P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage

作者：Wang Gelin; Han Ting; Nijhawan Deepak; Theodoropoulos Pano; Naidoo Jacinth; Yadavalli Sivaramakrishnan; Mirzaei Hamid; Pieper Andrew A; Ready Joseph M^*; McKnight Steven L

来源：Cell, 2014, 158(6): 1324-1334.

DOI：10.1016/j.cell.2014.07.040

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.

• 出版日期2014-9-11