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Cell. 2014 Sep 11;158(6):1324-1334. doi: 10.1016/j.cell.2014.07.040.

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

Author information

1
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA.
2
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.
3
Departments of Psychiatry, Neurology, and Veterans Affairs, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA.
4
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. Electronic address: joseph.ready@utsouthwestern.edu.
5
Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. Electronic address: steven.mcknight@utsouthwestern.edu.

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.

PMID:
25215490
PMCID:
PMC4163014
DOI:
10.1016/j.cell.2014.07.040
[Indexed for MEDLINE]
Free PMC Article

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