This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Prephenate dehydrogenase: The first committed step in tyrosine biosynthesis is the oxidative decarboxylation of prephenate to p-hydroxylphenylpyruvate (HPP). This reaction is catalyzed by prephenate dehydrogenase in the presence of NAD+ [1]. This enzyme is of paramount importance since it channels prephenate, a branch point intermediate in tyrosine and phenylalanine biosynthesis, to tyrosine synthesis. The biosynthesis of tyrosine is of critical importance for the growth and survival of enteric bacteria, yeasts, fungi and plants. Like the other aromatic amino acids, tyrosine plays dual roles in the biochemistry of the organism, acting as both a product and a precursor. In the former case, tyrosine is required for protein synthesis, whereas, in the latter example, it is a substrate for enzymes in downstream metabolic pathways. The aromatic metabolites derived from tyrosine include quinones [2, 3], cyanogenic glycosides [4], alkaloids [5, 6], flavonoids [7], and phenolic compounds derived from the phenylpropanoid pathway [7, 8]. Since many of these compounds are involved in primary biological processes, they are essential for viability. In plants, for example, flavonoids are important for normal development as they are involved in auxin transport [9-11], pollen germination [9, 12, 13], and signaling to symbiotic microorganisms [9, 14]. We have recently determined the crystal structure of prephenate dehydrogenase however we propose that our understanding of the mechanism of this enzyme hinges on determining its crystal structure in complex with know ligands. We recently obtained crystals of prephenate dehydrogenase in co-crystallization studies using prephenate, (4-hydroxyphenyl)pyruvate and tyrosine separately. We are requesting beam time for x-ray data collection to determine the structure of prephenate dehydrogenase in complex with these ligands.
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