P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage

Gelin Wang, Ting Han, Deepak Nijhawan, Pano Theodoropoulos, Jacinth Naidoo, Sivaramakrishnan Yadavalli, Hamid Mirzaei, Andrew A. Pieper, Joseph M. Ready, Steven L. McKnight

Research output: Contribution to journalArticle

97 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1324-1334
Number of pages11
JournalCell
Volume158
Issue number6
DOIs
StatePublished - Sep 11 2014

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Salvaging
Nicotinamide Phosphoribosyltransferase
NAD
Enzymes
Doxorubicin
Neurons
Derivatives
Niacinamide
Alkynes
Toxicity
Rodentia
Wounds and Injuries

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. / Wang, Gelin; Han, Ting; Nijhawan, Deepak; Theodoropoulos, Pano; Naidoo, Jacinth; Yadavalli, Sivaramakrishnan; Mirzaei, Hamid; Pieper, Andrew A.; Ready, Joseph M.; McKnight, Steven L.

In: Cell, Vol. 158, No. 6, 11.09.2014, p. 1324-1334.

Research output: Contribution to journalArticle

Wang, Gelin ; Han, Ting ; Nijhawan, Deepak ; Theodoropoulos, Pano ; Naidoo, Jacinth ; Yadavalli, Sivaramakrishnan ; Mirzaei, Hamid ; Pieper, Andrew A. ; Ready, Joseph M. ; McKnight, Steven L. / P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage. In: Cell. 2014 ; Vol. 158, No. 6. pp. 1324-1334.
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AU - Yadavalli, Sivaramakrishnan

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AU - Pieper, Andrew A.

AU - Ready, Joseph M.

AU - McKnight, Steven L.

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