NAD+---protein-arginine ADP-ribosyltransferase

 

Mono-ADP-ribosylation is a post-translational modification of proteins in which the ADP-ribose moiety of NAD is transferred to proteins. This process is responsible for the toxicity of some bacterial toxins (e.g., cholera and pertussis toxins). Arginine residues in proteins act as acceptors. Free arginine, agmatine [(4-aminobutyl)guanidine], arginine methyl ester and guanidine can also be active. The enzyme from some, but not all, species can also use NADP+ as acceptor (giving rise to Nomega-[(2'-phospho-ADP)-D-ribosyl]-protein-L-arginine as the product), but more slowly.

 

Reference Protein and Structure

Sequence
P20974 UniProt (2.4.2.31, 3.2.2.5) IPR000768 (Sequence Homologues) (PDB Homologues)
Biological species
Rattus norvegicus (Norway rat) Uniprot
PDB
1og1 - CRYSTAL STRUCTURE OF THE EUCARYOTIC MONO-ADP-RIBOSYLTRANSFERASE ART2.2 IN COMPLEX WITH TAD (2.0 Å) PDBe PDBsum 1og1
Catalytic CATH Domains
3.90.176.10 CATHdb (see all for 1og1)
Click To Show Structure

Enzyme Reaction (EC:2.4.2.31)

L-argininium residue
CHEBI:29965ChEBI
+
NAD(1-)
CHEBI:57540ChEBI
→
hydron
CHEBI:15378ChEBI
+
nicotinamide
CHEBI:17154ChEBI
+
N(omega)-alpha-(ADP-D-ribosyl)-L-arginine(1-) residue
CHEBI:83960ChEBI
Alternative enzyme names: ADP-ribosyltransferase, NAD(P)(+)-arginine ADP-ribosyltransferase, Mono(ADP-ribosyl)transferase, NAD(+):L-arginine ADP-D-ribosyltransferase, NAD(P)(+):L-arginine ADP-D-ribosyltransferase, NAD(P)(+)--arginine ADP-ribosyltransferase, Mono-ADP-ribosyltransferase, ART, ART1, ART2, ART3, ART4, ART5, ART6, ART7, NAD(P)(+)--protein-arginine ADP-ribosyltransferase, NAD(P)(+):protein-L-arginine ADP-D-ribosyltransferase,

Enzyme Mechanism

Introduction

The enzyme catalyses the transfer of the ADP-ribosyl moiety of NAD+ onto a nucleophile, which can be a water molecule (NAD+ hydrolysis) or any other nucleophilic group. The nucleophile may release a proton to be picked up by a base. Nicotinamide is an excellent leaving group whereas NADH is not a substrate.

Catalytic Residues Roles

UniProt PDB* (1og1)
Glu179 Glu159A Acts as a general acid/base. proton shuttle (general acid/base)
Arg204 Arg184A This is the substrate protein argenine that is adenylated and acts as a nucleophile. covalent catalysis, proton shuttle (general acid/base)
Ser167, Glu209 Ser147A, Glu189A Help stabilise the reactive intermediates and transition states formed during the course of the reaction. 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

References

  1. Ritter H et al. (2003), Biochemistry, 42, 10155-10162. Substrate Binding and Catalysis of Ecto-ADP-ribosyltransferase 2.2 from Rat†. DOI:10.1021/bi034625w. PMID:12939142.
  2. Holbourn KP et al. (2006), FEBS J, 273, 4579-4593. A family of killer toxins. Exploring the mechanism of ADP-ribosylating toxins. DOI:10.1111/j.1742-4658.2006.05442.x. PMID:16956368.
  3. Mueller-Dieckmann C et al. (2002), J Mol Biol, 322, 687-696. Structure of the ecto-ADP-ribosyl transferase ART2.2 from rat. PMID:12270706.

Step 1.

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Catalytic Residues Roles

Residue Roles
Glu159A proton shuttle (general acid/base)
Arg184A covalent catalysis, proton shuttle (general acid/base)
Ser147A electrostatic stabiliser
Glu189A electrostatic stabiliser

Chemical Components

Step 1.

Contributors

Alex Gutteridge, Craig Porter, Gemma L. Holliday