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. Nicotinamide adenine dinucleotide (NAD) is a molecule that is ubiquitous throughout all of life and is essential not only as a cofactor in redox reactions, but can also act as an adenosine diphosphate ribose (ADPR) donor. 'NAD consuming'enzymes, including ADP-ribosyl transferase, poly-ADP-ribosyl polymerase, cADP-ribose synthetase, and Sir2 protein deacetylase, can rapidly deplete cellular NAD stocks and in the process produce nicotinamide. Not only is it necessary for the NAD pool to be replenished, but the nicotinamide produced can act as a feedback inhibitor of these NAD consuming enzymes. While mammals can use nicotinamide directly to recycle NAD, most lower organisms must first convert it into nicotinic acid using a nicotinamidase enzyme. Not only does nicotinamidase play an essential role in NAD recycling, it can also act as a regulator of the NAD consuming enzymes by controlling cellular levels of nicotinamide. In addition, this enzyme has been shown to catalyze the conversion of the tuberculosis prodrug, pyrazinamide, into its active form, pyrazinoic acid. Structural studies completed to date have provided little information about substrate binding in the active site of this enzyme. A thorough study of ligand binding will provide crucial information about this enzyme's active site allowing for a deeper understanding of the mechanistic enzymology and providing essential details for structure-guided drug design efforts.
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