AI Article Synopsis
- - Adenosine 5'-tetraphosphate (Ap4) is a common molecule in mammalian cell signaling, but its full role in physiology is still not fully understood.
- - Two enzymes, NAMPT and NAPT, are primarily responsible for NAD biosynthesis but also have the ability to synthesize and break down Ap4 through a previously unrecognized ATPase activity.
- - The study found that while the drug FK866 inhibits NAMPT activity and reduces NAD levels, it actually leads to an increase in Ap4 levels, suggesting a relationship between NAMPT activity and Ap4 production that warrants further investigation.
Article 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.
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| http://dx.doi.org/10.1016/j.chembiol.2017.03.010 | DOI Listing |
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