GMP reductase

 

Guanosine monophosphate reductase (GMPR) is crucial for catalysis of the irreversible GMP deamination to IMP with the use of NADPH. It converts nucleobase, nucleoside and nucleotide derivatives of G to A nucleotides, and thus maintains the intracellular balance of A and G nucleotides. GMP is a homotetramer with mixed alpha helices and beta sheets.The monomers are stabilised by interactions across their edges and through Cys-Cys bonds. GMPR1 inhibitors are tested for applications is treating Alzheimer's disease and the increase of GMPR expression is linked to suppression of melanoma cancers.

 

Reference Protein and Structure

Sequence
P36959 UniProt (1.7.1.7) IPR005993 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
2ble - Structure of human guanosine monophosphate reductase GMPR1 in complex with GMP (1.9 Å) PDBe PDBsum 2ble
Catalytic CATH Domains
3.20.20.70 CATHdb (see all for 2ble)
Click To Show Structure

Enzyme Reaction (EC:1.7.1.7)

guanosine 5'-monophosphate(2-)
CHEBI:58115ChEBI
+
hydron
CHEBI:15378ChEBI
+
NADPH(4-)
CHEBI:57783ChEBI
→
IMP(2-)
CHEBI:58053ChEBI
+
NADP(3-)
CHEBI:58349ChEBI
+
ammonium
CHEBI:28938ChEBI
Alternative enzyme names: NADPH:GMP oxidoreductase (deaminating), NADPH(2):guanosine-5'-phosphate oxidoreductase (deaminating), Guanosine 5'-monophosphate reductase, Guanosine 5'-phosphate reductase, Guanosine monophosphate reductase, Guanylate reductase, NADPH:guanosine-5'-phosphate oxidoreductase (deaminating), Guanosine 5'-monophosphate oxidoreductase,

Enzyme Mechanism

Introduction

The reaction is two step process. The Thr188 and Glu289 dyad activate the amino group by donating a proton to it. In concert Cys186 performs a nucleophilic attack on the C2 atom of GMP resulting in the formation of a C-S bond between the enzyme and substrate. This C-S bond is then cleaved by the addition of a hydride from NADPH to the C2 atom of the substrate.

Catalytic Residues Roles

UniProt PDB* (2ble)
Cys186 Cys186(208)A Cys186 acts as a nucleophile attacking the C2 atom of GMP. nucleofuge, nucleophile
Thr188, Glu289 Thr188(210)A, Glu289(311)A The Thr188/Glu289 dyad act as proton donors and activators for the reaction by protonating the amino group on the substrate. This activates the amino group and initiates the reaction with Cys186. proton relay, proton acceptor, proton donor
*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, proton transfer, enzyme-substrate complex formation, hydride transfer, intramolecular rearrangement, enzyme-substrate complex cleavage, overall product formed

References

  1. Patton GC et al. (2011), Nat Chem Biol, 7, 950-958. Cofactor mobility determines reaction outcome in the IMPDH and GMPR (β-α)8 barrel enzymes. DOI:10.1038/nchembio.693. PMID:22037469.
  2. Rosenberg MM et al. (2018), Biochemistry, 57, 3146-3154. Dynamic Characteristics of Guanosine-5'-monophosphate Reductase Complexes Revealed by High-Resolution 31P Field-Cycling NMR Relaxometry. DOI:10.1021/acs.biochem.8b00142. PMID:29547266.
  3. Rosenberg MM et al. (2016), J Biol Chem, 291, 22988-22998. Substrate and Cofactor Dynamics on Guanosine Monophosphate Reductase Probed by High Resolution Field Cycling 31P NMR Relaxometry. DOI:10.1074/jbc.M116.739516. PMID:27613871.
  4. Li J et al. (2006), J Mol Biol, 355, 980-988. Crystal structure of human guanosine monophosphate reductase 2 (GMPR2) in complex with GMP. DOI:10.1016/j.jmb.2005.11.047. PMID:16359702.

Step 1. Cys186 performs a nucleophilic attack on C2 of the GMP. In concert Thr188 acts as a proton relay between Glu289 and the leaving amino group.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Cys186(208)A nucleophile
Thr188(210)A proton donor
Glu289(311)A proton donor
Thr188(210)A proton relay, proton acceptor

Chemical Components

ingold: bimolecular nucleophilic substitution, proton transfer, enzyme-substrate complex formation

Step 2. NADPH then donates a hydride to the C2 atom of GMP. This breaks the C-S bond formed by Cys186.

Download: Image, Marvin File

Catalytic Residues Roles

Residue Roles
Cys186(208)A nucleofuge

Chemical Components

hydride transfer, intramolecular rearrangement, enzyme-substrate complex cleavage, overall product formed
Download: Image, Marvin File

Step 1. Cys186 performs a nucleophilic attack on C2 of the GMP. In concert Thr188 acts as a proton relay between Glu289 and the leaving amino group.

Step 2. NADPH then donates a hydride to the C2 atom of GMP. This breaks the C-S bond formed by Cys186.

Products.

Contributors

Marko Babić, Antonio Ribeiro