title: P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage.
abstract: The P7C3 class of aminopropyl carbazole chemicals fosters the survival of neurons in a variety of rodent models of neurodegeneration or nerve cell injury. To uncover its mechanism of action, an active derivative of P7C3 was modified to contain both a benzophenone for photocrosslinking and an alkyne for CLICK chemistry. This derivative was found to bind nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme involved in the conversion of nicotinamide into nicotinamide adenine dinucleotide (NAD). Administration of active P7C3 chemicals to cells treated with doxorubicin, which induces NAD depletion, led to a rebound in intracellular levels of NAD and concomitant protection from doxorubicin-mediated toxicity. Active P7C3 variants likewise enhanced the activity of the purified NAMPT enzyme, providing further evidence that they act by increasing NAD levels through its NAMPT-mediated salvage.
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors.forename: Gelin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA; Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors.forename: Deepak
authors.initials: D
authors.lastname: Nijhawan
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors.forename: Pano
authors.initials: P
authors.lastname: Theodoropoulos
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors.forename: Jacinth
authors.initials: J
authors.lastname: Naidoo
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors.forename: Sivaramakrishnan
authors.initials: S
authors.lastname: Yadavalli
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Mirzaei
authors.affiliation: Departments of Psychiatry, Neurology, and Veterans Affairs, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. Electronic address: joseph.ready@utsouthwestern.edu.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Ready
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. Electronic address: steven.mcknight@utsouthwestern.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: McKnight
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D053858:Metabolic Networks and Pathways; D051379:Mice; D009243:NAD / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism
chemical_list: D002227:Carbazoles; D016207:Cytokines; D018696:Neuroprotective Agents; C552520:P7C3 compound; D009243:NAD; D004317:Doxorubicin; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human