Evidence for functional and regulatory cross-talk between the tricarboxylic acid cycle 2-oxoglutarate dehydrogenase complex and 2-oxoadipate dehydrogenase on the L-lysine, L-hydroxylysine and L-tryptophan degradation pathways from studies in vitro

Natalia S. Nemeria, Gary Gerfen, Luying Yang, Xu Zhang, Frank Jordan

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Herein are reported findings in vitro suggesting both functional and regulatory cross-talk between the human 2-oxoglutarate dehydrogenase complex (hOGDHc), a key regulatory enzyme within the tricarboxylic acid cycle (TCA cycle), and a novel 2-oxoadipate dehydrogenase complex (hOADHc) from the final degradation pathway of L-lysine, L-hydroxylysine and L-tryptophan. The following could be concluded from our studies by using hOGDHc and hOADHc assembled from their individually expressed components in vitro: (i) Different substrate preferences (k cat /K m ) were displayed by the two complexes even though they share the same dihydrolipoyl succinyltransferase (hE2o) and dihydrolipoyl dehydrogenase (hE3) components; (ii) Different binding modes were in evidence for the binary hE1o-hE2o and hE1a-hE2o subcomplexes according to fluorescence titrations using site-specifically labeled hE2o-derived proteins; (iii) Similarly to hE1o, the hE1a also forms the ThDP-enamine radical from 2-oxoadipate (electron paramagnetic resonance detection) in the oxidative half reaction; (iv) Both complexes produced superoxide/H 2 O 2 from O 2 in the reductive half reaction suggesting that hE1o, and hE1a (within their complexes) could both be sources of reactive oxygen species generation in mitochondria from 2-oxoglutarate and 2-oxoadipate, respectively; (v) Based on our findings, we speculate that hE2o can serve as a trans-glutarylase, in addition to being a trans-succinylase, a role suggested by others; (vi) The glutaryl-CoA produced by hOADHc inhibits hE1o, as does succinyl-CoA, suggesting a regulatory cross-talk between the two complexes on the different metabolic pathways.

Original languageEnglish (US)
Pages (from-to)932-939
Number of pages8
JournalBiochimica et Biophysica Acta - Bioenergetics
Volume1859
Issue number9
DOIs
StatePublished - Sep 2018

Keywords

  • 2-Oxoadipate dehydrogenase
  • 2-Oxoglutarate dehydrogenase
  • Inhibition by glutaryl-CoA and succinyl-CoA
  • L-Lysine degradation pathway
  • Superoxide and H O generation
  • ThDP-enamine radical

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

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