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2-oxoadipate dehydrogenase complex
Multienzyme complex From Wikipedia, the free encyclopedia
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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
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
The OADHC consists of three distinct enzymatic components:
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).[4]
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Function
Glutarylation of mitochondrial proteins
OADHC catalyzes the oxidative decarboxylation of 2-oxoadipate to glutaryl-CoA in the lysine and tryptophan degradation pathway.[5] Glutaryl-CoA can act as an acyl group donor for lysine glutarylation, a non-enzymatic post-translational modification.[5] OADHC itself has been shown to undergo autoglutarylation, which may inhibit its activity and create a feedback regulatory loop.[6] The mitochondrial sirtuin SIRT5 can remove glutaryl groups in a NAD+-dependent manner.[5]
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).[7] 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).[7]
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.[7] 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.[7]
The ROS-producing site within OADHC appears to be a flavin-containing region distinct from that in OGDC.[7] 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.[7]
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Structural and functional similarities
Summarize
Perspective
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).[8] 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).[8] Notably, OADHC and OGDC share the same E2 component (DLST), while PDC and BCKDC utilize distinct E2 components.[9][3][8] 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.[8]
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.
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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).[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
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]
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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
References
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