NAD+ glycohydrolase explained

NAD^+ nucleosidase
Ec Number:	3.2.2.5
Cas Number:	9032-65-9
Go Code:	0003953
NAD^+ glycohydrolase

In enzymology, a NAD⁺ glycohydrolase is an enzyme that catalyzes the chemical reaction

NAD⁺ + H₂O

\rightleftharpoons ADP-ribose + nicotinamide

Thus, the two substrates of this enzyme are NAD⁺ and H₂O, whereas its two products are ADP-ribose and nicotinamide. Unlike ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase (EC 3.2.2.6), which catalyzes the same reaction, this reaction does not proceed through a cyclic ADP-ribose.^{[1] [2]}

This enzyme participates in nicotinate and nicotinamide metabolism and calcium signaling pathway. Calcium metabolism involves the regulation of the levels of calcium in the body. The role this calcium plays also includes providing enough calcium for bone mineralization. It serves as the basis for the structure and rigidity of bones. Calcium metabolism can lead to a variety of diseases which can involve renal function. High concentrations of calcium can lead to cell death or apoptosis.

Nomenclature

This enzyme belongs to the family of hydrolases, specifically those glycosylases that hydrolyse N-glycosyl compounds. The systematic name of this enzyme class is NAD⁺ glycohydrolase. Other names in common use include

• NAD+ nucleosidase,
• NADase,
• DPNase,
• DPN hydrolase,
• NAD hydrolase,
• diphosphopyridine nucleosidase,
• nicotinamide adenine dinucleotide nucleosidase,
• NAD glycohydrolase,
• NAD nucleosidase, and
• nicotinamide adenine dinucleotide glycohydrolase.

Immunoregulation

NADase is important to regulating adaptive immunity as T cells contain enzymes such as CD38 and SARM1 that consumes NAD+.^[3]

CD38

CD38 is an enzyme that triggers inflammatory responses and type II CD38 contains an ecto-NADase or extracellular NADase, whereas type II CD38 contains an intracellular cADPR.^[4] CD38 consumes NAD, which can produce second messengers that help regulate immune activity.^[5] Cells that are programmed for cell death or apoptosis releases NAD+, and type II CD38 help recycle the extracellular NAD+ released from apoptosis, where both products of NADase, ADP-ribose and nicotinamide, can be used to resynthesize NAD+ via the NAD+ synthesis pathway. ADP-ribose must be converted to adenosine in order to enter the NAD+ synthesis pathway, where ADP-ribose first gets converted to AMP and then AMP gets converted to adenosine via non-classical adenosine generational pathway. The other product nicotinamide is membrane permeable, which allows the molecule to reenter the NAD synthesis pathway more easily. CD38 NADase is also found in tissues and cells other than T cells, and CD38 is the one of the main form of NADase activity in mammals.

SARM1

SARM1 is a Toll-like receptor protein and also functions as a intracellular NADase. Under normal circumstances NADase activity are inhibited in the presence of NAD+, where NAD+ binds to armadillo/heat motifs (ARMs), which inhibits the dimerization of the toll-like receptor domain that activates the NADase activity. If there are damages to the binding site of NAD+ or disruption that prevents the interaction between ARMs and the toll-like receptor domain, NADase activity will be turned on at a constitutive level. As a result SARM1 will have higher consumption of NAD+ and produce NADase products (ADP-ribose and nicotinamide) rather than the production of cADPR from ADP-ribosyl cyclase.

Further reading

• Putney JW . 2019 . Calcium Metabolism . Access Science . 10.1036/1097-8542.103100 .
• Hofmann EC, Rapoport S . [DPN- and TPN-specific nucleosidases in erythrocytes] . Biochimica et Biophysica Acta . 18 . 2 . 296 . October 1955 . 13276383 . 10.1016/0006-3002(55)90076-7 .
• Nakazawa K, Ueda K, Honjo T, Yoshihara K, Nishizuka Y, Hayaishi O . Nicotinamide adenine dinucleotide glycohydrolases and poly adenosine diphosphate ribose synthesis in rat liver . Biochemical and Biophysical Research Communications . 32 . 2 . 143–149 . July 1968 . 5672131 . 10.1016/0006-291X(68)90360-4 .
• Ueda K, Fukushima M, Okayama H, Hayaishi O . Nicotinamide adenine dinucleotide glycohydrolase from rat liver nuclei. Isolation and characterization of a new enzyme . The Journal of Biological Chemistry . 250 . 19 . 7541–7546 . October 1975 . 240831 . 10.1016/S0021-9258(19)40852-1 . free .
• Yamamoto-Katayama S, Ariyoshi M, Ishihara K, Hirano T, Jingami H, Morikawa K . Crystallographic studies on human BST-1/CD157 with ADP-ribosyl cyclase and NAD glycohydrolase activities . Journal of Molecular Biology . 316 . 3 . 711–723 . February 2002 . 11866528 . 10.1006/jmbi.2001.5386 .
• Mosca M, Bernardor J, Lemoine S, Bertholet-Thomas A, Bacchetta J . Rare diseases of phosphate and calcium metabolism: Crossing glances between nephrology and endocrinology . Annales d'Endocrinologie . 82 . 1 . 30–35 . February 2021 . 33316222 . 10.1016/j.ando.2020.12.005 . 229174185 .

Notes and References

1. Web site: ENZYME - 3.2.2.5 NAD(+) glycohydrolase . 2022-07-11 . enzyme.expasy.org.
2. Web site: ENZYME - 3.2.2.6 ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase . 2022-07-11 . enzyme.expasy.org.
3. Fang J, Chen W, Hou P, Liu Z, Zuo M, Liu S, Feng C, Han Y, Li P, Shi Y, Shao C . NAD⁺ metabolism-based immunoregulation and therapeutic potential . Cell & Bioscience . 13 . 1 . 81 . May 2023 . 37165408 . 10171153 . 10.1186/s13578-023-01031-5 . free .
4. Lee HC, Deng QW, Zhao YJ . The calcium signaling enzyme CD38 - a paradigm for membrane topology defining distinct protein functions . Cell Calcium . 101 . 102514 . January 2022 . 34896700 . 10.1016/j.ceca.2021.102514 .
5. Chini EN . CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions . Current Pharmaceutical Design . 2009 . 15 . 1 . 57–63 . 19149603 . 10.2174/138161209787185788 . 2883294 .