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Catalytic Site Atlas

CSA LITERATURE entry for 1pae

E.C. namenucleoside-diphosphate kinase
SpeciesDictyostelium discoideum (Slime mould)
E.C. Number (IntEnz) 2.7.4.6
CSA Homologues of 1paeThere are 90 Homologs
CSA Entries With UniProtID P22887
CSA Entries With EC Number 2.7.4.6
PDBe Entry 1pae
PDBSum Entry 1pae
MACiE Entry M0150

Literature Report

IntroductionNucleoside diphosphate kinase (NDPK) catalyses the phosphorylation of nucleoside diphosphates into triphosphates. The phosphate donor is usually ATP, but the diphosphate nucleotide substrate is non-specific for either base or ribose / deoxyribose. NDPK from Dictyostelium discoideum is used as a model because it is particularly easy to crystallise.
MechansimNDPK operates using a 'ping-pong' mechanism. The gamma-phosphate of ATP is transferred to the delta-N atom of the doubly protonated His 122 of NDPK, with the delta-N proton concomitantly transferred to the gamma-phosphate.
A nucleoside diphosphate binds in the active site. The phosphate group is transferred from His 122-P to the 5' hydroxyl of the ribose.
Both phosphoryl transfers are dissociative SN2-like reactions, similar to the uncatalysed reaction.
Tyr 56 stabilises the phosphohistidine intermediate by hydrogen bonding to phosphohistidine.
Lys 16 stabilises the gamma-phosphate through hydrogen bonding, lowering the transition state energy. Lys 16 also keeps Tyr 56 in the protonated state.
The 3' ribose / deoxyribose hydroxyl group is more catalytically important than Tyr 56 or Lys 16; in the first transfer to His 122, it hydrogen bonds to the gamma-phosphate group, forcing the substrate into a reactive conformation and stabilising the negative charge by hydrogen bonding. The enzymatic reaction can therefore be described as substrate-assisted.
Reaction

Catalytic Sites for 1pae

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrX5656macie:sideChainTyr 56 stabilises the phosphohistidine intermediate by hydrogen bonding to phosphohistidine.
LysX1616macie:sideChainLys 16 stabilises the negative charge on the phosphoryl group, lowering the transition state energy. Lys 16 also plays a role in keeping Tyr 56 protonated.

Literature References

Notes:
Schneider B
Mechanism of phosphoryl transfer by nucleoside diphosphate kinase pH dependence and role of the active site Lys16 and Tyr56 residues.
Eur J Biochem 2001 268 1964-1971
PubMed: 11277918
Hutter MC
The mechanism of phosphorylation of natural nucleosides and anti-HIV analogues by nucleoside diphosphate kinase is independent of their sugar substituents.
Chembiochem 2002 3 643-651
PubMed: 12324998
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