Understanding SARM1: An Enzyme with Key Roles in Cellular Processes
Biochemistry: Exploring the Building Blocks of Life
- SARM1 is an enzyme that regulates axonal degeneration and utilizes NAD.
- CZ-48 is a cell-permeant mimetic of NMN that activates SARM1 in vitro and in cellulo.
- NMN-adenylyltransferase knockout elevated cellular NMN and activated SARM1 to produce cADPR, confirming NMN as its endogenous activator.
Unveiling the Catalytic Activities of SARM1 and CD38
- CZ-48 activates SARM1 by causing a conformational change of the auto-inhibitory domain and dimerization of its catalytic domain.
- SARM1 catalysis is similar to CD38, despite having no sequence similarity.
- Both SARM1 and CD38 catalyze a similar set of reactions, but SARM1 has much higher NAD-cyclizing activity, leading to elevated cADPR production.
- CZ-48 selectively activates SARM1 but inhibits CD38.
CZ-48: A Specific Modulator of SARM1
- In cells overexpressing SARM1, CZ-48 increases cADPR levels, depletes NAD and ATP, and induces non-apoptotic death.
- CZ-48 acts as a specific modulator of SARM1 functions in cells.
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CZ-48: A Powerful Tool for Studying SARM1 and CD38
- CZ-48 is a compound that can enter cells and mimic the effects of NMN.
- CZ-48 activates SARM1, a protein involved in cellular processes.
- CZ-48 has an inhibitory effect on CD38 enzyme activity.
- SARM1 and CD38 have similar catalytic functions, but SARM1 has higher cyclase activity.
- Activation of SARM1 by CZ-48 or NMN leads to changes in its conformation.
- Activation of SARM1 results in the production of cADPR, depletion of NAD, and non-apoptotic cell death.
Investigating the Mechanism of SARM1 Activation
- The study examined the mechanism of SARM1 activation triggered by CZ-48 and NMN.
- SARM1 is a large molecule that can form constitutive dimers.
- Activation of SARM1 by CZ-48 leads to the accumulation of cellular cADPR.
- SARM1 is regulated by NMN and CZ-48 and can induce non-apoptotic cell death.
- CZ-48 selectively activates SARM1 and inhibits CD38.
Title of paper: A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death
Author(s): Zhao ZY, Xie XJ, Li WH, Liu J, Chen Z, Zhang B, Li T, Li SL, Lu JG, Zhang L, Zhang LH, Xu Z, Lee HC, Zhao YJ.
Year published: 2019
Published in: iScience
Original article can be found here.