Original Paper

Neurochemical Research

, Volume 32, Issue 4, pp 871-891

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

  • Victoria I. BunikAffiliated withSchool of Bioengineering and Bioinformatics, and Belozersky Institute of Physico-Chemical Biology, Moscow State University
  • , John V. SchlossAffiliated withNeuroSystec
  • , John T. PintoAffiliated withBurke Medical Research Institute
  • , Gary E. GibsonAffiliated withBurke Medical Research InstituteDepartment of Neurology and Neuroscience, Weill Medical College of Cornell University
  • , Arthur J. L. CooperAffiliated withBurke Medical Research InstituteDepartment of Neurology and Neuroscience, Weill Medical College of Cornell UniversityDepartment of Biochemistry, Weill Medical College of Cornell University Email author 

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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.

Keywords

Branched chain α-keto acid dehydrogenase complex Carbanion intermediates α-Ketoglutarate dehydrogenase complex Pyridoxal 5′-phosphate Pyruvate dehydrogenase complex Thiamine diphosphate