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Role of the 2-Oxo Acid Dehydrogenase Complexes in Metabolism: Genetics, Structure and Function

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 12917

Special Issue Editors

Prof. Dr. Frank Jordan

E-Mail Website
Guest Editor
Department of Chemistry, Rutgers University, Newark, NJ 07103, USA
Interests: structures of proteins; enzymes and mechanism of enzymatic reactions
Dr. Natalia S. Nemeria

E-Mail Website
Co-Guest Editor
Department of Chemistry, Rutgers University, Newark, NJ 07103, USA
Interests: enzyme; metabolism; oxoglutarate dehydrogenase; ketoglutaric acid; oxidoreductases

Special Issue Information

Dear Colleagues, 

The aim of this Special Issue is to bring together the latest research on 2-oxo acid dehydrogenase complexes (OADHc), the key players in cell metabolism, enabling researchers to present their recent findings and to share their opinions on the recent advances in the field.

Recent genetic studies identified several bi-allelic variants in the OGDHL gene that correlated with neurodevelopmental phenotypes, and the rare variants in the OGDHL and DHTKD1 genes were implicated in the genetic ethiology of eosinophilic esophagitis. The reduced activities of the 2-oxoglutarate dehydrogenase complex (OGDHc) in the TCA cycle were correlated with neurodegenerative diseases, particularly Alzheimer’s disease. Recent findings also provided evidence for a close link between the post-translational modifications (PTMs) of proteins by succinylation and glutarylation, as well as the OGDHc and the function of its E2o component identification of target proteins. Therefore, an understanding of the molecular mechanisms of the SIRT 5 (NAD+) deacylase remains challenging. Especially interesting are the Cryo-EM structural findings on the OADHc from native cell extracts and on a sample assembled in vitro, which provide a framework for understanding the component assembly and intermediate channeling in these striking enzymatic assemblies with a typical size 4–10 MDa. This research topic will enhance our current understanding of protein interactions in metabolism related to human diseases.

Prof. Dr. Frank Jordan
Dr. Natalia S. Nemeria
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodegenerative and neurodevelopmental diseases
  • 2-oxo acid dehydrogenases pathogenic variants
  • mitochondrial dysfunction
  • reactive oxygen species (ROS)
  • pyruvate,α-oxoglutarate and 2-oxoadipate dehydrogenase complexes
  • macromolecular assemblies
  • post-translational modifications (PTMs) of proteins by succinylation and glutarylation
  • molecular mechanisms of SIRT 5 (NAD+)
  • X-ray structures of a disease-causing variants
  • cryo-EM reconstruction of macromolecular complexes

Published Papers (5 papers)

