![]() The Jordan group in vitro and the Houten group in vivo (11) found evidence for the formation of a respective hybrid 2-oxo acid dehydrogenase complex, containing components hE1o, hE2o, hE3, and hE1a, suggesting a potential crosstalk between hOGDHc in the TCA cycle and hOADHc in L-lysine catabolism. However, the DLGT gene encoding the dihydrolipoamide glutaryl-transferase component (hE2a) of hOADHc has not been identified. In general, members of the 2-oxo acid dehydrogenase complex family have unique E1 and E2 components but share the E3 component. The human 2-oxoadipate dehydrogenase (hE1a, also known as hDHTKD1) is the first component of the 2-oxoadipate dehydrogenase complex (OADHc) in the L-lysine degradation pathway that converts 2-oxoadipic acid (OA) into glutaryl-CoA and NADH (+H +) according to the suggested mechanism for OGDHc ( Scheme 1). Among recently reported findings is the involvement of OGDHc in post-translational modifications (PTM) of histones in the nucleus by succinylation/glycosylation in mammalian cells, suggesting a tight link between the metabolic function of OGDHc and the epigenetic regulation of gene expression by PTMs. Reduced hOGDHc activity is associated with a number of neurodegenerative diseases however, the link between reductions in mitochondrial TCA cycle enzymes and neurodegeneration has not been established. The OGDHc represents one of the main regulators of mitochondrial metabolism through NADH and reactive oxygen species (ROS) levels and affects cell metabolic and signaling pathways through the coupling of 2-oxoglutarate (OG) metabolism to gene transcription, related to tumor cell proliferation and aging. The hE1o with tightly but not covalently bound thiamin diphosphate (ThDP) decarboxylates 2-oxoglutarate to a reactive intermediate, the enamine or C2α-carbanion, which then reductively succinylates the lipoyllysyl arm of the hE2o next, the succinyl group is transferred via a transthiolesterification mechanism to CoA producing the succinyl-CoA product finally, the hE3 component reoxidizes the dihydrolipoyllysyl-hE2 to lipoyllysyl-hE2 producing an equivalent of NADH in the process and setting up the complex for the next turnover ( Scheme 1). The human 2-oxoglutarate (α-ketoglutarate) dehydrogenase complex (hOGDHc) is a key enzyme in the tricarboxylic acid (TCA) cycle, comprising multiple copies (subunits) of three components: the 2-oxoglutarate dehydrogenase (hE1o), dihydrolipoyl succinyltransferase (hE2o), and dihydrolipoamide dehydrogenase (hE3), with an overall molecular mass of ~4 MDa. (iii) The C-termini are involved in dynamic interactions in complexes, suggesting the presence of at least two conformations in solution. (ii) The hE2o linker region exhibits the highest number of H-bonds with the N-terminus and α/β1 helix of hE1o, yet with the interdomain linker and α/β1 helix of hE1a. The MD simulation studies led to the following conclusions: (i) The N-terminal regions in E1s are shielded by, but do not interact directly with hE2o. The CL-MS studies revealed the most prominent loci for hE1o-hE2o and hE1a-hE2o interactions and suggested different binding modes. Here we report chemical cross-linking mass spectrometry (CL-MS) and molecular dynamics (MD) simulation analyses to understand assembly in binary subcomplexes. Findings raised fundamental questions about the assembly of hE1a (2-oxoadipate-dependent E1 component) and hE1o (2-oxoglutarate-dependent E1) to the common hE2o core component. Evidence was obtained for formation of a hybrid complex between the hOGDHc and its homologue the 2-oxoadipate dehydrogenase complex (hOADHc) in the L-lysine metabolic pathway, suggesting a crosstalk between the two distinct pathways. The human 2-oxoglutarate dehydrogenase complex (hOGDHc) is a key enzyme in the tricarboxylic acid cycle and is one of the main regulators of mitochondrial metabolism through NADH and reactive oxygen species levels.
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