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 J. Gerfen, Luying Yang, Xu Zhang, Frank Jordan

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3 Citations (Scopus)

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 (kcat/Km) 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/H2O2 from O2 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)
JournalBiochimica et Biophysica Acta - Bioenergetics
DOIs
StateAccepted/In press - Jan 1 2018

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Hydroxylysine
Ketoglutarate Dehydrogenase Complex
Citric Acid Cycle
Tryptophan
Lysine
Oxidoreductases
Dihydrolipoamide Dehydrogenase
Degradation
Mitochondria
Electron Spin Resonance Spectroscopy
Metabolic Networks and Pathways
Titration
Superoxides
Paramagnetic resonance
Reactive Oxygen Species
Fluorescence
Substrates
Enzymes
Proteins
In Vitro Techniques

Keywords

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

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

Cite this

@article{2ff587b9ffaf4e0581b1291f9a56f744,
title = "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",
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 (kcat/Km) 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/H2O2 from O2 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.",
keywords = "2-Oxoadipate dehydrogenase, 2-Oxoglutarate dehydrogenase, Inhibition by glutaryl-CoA and succinyl-CoA, L-Lysine degradation pathway, Superoxide and HO generation, ThDP-enamine radical",
author = "Nemeria, {Natalia S.} and Gerfen, {Gary J.} and Luying Yang and Xu Zhang and Frank Jordan",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.bbabio.2018.05.001",
language = "English (US)",
journal = "Biochimica et Biophysica Acta - Bioenergetics",
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TY - JOUR

T1 - 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

AU - Nemeria, Natalia S.

AU - Gerfen, Gary J.

AU - Yang, Luying

AU - Zhang, Xu

AU - Jordan, Frank

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 (kcat/Km) 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/H2O2 from O2 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.

AB - 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 (kcat/Km) 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/H2O2 from O2 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.

KW - 2-Oxoadipate dehydrogenase

KW - 2-Oxoglutarate dehydrogenase

KW - Inhibition by glutaryl-CoA and succinyl-CoA

KW - L-Lysine degradation pathway

KW - Superoxide and HO generation

KW - ThDP-enamine radical

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U2 - 10.1016/j.bbabio.2018.05.001

DO - 10.1016/j.bbabio.2018.05.001

M3 - Article

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JO - Biochimica et Biophysica Acta - Bioenergetics

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