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Enzyme-Catalyzed Side Reactions with Molecular Oxygen may Contribute to Cell Signaling and Neurodegenerative Diseases

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Abstract

A link between neurodegeneration and well-characterized enzymatic and non-enzymatic reactions that produce reactive oxygen species (ROS) from O2 is well established. Several enzymes that contain pyridoxal 5′-phosphate (PLP) or thiamine diphosphate (ThDP) catalyze side reactions (paracatalytic reactions) in the presence of ambient O2. These side reactions produce oxidants such as hydrogen peroxide [H2O2] or extremely reactive peracids [RC(O)OOH]. We hypothesize that although these enzymes normally produce oxidants at low or undetectable levels, changes in substrate levels or disease-induced structural alterations may enhance interactions with O2, thereby generating higher levels of reactive oxidants. These oxidants may damage the enzymes producing them, alter nearby macromolecules and/or destroy important metabolites/coenzymes. We propose that paracatalytic reactions with O2 catalyzed by PLP-dependent decarboxylases and by ThDP-dependent enzymes within the α-keto acid dehydrogenase complexes may contribute to normal cellular signaling and to cellular damage in neurodegenerative diseases.

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Abbreviations

AD:

Alzheimer disease

ALS II:

Acetolactate synthase isozyme II

BCKADC:

Branched chain α-keto acid dehydrogenase complex

CSAD:

Cysteine sulfinic acid decarboxylase

DDC:

Dopa decarboxylase

dopal:

3,4-dihydroxyphenylacetaldehyde

E1b:

Branched-chain α-keto acid dehydrogenase

E1k:

α-Ketoglutarate dehydrogenase

E1p:

Pyruvate dehydrogenase

E2k:

Dihydrolipoamide succinyl transferase

E3 :

Dihydrolipoamide dehydrogenase

GABA:

γ-Aminobutyric acid

GAD:

Glutamate decarboxylase

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GSH:

Glutathione

GSSG:

Glutathione disulfide

KG:

α-Ketoglutarate

KGDHC:

α-Ketoglutarate dehydrogenase complex

ODC:

Ornithine decarboxylase

PAAS:

Phenylacetaldehyde synthase

PDHC:

Pyruvate dehydrogenase complex

PLP:

Pyridoxal 5′-phosphate

PMP:

Pyridoxamine 5′-phosphate

ROS:

Reactive oxygen species

RNS:

Reactive nitrogen species

Rubisco:

Ribulose 1,5-bisphosphate carboxylase/oxygenase

SOD:

Superoxide dismutase

TCA:

Tricarboxylic acid

ThDP:

Thiamine diphosphate

TNB:

5-Thionitrobenzoate

Tx:

Thioredoxin

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Acknowledgments

VIB greatly acknowledges a longstanding support of her work on the mechanism of the catalysis and regulation of the α-keto acid dehydrogenase complexes by the Alexander von Humboldt Foundation (Bonn, Germany). JVS gratefully acknowledges support by the Office of Naval Research (N00014-94-1-0457; N00014-00-1-01-02; N00014-03-1-0450) and NIH (GM48568). Work cited from the AJLC and GEG laboratories was supported by NIH grants AG14930, AG14600 and AG19589.

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Authors and Affiliations

  1. School of Bioengineering and Bioinformatics, and Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, 119992, Russia

    Victoria I. Bunik

  2. NeuroSystec, Mann Biomedical Park, Valencia, CA, 91355, USA

    John V. Schloss

  3. Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY, 10605, USA

    John T. Pinto, Gary E. Gibson & Arthur J. L. Cooper

  4. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, 10021, USA

    Gary E. Gibson & Arthur J. L. Cooper

  5. Department of Biochemistry, Weill Medical College of Cornell University, New York, NY, 10021, USA

    Arthur J. L. Cooper

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  1. Victoria I. Bunik
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  2. John V. Schloss
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  3. John T. Pinto
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  4. Gary E. Gibson
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  5. Arthur J. L. Cooper
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Correspondence to Arthur J. L. Cooper.

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Special issue dedicated to John P. Blass.

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Bunik, V.I., Schloss, J.V., Pinto, J.T. et al. Enzyme-Catalyzed Side Reactions with Molecular Oxygen may Contribute to Cell Signaling and Neurodegenerative Diseases. Neurochem Res 32, 871–891 (2007). https://doi.org/10.1007/s11064-006-9239-z

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  • DOI: https://doi.org/10.1007/s11064-006-9239-z

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