MISINCORPORATION OF AMINO ACID ANALOGS IN SELECTED HUMAN AND MURINE PROTEINS

Battelle Pacific Northwest Laboratories, Richland WA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Azetidine-2-carboxylic acid (Aze), a toxic and teratogenic compound, is the lower homologue of proline, lacking one member in its ring. It is readily misincorporated in place of proline into the proteins of species ranging from prokaryotes to humans. Aze is present in high concentration in the bulbs of sugar beets, which account for 30% of the world's sucrose supply. Sugar beet byproducts (dried pulp and molasses) contain Aze;they are widely used as feed for dairy and meat livestock. Proline-rich stretches in proteins, such as the apoptotic domain of p53, in which 11 of 28 residues are prolyls, and the consensual epitope of myelin basic protein, which embraces the sequence PRTPPP, are vulnerable targets for corrupting substitution of Aze for proline. There are tight geological, chronological, migrational, and enzootic epidemiologic correlations between exposure to Aze and the occurrence of multiple sclerosis. We aim to characterize the extent of Aze misincorporation in selected proteins in selected mice and human proteins under different conditions. The UStag mass spectrometry approach will be used to detect Aze substitutions in the tissue proteins of Aze-exposed murine pups, in the lesions and in non-involved regions of brains from patients who died with multiple sclerosis, and in the blood proteins of humans living in various regions of North America. These data will provide information needed to assess the role of Aze in the pathogenesis of disease.