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Research

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23 pages, 11433 KiB  
Article
Structural and Biochemical Investigation of Selected Pathogenic Mutants of the Human Dihydrolipoamide Dehydrogenase
by Eszter Szabo, Eva Nemes-Nikodem, Krisztina Rubina Vass, Zsofia Zambo, Eszter Zrupko, Beata Torocsik, Oliver Ozohanics, Balint Nagy and Attila Ambrus
Int. J. Mol. Sci. 2023, 24(13), 10826; https://doi.org/10.3390/ijms241310826 - 28 Jun 2023
Viewed by 1147
Abstract
Clinically relevant disease-causing variants of the human dihydrolipoamide dehydrogenase (hLADH, hE3), a common component of the mitochondrial α-keto acid dehydrogenase complexes, were characterized using a multipronged approach to unravel the molecular pathomechanisms that underlie hLADH deficiency. The G101del and M326V substitutions both reduced [...] Read more.
Clinically relevant disease-causing variants of the human dihydrolipoamide dehydrogenase (hLADH, hE3), a common component of the mitochondrial α-keto acid dehydrogenase complexes, were characterized using a multipronged approach to unravel the molecular pathomechanisms that underlie hLADH deficiency. The G101del and M326V substitutions both reduced the protein stability and triggered the disassembly of the functional/obligate hLADH homodimer and significant FAD losses, which altogether eventually manifested in a virtually undetectable catalytic activity in both cases. The I12T-hLADH variant proved also to be quite unstable, but managed to retain the dimeric enzyme form; the LADH activity, both in the forward and reverse catalytic directions and the affinity for the prosthetic group FAD were both significantly compromised. None of the above three variants lent themselves to an in-depth structural analysis via X-ray crystallography due to inherent protein instability. Crystal structures at 2.89 and 2.44 Å resolutions were determined for the I318T- and I358T-hLADH variants, respectively; structure analysis revealed minor conformational perturbations, which correlated well with the residual LADH activities, in both cases. For the dimer interface variants G426E-, I445M-, and R447G-hLADH, enzyme activities and FAD loss were determined and compared against the previously published structural data. Full article
(This article belongs to the Special Issue Role of the 2-Oxo Acid Dehydrogenase Complexes in Metabolism: Genetics, Structure and Function)
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21 pages, 9604 KiB  
Article
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
by Oliver Ozohanics, Xu Zhang, Natalia S. Nemeria, Attila Ambrus and Frank Jordan
Int. J. Mol. Sci. 2023, 24(5), 4555; https://doi.org/10.3390/ijms24054555 - 25 Feb 2023
Cited by 3 | Viewed by 1410
Abstract
The human 2-oxoglutarate dehydrogenase complex (hOGDHc) is a key enzyme in the tricarboxylic acid cycle and is one of the main regulators of mitochondrial metabolism through NADH and reactive oxygen species levels. Evidence was obtained for formation of a hybrid complex between the [...] Read more.
The human 2-oxoglutarate dehydrogenase complex (hOGDHc) is a key enzyme in the tricarboxylic acid cycle and is one of the main regulators of mitochondrial metabolism through NADH and reactive oxygen species levels. Evidence was obtained for formation of a hybrid complex between the hOGDHc and its homologue the 2-oxoadipate dehydrogenase complex (hOADHc) in the L-lysine metabolic pathway, suggesting a crosstalk between the two distinct pathways. Findings raised fundamental questions about the assembly of hE1a (2-oxoadipate-dependent E1 component) and hE1o (2-oxoglutarate-dependent E1) to the common hE2o core component. Here we report chemical cross-linking mass spectrometry (CL-MS) and molecular dynamics (MD) simulation analyses to understand assembly in binary subcomplexes. The CL-MS studies revealed the most prominent loci for hE1o-hE2o and hE1a-hE2o interactions and suggested different binding modes. The MD simulation studies led to the following conclusions: (i) The N-terminal regions in E1s are shielded by, but do not interact directly with hE2o. (ii) The hE2o linker region exhibits the highest number of H-bonds with the N-terminus and α/β1 helix of hE1o, yet with the interdomain linker and α/β1 helix of hE1a. (iii) The C-termini are involved in dynamic interactions in complexes, suggesting the presence of at least two conformations in solution. Full article
(This article belongs to the Special Issue Role of the 2-Oxo Acid Dehydrogenase Complexes in Metabolism: Genetics, Structure and Function)
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17 pages, 4209 KiB  
Article
Phosphonate Inhibitors of Pyruvate Dehydrogenase Perturb Homeostasis of Amino Acids and Protein Succinylation in the Brain
by Artem V. Artiukhov, Vasily A. Aleshin, Irina S. Karlina, Alexey V. Kazantsev, Daria A. Sibiryakina, Alexander L. Ksenofontov, Nikolay V. Lukashev, Anastasia V. Graf and Victoria I. Bunik
Int. J. Mol. Sci. 2022, 23(21), 13186; https://doi.org/10.3390/ijms232113186 - 29 Oct 2022
Cited by 9 | Viewed by 1978
Abstract
Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for brain glucose and neurotransmitter metabolism, which is dysregulated in many pathologies. Using specific inhibitors of PDHC in vivo, we determine biochemical and physiological responses to PDHC dysfunction. Dose dependence of the responses to membrane-permeable dimethyl [...] Read more.
Mitochondrial pyruvate dehydrogenase complex (PDHC) is essential for brain glucose and neurotransmitter metabolism, which is dysregulated in many pathologies. Using specific inhibitors of PDHC in vivo, we determine biochemical and physiological responses to PDHC dysfunction. Dose dependence of the responses to membrane-permeable dimethyl acetylphosphonate (AcPMe2) is non-monotonous. Primary decreases in glutathione and its redox potential, methionine, and ethanolamine are alleviated with increasing PDHC inhibition, the alleviation accompanied by physiological changes. A comparison of 39 brain biochemical parameters after administration of four phosphinate and phosphonate analogs of pyruvate at a fixed dose of 0.1 mmol/kg reveals no primary, but secondary changes, such as activation of 2-oxoglutarate dehydrogenase complex (OGDHC) and decreased levels of glutamate, isoleucine and leucine. The accompanying decreases in freezing time are most pronounced after administration of methyl acetylphosphinate and dimethyl acetylphosphonate. The PDHC inhibitors do not significantly change the levels of PDHA1 expression and phosphorylation, sirtuin 3 and total protein acetylation, but increase total protein succinylation and glutarylation, affecting sirtuin 5 expression. Thus, decreased production of the tricarboxylic acid cycle substrate acetyl-CoA by inhibited PDHC is compensated by increased degradation of amino acids through the activated OGDHC, increasing total protein succinylation/glutarylation. Simultaneously, parasympathetic activity and anxiety indicators decrease. Full article
(This article belongs to the Special Issue Role of the 2-Oxo Acid Dehydrogenase Complexes in Metabolism: Genetics, Structure and Function)
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20 pages, 3179 KiB  
Article
Functional Versatility of the Human 2-Oxoadipate Dehydrogenase in the L-Lysine Degradation Pathway toward Its Non-Cognate Substrate 2-Oxopimelic Acid
by Natalia S. Nemeria, Balint Nagy, Roberto Sanchez, Xu Zhang, João Leandro, Attila Ambrus, Sander M. Houten and Frank Jordan
Int. J. Mol. Sci. 2022, 23(15), 8213; https://doi.org/10.3390/ijms23158213 - 26 Jul 2022
Cited by 3 | Viewed by 1780
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Role of the 2-Oxo Acid Dehydrogenase Complexes in Metabolism: Genetics, Structure and Function)
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Review

