Enzyme-catalyzed side reactions with molecular oxygen may contribute to cell signaling and neurodegenerative diseases.
A link between neurodegeneration and well-characterized enzymatic and non-enzymatic reactions that produce reactive oxygen species (ROS) from O(2) 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 O(2). These side reactions produce oxidants such as hydrogen peroxide [H(2)O(2)] 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 O(2), 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 O(2) catalyzed by PLP-dependent decarboxylases and by ThDP-dependent enzymes within the alpha-keto acid dehydrogenase complexes may contribute to normal cellular signaling and to cellular damage in neurodegenerative diseases.
Bunik
Victoria I
VI
School of Bioengineering and Bioinformatics, and Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, Russia.
Schloss
John V
JV
Pinto
John T
JT
Gibson
Gary E
GE
Cooper
Arthur J L
AJ
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002384:Catalysis; D006801:Humans; D009154:Mutation / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry*; D010101:Oxygen Consumption / Q000502:physiology; D011732:Pyridoxal Phosphate / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013835:Thiamine Pyrophosphate / Q000378:metabolism
D000975:Antioxidants; D017382:Reactive Oxygen Species; D011732:Pyridoxal Phosphate; D013835:Thiamine Pyrophosphate; D010100:Oxygen