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Functional Versatility of the Human 2-Oxoadipate Dehydrogenase in the L-Lysine Degradation Pathway toward Its Non-Cognate Substrate 2-Oxopimelic Acid.
Nemeria, Natalia S; Nagy, Balint; Sanchez, Roberto; Zhang, Xu; Leandro, João; Ambrus, Attila; Houten, Sander M; Jordan, Frank.
Afiliación
  • Nemeria NS; Department of Chemistry, Rutgers University-Newark, Newark, NJ 07102-1811, USA.
  • Nagy B; Department of Biochemistry, Institute of Biochemistry and Molecular Biology, Semmelweis University, 1082 Budapest, Hungary.
  • Sanchez R; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6501, USA.
  • Zhang X; Department of Chemistry, Rutgers University-Newark, Newark, NJ 07102-1811, USA.
  • Leandro J; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6501, USA.
  • Ambrus A; Department of Biochemistry, Institute of Biochemistry and Molecular Biology, Semmelweis University, 1082 Budapest, Hungary.
  • Houten SM; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6501, USA.
  • Jordan F; Department of Chemistry, Rutgers University-Newark, Newark, NJ 07102-1811, USA.
Int J Mol Sci ; 23(15)2022 Jul 26.
Article en En | MEDLINE | ID: mdl-35897808
The human 2-oxoadipate dehydrogenase complex (OADHc) in L-lysine catabolism is involved in the oxidative decarboxylation of 2-oxoadipate (OA) to glutaryl-CoA and NADH (+H+). Genetic findings have linked the DHTKD1 encoding 2-oxoadipate dehydrogenase (E1a), the first component of the OADHc, to pathogenesis of AMOXAD, eosinophilic esophagitis (EoE), and several neurodegenerative diseases. A multipronged approach, including circular dichroism spectroscopy, Fourier Transform Mass Spectrometry, and computational approaches, was applied to provide novel insight into the mechanism and functional versatility of the OADHc. The results demonstrate that E1a oxidizes a non-cognate substrate 2-oxopimelate (OP) as well as OA through the decarboxylation step, but the OADHc was 100-times less effective in reactions producing adipoyl-CoA and NADH from the dihydrolipoamide succinyltransferase (E2o) and dihydrolipoamide dehydrogenase (E3). The results revealed that the E2o is capable of producing succinyl-CoA, glutaryl-CoA, and adipoyl-CoA. The important conclusions are the identification of: (i) the functional promiscuity of E1a and (ii) the ability of the E2o to form acyl-CoA products derived from homologous 2-oxo acids with five, six, and even seven carbon atoms. The findings add to our understanding of both the OADHc function in the L-lysine degradative pathway and of the molecular mechanisms leading to the pathogenesis associated with DHTKD1 variants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Errores Innatos del Metabolismo de los Aminoácidos / Complejo Cetoglutarato Deshidrogenasa Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Errores Innatos del Metabolismo de los Aminoácidos / Complejo Cetoglutarato Deshidrogenasa Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza