared by some 2-oxoacid (“o”) complexes, such as the OADHC and the 2-oxoglutarate dehydrogenase complex (OGDC), but not by others like the pyruvate dehydrogenase complex (PDHC) or branched-chain α-ketoacid dehydrogenase complex (BCKDC).[3]
Function
[edit]Glutarylation of mitochondrial proteins
[edit]OADHC catalyzes the oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA in the lysine and tryptophan degradation pathway.[4] Glutaryl-CoA can act as an acyl group donor for lysine glutarylation, a non-enzymatic post-translational modification.[4] OADHC itself has been shown to undergo autoglutarylation, which may inhibit its activity and create a feedback regulatory loop.[5] The mitochondrial sirtuin SIRT5 can remove glutaryl groups in a NAD+-dependent manner.[4]
Reactive oxygen species (ROS)
[edit]The OADHC produces superoxide and hydrogen peroxide at levels comparable to the flavin site of Complex I, a known source of mitochondrial reactive oxygen species (ROS).[6] However, its activity is much lower than that of other related enzymes—approximately sevenfold lower than the 2-oxoglutarate dehydrogenase complex (OGDC), fourfold lower than the pyruvate dehydrogenase complex (PDC), and about half that of the branched-chain α-ketoacid dehydrogenase complex (BCKDC).[6]
ROS production increases when the NAD(P)H to NAD(P)+ ratio is high, but only during the forward reaction where 2-oxoadipate is converted into glutaryl-CoA.[6] In contrast, reverse electron flow through isolated E3 with NADH does not generate ROS, indicating that full substrate turnover by the intact complex is required.[6]
The ROS-producing site within OADHC appears to be a flavin-containing region distinct from that in OGDC.[6] OADHC thus represents a mitochondrial ROS source and is part of the NADH isopotential pool—a group of enzymes with similar redox characteristics that generate ROS under highly reduced conditions.[6]
Structural and functional similarities
[edit]The 2-oxoadipate dehydrogenase complex (OADHC) is one of four mitochondrial 2-oxoacid dehydrogenase complexes, alongside the 2-oxoglutarate dehydrogenase complex (OGDC), the branched-chain α-ketoacid dehydrogenase complex (BCKDC), and pyruvate dehydrogenase complex (PDC).[7] All of these multienzyme systems catalyze the oxidative decarboxylation of their respective 2-oxoacid substrates and share a common modular architecture, consisting of three core components: E1 (a substrate-specific decarboxylase), E2 (dihydrolipoamide acyltransferase), and E3 (dihydrolipoamide dehydrogenase).[7] Notably, OADHC and OGDC share the same E2 component (DLST), while PDC and BCKDC utilize distinct E2 components.[8][9][7] All four complexes, however, share the same E3 component and depend on the same essential cofactors: thiamine pyrophosphate (TPP), lipoic acid, FAD, NAD⁺, and CoA.[7]
| 2-oxoadipate dehydrogenase complex (OADHC) | Oxoglutarate dehydrogenase complex (OGDC) | Branched-chain α-ketoacid dehydrogenase complex (BCKDC) | Pyruvate dehydrogenase complex (PDC) | ||
|---|---|---|---|---|---|
| Pathway | Degradation of lysine, tryptophan & hydroxylysine | Citric acid cycle | Degradation of branched-chain amino acids: leucine, isoleucine and valine | Connection of glycolysis with citric acid cycle | |
| Substrate | 2-oxoadipate | 2-oxoglutarate | Branched-chain α-ketoacids | Pyruvate | |
| Product | Glutaryl-CoA | Succinyl-CoA | Acyl-CoA derivatives | Acetyl-CoA | |
| Component | E1 | DHTKD1 | OGDH | BCKDHA, BCKDHB | PDHA1, PDHB |
| E2 | DLST | DBT | DLAT | ||
| E3 | DLD | DLD, PDHX | |||
| Cofactor | Thiamine pyrophosphate (TPP), lipoic acid, coenzyme A, FAD, NAD | ||||
Beyond its similarities with other members of the 2-oxoacid dehydrogenase complex family, OADHC also shares key features with the glycine cleavage system (GCS). Instead of being a three-component multienzyme complex, the GCS consists of four distinct proteins (P, H, T, and L), with the L-protein being identical to the E3 component (DLD) found in 2-oxoacid dehydrogenase complexes. Like the latter, the GCS depends on common cofactors such as lipoic acid, FAD, and NAD+. Unlike the 2-oxoacid dehydrogenase complexes, the GCS uniquely requires tetrahydrofolate (THF). This shared use of the E3/DLD component highlights a core biochemical link between the 2-oxoacid dehydrogenase complexes and the GCS, despite their distinct substrates, cofactor dependencies, and roles in ROS production and metabolic regulation.
