Other NAD⁺-utilizing enzymes

The term Other NAD⁺-utilizing enzymes refers to a functional category of proteins that consume Nicotinamide Adenine Dinucleotide (NAD+) as a substrate, excluding the primary Sirtuin and Poly(ADP-ribose) polymerase (PARP) families. This group prominently includes the ADP-ribosyl cyclases CD38 and CD157, as well as the pro-degenerative enzyme SARM1 (Sterile Alpha and TIR Motif-containing protein 1) (Chini et al., 2018, Biochem. Soc. Trans.). These enzymes primarily function as NAD+ glycohydrolases, breaking down NAD+ into nicotinamide and ADP-ribose or cyclic ADP-ribose (cADPR), the latter of which serves as a potent second messenger for calcium mobilization (Malavasi et al., 2008, Physiol. Rev.). Pathological overactivation of these enzymes is linked to cellular NAD+ depletion, a hallmark of aging, metabolic decline, and neurodegeneration (Essuman et al., 2017, Neuron). Clinically, CD38 is a validated therapeutic target in hematologic malignancies, with monoclonal antibodies like Daratumumab and Isatuximab used to treat multiple myeloma (Hogan et al., 2019, Front. Immunol.). Additionally, SARM1 is an emerging target for neuroprotection, with small-molecule inhibitors under development to prevent axonal loss in conditions such as peripheral neuropathy and amyotrophic lateral sclerosis (ALS).

Other names

NAD+ consumersNAD+ glycohydrolasesNon-sirtuin non-PARP NAD+ utilizing enzymesADP-ribosyl cyclases

Inhibition of NAD+ glycohydrolase activity to preserve cellular NAD+ levels or targeted depletion of cells expressing the enzyme (e.g., CD38+ plasma cells).