2-oxoadipate dehydrogenase complex

Multienzyme complex 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 The enzymatic activity of the 2-oxoadipate dehydrogenase complex can be summarized by the following reaction: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 en 295 23 8078–8095 10.1074/jbc.RA120.012761 7278340 32303640 free 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.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 en 23 15 8213 10.3390/ijms23158213 1422-0067 9367764 35897808 free Components The OADHC consists of three distinct enzymatic components: +ComponentEC numberNameGeneCofactorE1a 2-oxoadipate dehydrogenaseDHTKD1Thiamine pyrophosphate (TPP)E2o 2.3.1.61Dihydrolipoyl succinyltransferaseDLSTLipoic acid, coenzyme AE3 1.8.1.4Dihydrolipoyl dehydrogenaseDLDFAD, NADE1a 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).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 en 11 5 407 10.3390/life11050407 2075-1729 8146983 33946784 free 2021Life...11..407N Function Glutarylation of mitochondrial proteins OADHC catalyzes the oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA in the lysine and tryptophan degradation pathway.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 en 19 4 605–617 10.1016/j.cmet.2014.03.014 4108075 24703693 free Glutaryl-CoA can act as an acyl group donor for lysine glutarylation, a non-enzymatic post-translational modification. OADHC itself has been shown to undergo autoglutarylation, which may inhibit its activity and create a feedback regulatory loop.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 10.3389/fmed.2022.896263 2296-858X 9198357 35721081 free The mitochondrial sirtuin SIRT5 can remove glutaryl groups in a NAD+-dependent manner. Reactive oxygen species (ROS) 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).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 en 91 247–255 10.1016/j.freeradbiomed.2015.12.020 free 26708453 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). 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. 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. The ROS-producing site within OADHC appears to be a flavin-containing region distinct from that in OGDC. 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. Structural and functional similarities 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).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 en 72 103155 10.1016/j.redox.2024.103155 11021975 38615490 free 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). Notably, OADHC and OGDC share the same E2 component (DLST), while PDC and BCKDC utilize distinct E2 components.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 10.1016/j.freeradbiomed.2017.11.018 29191460 0891-5849 free 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 10.1016/j.bbabio.2018.05.001 0005-2728 free 29752936 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. +2-oxoacid dehydrogenase complexes2-oxoadipate dehydrogenase complex (OADHC)Oxoglutarate dehydrogenase complex (OGDC)Branched-chain α-ketoacid dehydrogenase complex (BCKDC)Pyruvate dehydrogenase complex (PDC)PathwayDegradation of lysine, tryptophan & hydroxylysineCitric acid cycleDegradation of branched-chain amino acids:Connection of glycolysis with citric acid cycleLeucineIsoleucineValineSubstrate2-oxoadipate2-oxoglutarateα-ketoisocaproateα-keto-β-methylvalerateα-ketoisovaleratePyruvateProductGlutaryl-CoASuccinyl-CoAIsovaleryl-CoA2-Methylbutyryl-CoAIsobutyryl-CoAAcetyl-CoAComponentE1DHTKD1OGDHBCKDHA, BCKDHBPDHA1, PDHBE2DLSTDBTDLATE3DLDDLD, PDHXCofactorThiamine pyrophosphate (TPP), lipoic acid, coenzyme A, FAD, NADBeyond 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 Alpha‑aminoadipic and alpha‑ketoadipic aciduria (AMOXAD) 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). This condition leads to accumulation of 2-oxoadipate and 2-aminoadipate in plasma and urine due to impaired degradation of lysine, hydroxylysine, and tryptophan. Clinical symptoms vary widely, ranging from asymptomatic biochemical abnormalities to developmental delay, epilepsy, or hypotonia. The precise clinical significance of these metabolite accumulations remains unclear. Lipoylation disorders Defects in mitochondrial lipoylation pathways can impair multiple 2-oxoacid dehydrogenase complexes, including the OADHC. In fibroblasts from individuals with LIPT1 deficiency, reduced OADHC-dependent metabolic flux has been observed. 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. Note 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 Dehydrogenase Keto acid References Biology no Category:EC 1.2.4