Clinical relevance
[edit]Alpha‑aminoadipic and alpha‑ketoadipic aciduria (AMOXAD)
[edit]Biallelic mutations in the DHTKD1 gene, which encodes the E1a component of the OADHC, cause a rare autosomal recessive disorder known as alpha-aminoadipic and alpha-oxoadipic aciduria (AMOXAD).[1] This condition leads to accumulation of 2-oxoadipate and 2-aminoadipate in plasma and urine due to impaired degradation of lysine, hydroxylysine, and tryptophan.[1] Clinical symptoms vary widely, ranging from asymptomatic biochemical abnormalities to developmental delay, epilepsy, or hypotonia.[1] The precise clinical significance of these metabolite accumulations remains unclear.[1]
Lipoylation disorders
[edit]Defects in mitochondrial lipoylation pathways can impair multiple 2-oxoacid dehydrogenase complexes, including the OADHC.[1] In fibroblasts from individuals with LIPT1 deficiency, reduced OADHC-dependent metabolic flux has been observed.[1] While the effects on OADHC are less thoroughly characterized than for PDHC or OGDHC, the findings indicate that OADHC activity is also sensitive to impaired lipoylation.[1]
Note
[edit]Unlike 2-oxoglutarate dehydrogenase complex, the “2-” in 2-oxoadipate dehydrogenase complex should not be omitted, as “oxoadipate” alone could refer to other isomers such as 3-oxoadipate.
See also
[edit]References
[edit]- ^ a b c d e f g h Zhang, Xu; Nemeria, Natalia S.; Leandro, João; Houten, Sander; Lazarus, Michael; Gerfen, Gary; Ozohanics, Oliver; Ambrus, Attila; Nagy, Balint; Brukh, Roman; Jordan, Frank (June 2020). "Structure–function analyses of the G729R 2-oxoadipate dehydrogenase genetic variant associated with a disorder of l-lysine metabolism". Journal of Biological Chemistry. 295 (23): 8078–8095. doi:10.1074/jbc.RA120.012761. PMC 7278340. PMID 32303640.
- ^ Nemeria, Natalia S.; Nagy, Balint; Sanchez, Roberto; Zhang, Xu; Leandro, João; Ambrus, Attila; Houten, Sander M.; Jordan, Frank (2022-07-26). "Functional Versatility of the Human 2-Oxoadipate Dehydrogenase in the L-Lysine Degradation Pathway toward Its Non-Cognate Substrate 2-Oxopimelic Acid". International Journal of Molecular Sciences. 23 (15): 8213. doi:10.3390/ijms23158213. ISSN 1422-0067. PMC 9367764. PMID 35897808.
- ^ Nemeria, Natalia S.; Zhang, Xu; Leandro, Joao; Zhou, Jieyu; Yang, Luying; Houten, Sander M.; Jordan, Frank (2021-04-29). "Toward an Understanding of the Structural and Mechanistic Aspects of Protein-Protein Interactions in 2-Oxoacid Dehydrogenase Complexes". Life. 11 (5): 407. doi:10.3390/life11050407. ISSN 2075-1729. PMC 8146983. PMID 33946784.
- ^ a b c Tan, Minjia; Peng, Chao; Anderson, Kristin A.; Chhoy, Peter; Xie, Zhongyu; Dai, Lunzhi; Park, Jeongsoon; Chen, Yue; Huang, He; Zhang, Yi; Ro, Jennifer; Wagner, Gregory R.; Green, Michelle F.; Madsen, Andreas S.; Schmiesing, Jessica (April 2014). "Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5". Cell Metabolism. 19 (4): 605–617. doi:10.1016/j.cmet.2014.03.014. PMC 4108075. PMID 24703693.
- ^ Boyko, Alexandra I.; Karlina, Irina S.; Zavileyskiy, Lev G.; Aleshin, Vasily A.; Artiukhov, Artem V.; Kaehne, Thilo; Ksenofontov, Alexander L.; Ryabov, Sergey I.; Graf, Anastasia V.; Tramonti, Angela; Bunik, Victoria I. (2022-06-01). "Delayed Impact of 2-Oxoadipate Dehydrogenase Inhibition on the Rat Brain Metabolism Is Linked to Protein Glutarylation". Frontiers in Medicine. 9. doi:10.3389/fmed.2022.896263. ISSN 2296-858X. PMC 9198357. PMID 35721081.
- ^ a b c d e f Goncalves, Renata L.S.; Bunik, Victoria I.; Brand, Martin D. (February 2016). "Production of superoxide/hydrogen peroxide by the mitochondrial 2-oxoadipate dehydrogenase complex". Free Radical Biology and Medicine. 91: 247–255. doi:10.1016/j.freeradbiomed.2015.12.020.
- ^ a b c d Mailloux, Ryan J. (June 2024). "The emerging importance of the α-keto acid dehydrogenase complexes in serving as intracellular and intercellular signaling platforms for the regulation of metabolism". Redox Biology. 72: 103155. doi:10.1016/j.redox.2024.103155. PMC 11021975. PMID 38615490.
- ^ Nemeria, Natalia S.; Gerfen, Gary; Nareddy, Pradeep Reddy; Yang, Luying; Zhang, Xu; Szostak, Michal; Jordan, Frank (2018-02-01). "The mitochondrial 2-oxoadipate and 2-oxoglutarate dehydrogenase complexes share their E2 and E3 components for their function and both generate reactive oxygen species". Free Radical Biology and Medicine. 115: 136–145. doi:10.1016/j.freeradbiomed.2017.11.018. ISSN 0891-5849.
- ^ Nemeria, Natalia S.; Gerfen, Gary; Yang, Luying; Zhang, Xu; Jordan, Frank (2018-09-01). "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". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 20th European Bioenergetics Conference. 1859 (9): 932–939. doi:10.1016/j.bbabio.2018.05.001. ISSN 0005-2728.
