ArticleHuman molecular genetics2020
DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo.
Article in Human molecular genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 34 citations in OpenAlex.
- Aminoadipate-semialdehyde synthase, a potential target for substrate reduction therapy in glutaric aciduria type 1.Scientific reports · 2026Article
- Lipoyl deglutarylation by ABHD11 regulates mitochondrial and T cell metabolism.Nature chemical biology · 2025Article
- Covalent Docking to the Active Sites of Thiamine Diphosphate-Dependent Enzymes.Molecules (Basel, Switzerland) · 2025Article
- Rutin Attenuates Oxidative Stress Responses and Hepatocyte Metabolomics in β-Hydroxybutyric Acid-Induced Hepatocyte Injury in Calves.International journal of molecular sciences · 2025Article
- Characterization, Structure, and Inhibition of the Human Succinyl-CoA:glutarate-CoA Transferase, a Putative Genetic Modifier of Glutaric Aciduria Type 1.ACS chemical biology · 2024Article
- Clinical, biochemical and molecular characterization of a new case withJIMD reports · 2024Article
- Characterization, structure and inhibition of the human succinyl-CoA:glutarate-CoA transferase, a genetic modifier of glutaric aciduria type 1.bioRxiv : the preprint server for biology · 2024Article
- Mitochondrial Alpha-Keto Acid Dehydrogenase Complexes: Recent Developments on Structure and Function in Health and Disease.Sub-cellular biochemistry · 2024Review
- Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity.Genome medicine · 2023Article
- Acyl-CoA dehydrogenase substrate promiscuity: Challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism.Journal of inherited metabolic disease · 2023Article
- Biochemical characterization of patients with dihydrolipoamide dehydrogenase deficiency.JIMD reports · 2023Article
- Review
- Probing the E1o-E2o and E1a-E2o Interactions in Binary Subcomplexes of the Human 2-Oxoglutarate Dehydrogenase and 2-Oxoadipate Dehydrogenase Complexes by Chemical Cross-Linking Mass Spectrometry and Molecular Dynamics Simulation.International journal of molecular sciences · 2023Article
- 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 · 2022Article
- HeterozygousGenes · 2021Article
- The biochemical subtype is a predictor for cognitive function in glutaric aciduria type 1: a national prospective follow-up study.Scientific reports · 2021Observational
- Toward an Understanding of the Structural and Mechanistic Aspects of Protein-Protein Interactions in 2-Oxoacid Dehydrogenase Complexes.Life (Basel, Switzerland) · 2021Review
- Knock-Out ofFrontiers in endocrinology · 2021Article
- Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex.ACS chemical biology · 2020Article
- Structure-function analyses of the G729R 2-oxoadipate dehydrogenase genetic variant associated with a disorder of l-lysine metabolism.The Journal of biological chemistry · 2020Article
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Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
Abstract
Glutaric aciduria type 1 (GA1) is an inborn error of lysine degradation characterized by a specific encephalopathy that is caused by toxic accumulation of lysine degradation intermediates. Substrate reduction through inhibition of DHTKD1, an enzyme upstream of the defective glutaryl-CoA dehydrogenase, has been investigated as a potential therapy, but revealed the existence of an alternative enzymatic source of glutaryl-CoA. Here, we show that loss of DHTKD1 in glutaryl-CoA dehydrogenase-deficient HEK-293 cells leads to a 2-fold decrease in the established GA1 clinical biomarker glutarylcarnitine and demonstrate that oxoglutarate dehydrogenase (OGDH) is responsible for this remaining glutarylcarnitine production. We furthermore show that DHTKD1 interacts with OGDH, dihydrolipoyl succinyltransferase and dihydrolipoamide dehydrogenase to form a hybrid 2-oxoglutaric and 2-oxoadipic acid dehydrogenase complex. In summary, 2-oxoadipic acid is a substrate for DHTKD1, but also for OGDH in a cell model system. The classical 2-oxoglutaric dehydrogenase complex can exist as a previously undiscovered hybrid containing DHTKD1 displaying improved kinetics towards 2-oxoadipic acid.
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