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Dihydrolipoamide dehydrogenase, pyruvate oxidation, and acetylation-dependent mechanisms intersecting drug iatrogenesis

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Abstract

In human metabolism, pyruvate dehydrogenase complex (PDC) is one of the most intricate and large multimeric protein systems representing a central hub for cellular homeostasis. The worldwide used antiepileptic drug valproic acid (VPA) may potentially induce teratogenicity or a mild to severe hepatic toxicity, where the underlying mechanisms are not completely understood. This work aims to clarify the mechanisms that intersect VPA-related iatrogenic effects to PDC-associated dihydrolipoamide dehydrogenase (DLD; E3) activity. DLD is also a key enzyme of α-ketoglutarate dehydrogenase, branched-chain α-keto acid dehydrogenase, α-ketoadipate dehydrogenase, and the glycine decarboxylase complexes. The molecular effects of VPA will be reviewed underlining the data that sustain a potential interaction with DLD. The drug-associated effects on lipoic acid-related complexes activity may induce alterations on the flux of metabolites through tricarboxylic acid cycle, branched-chain amino acid oxidation, glycine metabolism and other cellular acetyl-CoA-connected reactions. The biotransformation of VPA involves its complete β-oxidation in mitochondria causing an imbalance on energy homeostasis. The drug consequences as histone deacetylase inhibitor and thus gene expression modulator have also been recognized. The mitochondrial localization of PDC is unequivocal, but its presence and function in the nucleus were also demonstrated, generating acetyl-CoA, crucial for histone acetylation. Bridging metabolism and epigenetics, this review gathers the evidence of VPA-induced interference with DLD or PDC functions, mainly in animal and cellular models, and highlights the uncharted in human. The consequences of this interaction may have significant impact either in mitochondrial or in nuclear acetyl-CoA-dependent processes.

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Abbreviations

Acetyl-CoA:

Acetyl-Coenzyme A

ACLY:

ATP citrate lyase

ACSS:

Acetyl-CoA synthetase

ALT:

Alanine aminotransferase

ATP:

Adenosine triphosphate

BCAA:

Branched-chain amino acid

BCKA:

Branched-chain α-ketoacid

BCKADC:

Branched-chain α-ketoacid dehydrogenase complex

DCA:

Dichloroacetate

E1:

Pyruvate dehydrogenase (component E1)

E2:

Dihydrolipoamide transacetylase (component E2)

E3/DLD:

Dihydrolipoamide dehydrogenase (component E3)

E3BP:

E3-binding protein

E3BD:

E3-binding protein domains

FAO:

Fatty acid β-oxidation

GCS:

Glycine cleavage system

GDC:

Glycine decarboxylase complex

HAT:

Histone acetyltransferase

HCC:

Hepatocellular carcinoma

HDACi:

Histone deacetylase inhibitor

hE3:

Human E3

KAT:

Protein lysine acetyltransferase

KDAC:

Protein lysine deacetylase

KDACi:

Protein lysine deacetylase inhibitor

α-KADC:

α-Ketoadipate dehydrogenase complex

α-KGDC:

α-Ketoglutarate dehydrogenase complex

LA:

Lipoic acid

LDH:

Lactate dehydrogenase

MICA:

5-Methoxyindole-2-carboxylic acid

MPC:

Mitochondrial pyruvate carrier

NAD(H):

Nicotinamide adenine dinucleotide (reduced form)

NAG:

N-Acetylglutamate

OAA:

Oxaloacetate

OXPHOS:

Oxidative phosphorylation

PC:

Pyruvate carboxylase

PDC:

Pyruvate dehydrogenase complex

PDK:

Pyruvate dehydrogenase kinase

PDP:

Pyruvate dehydrogenase phosphatase

PTM:

Post-translational modification

TCA:

Tricarboxylic acid

TPP:

Thiamine pyrophosphate

UC:

Urea cycle

Valproyl-CoA:

Valproyl-Coenzyme A

VDAC:

Voltage-dependent anion channel

VPA:

Valproic acid

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Acknowledgements

Financial support was provided by Fundação para a Ciência e a Tecnologia (FCT, Portugal), through iMED.ULisboa: UID/DTP/04138/2019-2020.

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Financial support was provided by Fundação para a Ciência e a Tecnologia (FCT, Portugal), through iMED.ULisboa: UID/DTP/04138/2019-2020.

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  1. The Research Institute for Medicines (iMed.ULisboa), Metabolism and Genetics Group, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal

    I. F. Duarte, J. Caio, M. F. Moedas, L. A. Rodrigues, A. P. Leandro, I. A. Rivera & M. F. B. Silva

  2. Division of Molecular Metabolism, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    M. F. Moedas

  3. Department of Biochemistry and Human Biology, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa, Portugal

    A. P. Leandro, I. A. Rivera & M. F. B. Silva

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IFD and MFBS wrote the manuscript and performed the literature search. All authors critically revised the versions of the manuscript. All authors read and approved the final manuscript.

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Duarte, I.F., Caio, J., Moedas, M.F. et al. Dihydrolipoamide dehydrogenase, pyruvate oxidation, and acetylation-dependent mechanisms intersecting drug iatrogenesis. Cell. Mol. Life Sci. 78, 7451–7468 (2021). https://doi.org/10.1007/s00018-021-03996-3

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