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28 pages, 3643 KiB  
Review
The α-Ketoglutarate Dehydrogenase Complex as a Hub of Plasticity in Neurodegeneration and Regeneration
by Grace E. Hansen and Gary E. Gibson
Int. J. Mol. Sci. 2022, 23(20), 12403; https://doi.org/10.3390/ijms232012403 - 17 Oct 2022
Cited by 19 | Viewed by 5810
Abstract
Abnormal glucose metabolism is central to neurodegeneration, and considerable evidence suggests that abnormalities in key enzymes of the tricarboxylic acid (TCA) cycle underlie the metabolic deficits. Significant recent advances in the role of metabolism in cancer provide new insight that facilitates our understanding [...] Read more.
Abnormal glucose metabolism is central to neurodegeneration, and considerable evidence suggests that abnormalities in key enzymes of the tricarboxylic acid (TCA) cycle underlie the metabolic deficits. Significant recent advances in the role of metabolism in cancer provide new insight that facilitates our understanding of the role of metabolism in neurodegeneration. Research indicates that the rate-limiting step of the TCA cycle, the α-ketoglutarate dehydrogenase complex (KGDHC) and its substrate alpha ketoglutarate (KG), serve as a signaling hub that regulates multiple cellular processes: (1) is the rate-limiting step of the TCA cycle, (2) is sensitive to reactive oxygen species (ROS) and produces ROS, (3) determines whether KG is used for energy or synthesis of compounds to support growth, (4) regulates the cellular responses to hypoxia, (5) controls the post-translational modification of hundreds of cell proteins in the mitochondria, cytosol, and nucleus through succinylation, (6) controls critical aspects of transcription, (7) modulates protein signaling within cells, and (8) modulates cellular calcium. The primary focus of this review is to understand how reductions in KGDHC are translated to pathologically important changes that underlie both neurodegeneration and cancer. An understanding of each role is necessary to develop new therapeutic strategies to treat neurodegenerative disease. Full article
(This article belongs to the Special Issue Role of the 2-Oxo Acid Dehydrogenase Complexes in Metabolism: Genetics, Structure and Function)
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