ADP-ribosyl cyclase

 

ADP-ribosyl cyclase catalyses the elimination of nicotinamide from NAD and cyclisation of cADPR. It has been identified in many organisms from microbes to mammals. The product from this enzyme, cADPR, is a second messenger in cellular calcium signalling pathways and it regulates the concentration of calcium ions in a variety of mammalian and non-mammalian cell types.

 

Reference Protein and Structure

Sequence
P29241 UniProt (2.4.99.20, 3.2.2.6) IPR003193 (Sequence Homologues) (PDB Homologues)
Biological species
Aplysia californica (California sea hare) Uniprot
PDB
1r16 - Aplysia ADP ribosyl cyclase with bound pyridylcarbinol and R5P (2.0 Å) PDBe PDBsum 1r16
Catalytic CATH Domains
3.40.50.720 CATHdb (see all for 1r16)
Click To Show Structure

Enzyme Reaction (EC:3.2.2.6)

water
CHEBI:15377ChEBI
+
NAD(1-)
CHEBI:57540ChEBI
→
hydron
CHEBI:15378ChEBI
+
nicotinamide
CHEBI:17154ChEBI
+
cyclic ADP-ribose(2-)
CHEBI:73672ChEBI
Alternative enzyme names: NAD(+) nucleosidase, NADase, DPNase, DPN hydrolase, NAD hydrolase, Nicotinamide adenine dinucleotide nucleosidase, NAD glycohydrolase, NAD nucleosidase, Nicotinamide adenine dinucleotide glycohydrolase, CD38 (gene name), BST1 (gene name),

Enzyme Mechanism

Introduction

Glu203 nucleophilically attacks the ribose C1' which nicotinamide attached to. The nucleophilic attack eliminates the nicotinamide and leads to the formation of a Glu179-R5P intermediate. N1 of purine group then acts as a nucleophile to attack the ester bond between Glu203 and ribose, resulting in cyclisation to form cADPR. Glu122 provides stabilisation of hydrolysis at ribose C1' by Glu203.

Catalytic Residues Roles

UniProt PDB* (1r16)
Phe198 Phe174A Stabilises adenine folding back on itself with hydrophobic interactions to help position N1 to nucleophilically attack the ribosyl end of the intermediate to form cyclic ADP-ribose. hydrophobic interaction
Glu203 Glu179A A nucleophile that attacks the ribose C1' to eliminate nicotinamide and form a covalent intermediate. covalent catalysis, covalently attached, nucleophile
Glu122 Glu98A Stabilise the hydrolysis reaction at ribose C1' by Glu 203. electrostatic stabiliser
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

bimolecular nucleophilic substitution, intramolecular nucleophilic substitution

References

  1. Love ML et al. (2004), Structure, 12, 477-486. ADP-Ribosyl Cyclase. DOI:10.1016/j.str.2004.02.006. PMID:15016363.
  2. Graeff R et al. (2009), J Biol Chem, 284, 27629-27636. Mechanism of cyclizing NAD to cyclic ADP-ribose by ADP-ribosyl cyclase and CD38. DOI:10.1074/jbc.M109.030965. PMID:19640843.
  3. Munshi C et al. (1999), J Biol Chem, 274, 30770-30777. Characterization of the Active Site of ADP-ribosyl Cyclase. DOI:10.1074/jbc.274.43.30770. PMID:10521467.

Step 1.

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Catalytic Residues Roles

Residue Roles
Phe174A hydrophobic interaction
Glu179A nucleophile
Glu98A electrostatic stabiliser
Glu179A covalent catalysis, covalently attached

Chemical Components

ingold: bimolecular nucleophilic substitution, ingold: intramolecular nucleophilic substitution

Step 1.

Contributors

Mei Leung, Gemma L. Holliday, Morwenna Hall