DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo
| Autor: | Natalia S. Nemeria, Frank Jordan, Chunli Yu, Xu Zhang, Sander M. Houten, Robert J. DeVita, Ronald C. Hendrickson, João Leandro, Jan Aten, Tetyana Dodatko, Roberto Sanchez |
|---|---|
| Přispěvatelé: | Pathology, Biomedical Engineering and Physics, Graduate School, ACS - Atherosclerosis & ischemic syndromes |
| Rok vydání: | 2020 |
| Předmět: |
Coenzyme A
Dehydrogenase Biology Substrate Specificity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Oxidoreductase Genetics Humans DHTKD1 Ketoglutarate Dehydrogenase Complex Amino Acid Metabolism Inborn Errors Molecular Biology Cells Cultured Genetics (clinical) 030304 developmental biology chemistry.chemical_classification 0303 health sciences Dihydrolipoamide dehydrogenase Glutaryl-CoA Dehydrogenase Brain Diseases Metabolic Ketone Oxidoreductases General Medicine General Article One HEK293 Cells Biochemistry chemistry OGDH Acyl Coenzyme A Oxoglutarate dehydrogenase complex 030217 neurology & neurosurgery Glutaric Acidemia Type 1 |
| Zdroj: | Leandro, J, Dodatko, T, Aten, J, Nemeria, N S, Zhang, X, Jordan, F, Hendrickson, R C, Sanchez, R, Yu, C, DeVita, R J & Houten, S M 2020, ' DHTKD1 and OGDH display substrate overlap in cultured cells and form a hybrid 2-oxo acid dehydrogenase complex in vivo ', Human Molecular Genetics, vol. 29, no. 7, pp. 1168-1179 . https://doi.org/10.1093/HMG/DDAA037 Human molecular genetics, 29(7), 1168-1179. Oxford University Press Hum Mol Genet Human Molecular Genetics, 29(7), 1168-1179. Oxford University Press |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddaa037 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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