STRUCTURAL DETERMINATIONS OF GLUTAMINE-DEPENDENT NAD SYNTHETASES AND OF ENZYMES

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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. 1) Glutamine?dependent NAD+ synthetase catalyzes the last step of the de novo and recycling pathways in NAD+ biosynthesis. This enzyme is essential for survival of replicating and non-replicating M. tuberculosis and as such it is an attractive drug target. In humans NAD synthetase independent pathways participate in NAD biosynthesis. We are working on the structural and kinetic characterizations of the H. sapiens and M. tuberculosis enzymes. 2) Pyrrolobenzodiazepine are natural products with strong antitumor properties. We are studying the biosynthesis of these compounds and we have identified two enzymes that catalyze unusual chemical reactions and that have no homologous in the PBD database. Therefore, the second project includes the structural determination of these unprecedented enzymes involved in pyrrolobenzodiazepine biosynthesis.