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 journalArticlepeer-review

116 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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