Synthesis and Degradation of Adenosine 5′-Tetraphosphate by Nicotinamide and Nicotinate Phosphoribosyltransferases. Issue 5 (18th May 2017)

• Record Type: Journal Article
• Authors: Amici, Adolfo; Grolla, Ambra A.; Del Grosso, Erika; Bellini, Roberta; Bianchi, Michele; Travelli, Cristina; Garavaglia, Silvia; Sorci, Leonardo; Raffaelli, Nadia; Ruggieri, Silverio; Genazzani, Armando A.; Orsomando, Giuseppe
• Is Part Of: Cell chemical biology. Volume 24:Issue 5(2017)
• Page Start: 553
• Page End: 564.e4
• Publication Date: 2017-05-18
• Subjects: type II phosphoribosyltransferases -- NAMPT -- NAPT -- NadV -- PncB -- ATPase -- Ap4 -- FK866 -- B16 cells -- mouse plasma; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.03.010
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Ap4 is identified as a novel ATP-derived product of NAMPT and NAPT A phosphor-transfer mechanism for reversible synthesis of Ap4 from ATP is proposed The FK866-inhibited NAMPT enzyme still catalyzes Ap4 synthesis A correlation between NAMPT and Ap4 levels in murine cells and plasma is observed Abstract : Amici et al. present a novel phosphor-transfer reaction catalyzed by NAMPT and NAPT, two key enzymes for NAD biosynthesis. This property allows NAMPT to regulate in vivo adenosine 5-tetraphosphate (Ap4) levels, thus conferring an unpredicted signaling role to this enzyme.