TY - JOUR
T1 - P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage.
AU - Wang, Gelin
AU - Han, Ting
AU - Nijhawan, Deepak
AU - Theodoropoulos, Pano
AU - Naidoo, Jacinth
AU - Yadavalli, Sivaramakrishnan
AU - Mirzaei, Hamid
AU - Pieper, Andrew A.
AU - Ready, Joseph M.
AU - McKnight, Steven L.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2014.07.040
DO - 10.1016/j.cell.2014.07.040
M3 - Article
C2 - 25215490
AN - SCOPUS:84907390733
SN - 0092-8674
VL - 158
SP - 1324
EP - 1334
JO - Cell
JF - Cell
IS - 6
ER -