Review of tyrosine and lysine as new motifs for organophosphate binding to proteins that have no active site serine.
The accepted target for organophosphorus agent (OP) binding to enzymes is the active site serine in the consensus sequence Gly X Ser X Gly. New motifs have been identified by using mass spectrometry to fragment OP-labeled peptides. It has been found that OP can make covalent bonds with tyrosine and lysine in proteins that have no active site serine. The OP-tyrosine bond is stable, and does not undergo the decay seen with OP-serine. Information on OP binding to tyrosine has been applied to diagnosis of OP exposure, through the use of mass spectrometry to detect OP-labeled albumin in human and animal plasma. It is expected that the new OP binding motif will aid in the search for a mechanism of low dose OP toxicity. It is hypothesized that proteins involved in axonal transport, especially proteins whose function depends on reversible phosphorylation, are prime candidates for a role in OP-induced neurodegeneration. Treatment of neurodegenerative disorders could be developed by identifying methods to reverse OP binding to tyrosine.
Lockridge
Oksana
O
Eppley Institute, 985950 University of Nebraska Medical Center, Omaha, NE 68198-5950, United States. olockrid@unmc.edu
Schopfer
Lawrence M
LM
D000818:Animals; D020134:Catalytic Domain; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D010755:Organophosphates / Q000378:metabolism* / Q000633:toxicity; D011485:Protein Binding; D014443:Tyrosine / Q000378:metabolism*
D010755:Organophosphates; D014443:Tyrosine; D006867:Hydrolases; D008239:Lysine