Format

Send to

Choose Destination
Cell Chem Biol. 2017 May 18;24(5):553-564.e4. doi: 10.1016/j.chembiol.2017.03.010. Epub 2017 Apr 13.

Synthesis and Degradation of Adenosine 5'-Tetraphosphate by Nicotinamide and Nicotinate Phosphoribosyltransferases.

Author information

1
Department of Clinical Sciences, Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, 60131 Ancona, Italy.
2
Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy.
3
Department of Agricultural, Food and Environmental Sciences, Polytechnic University of Marche, Via Brecce Bianche 10, 60131 Ancona, Italy.
4
Department of Pharmaceutical Sciences, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy. Electronic address: armando.genazzani@uniupo.it.
5
Department of Clinical Sciences, Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, 60131 Ancona, Italy. Electronic address: g.orsomando@univpm.it.

Abstract

Adenosine 5'-tetraphosphate (Ap4) is a ubiquitous metabolite involved in cell signaling in mammals. Its full physiological significance remains unknown. Here we show that two enzymes committed to NAD biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT) and nicotinate phosphoribosyltransferase (NAPT), can both catalyze the synthesis and degradation of Ap4 through their facultative ATPase activity. We propose a mechanism for this unforeseen additional reaction, and demonstrate its evolutionary conservation in bacterial orthologs of mammalian NAMPT and NAPT. Furthermore, evolutionary distant forms of NAMPT were inhibited in vitro by the FK866 drug but, remarkably, it does not block synthesis of Ap4. In fact, FK866-treated murine cells showed decreased NAD but increased Ap4 levels. Finally, murine cells and plasma with engineered or naturally fluctuating NAMPT levels showed matching Ap4 fluctuations. These results suggest a role of Ap4 in the actions of NAMPT, and prompt to evaluate the role of Ap4 production in the actions of NAMPT inhibitors.

KEYWORDS:

ATPase; Ap4; B16 cells; FK866; NAMPT; NAPT; NadV; PncB; mouse plasma; type II phosphoribosyltransferases

PMID:
28416276
DOI:
10.1016/j.chembiol.2017.03.010
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center