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SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Angeletti, Carlo 
Amici, Adolfo 
Gilley, Jonathan 
Trapanotto, Antonio G 

Abstract

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.

Description

Funder: UNIVPM


Funder: Bill and Melinda Gates Foundation


Funder: Gates Cambridge Trust

Keywords

Biological sciences, Molecular physiology, Neuroscience

Journal Title

iScience

Conference Name

Journal ISSN

2589-0042
2589-0042

Volume Title

25

Publisher

Elsevier BV
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/S009582/1)
Wellcome Trust (210904/Z/18/Z)
Medical Research Council (2251244)