SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites
Carlo Angeletti,
Adolfo Amici,
Jonathan Gilley,
Andrea Loreto,
Antonio G. Trapanotto,
Christina Antoniou,
Elisa Merlini,
Michael P. Coleman,
Giuseppe Orsomando
Affiliations
Carlo Angeletti
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy
Adolfo Amici
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy
Jonathan Gilley
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK
Andrea Loreto
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK
Antonio G. Trapanotto
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy
Christina Antoniou
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK
Elisa Merlini
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK
Michael P. Coleman
John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Robinson Way, CB2 0PY Cambridge, UK; Corresponding author
Giuseppe Orsomando
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche, Via Ranieri 67, Ancona 60131, Italy; Corresponding author
Summary: SARM1 is an NAD(P) glycohydrolase and TLR adapter with an essential, prodegenerative role in programmed axon death (Wallerian degeneration). Like other NAD(P)ases, it catalyzes multiple reactions that need to be fully investigated. Here, we compare these multiple activities for recombinant human SARM1, human CD38, and Aplysia californica ADP ribosyl cyclase. SARM1 has the highest transglycosidation (base exchange) activity at neutral pH and with some bases this dominates NAD(P) hydrolysis and cyclization. All SARM1 activities, including base exchange at neutral pH, are activated by an increased NMN:NAD ratio, at physiological levels of both metabolites. SARM1 base exchange occurs also in DRG neurons and is thus a very likely physiological source of calcium-mobilizing agent NaADP. Finally, we identify regulation by free pyridines, NADP, and nicotinic acid riboside (NaR) on SARM1, all of therapeutic interest. Understanding which specific SARM1 function(s) is responsible for axon degeneration is essential for its targeting in disease.
