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. We are currently studying enzymes catalyzing two independent pathways: 1) xylose assimilation in yeast and 2) NAD+ biosynthesis and salvage. The first is a continuation of work done primarily at SSRL where we have begun characterization of three enzymes (xylose reductase, xylitol dehydrogenase and xylulose kinase) forming a heterologous pathway which should allow budding yeast to metabolically integrate the pentose xylose, a primary constituent in agricultural waste. Structures are guiding protein engineering efforts which will alter nucleotide specificity allowing recycling of the cosubstrate in the high-flux pathway. Additionally, we are trying to use the xylulose kinase structure to improve utilization of the low intracellular concentrations of the substrate. The second project concerns the conversion of tryptophan to NAD, a process that is mediated by six different enzymes in eukaryotes. Since the enzymes catalyzing this essential pathway diverge quite a bit between prokaryotes, lower and higher eukaryotes many are plausible targets for drug design. Compounds modulating tryptophan degradation are also likely to have use in controlling inflammation and also in neuroprotection in a wide range of neurodegenerative disorders.
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