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Search The CSA
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Catalytic Site Atlas

CSA LITERATURE entry for 1r44

E.C. nameD-Ala-D-Ala dipeptidase
SpeciesEnterococcus faecium (Bacteria)
E.C. Number (IntEnz) 3.4.13.22
CSA Homologues of 1r44
CSA Entries With UniProtID Q06241
CSA Entries With EC Number 3.4.13.22
PDBe Entry 1r44
PDBSum Entry 1r44
MACiE Entry 1r44

Literature Report

IntroductionVanXis a Zn(II)-containing metalloenzyme that cleaves D-alanyl-D-alanine dipeptide (D-ala-D-ala), increasing the cytoplasmic pool of free D-ala available for use by VanA to form D-ala-D-lac. The enzyme is stereospecific and is found in solution as a mixture of monomers and dimers. The dipeptidase is a critical component of a system that mediates transposon-based, high-level vancomycin resistance in enterococci.
Vancomycin acts by binding to the terminal D-ala-D-ala moiety of the bacterial peptidoglycan precursor, interfering with growth of the peptidoglycan chain and normal cell wall formation. The substitution of D-ala-D-ala by D-ala-D-lac at the extracellular terminus of the peptidoglycan chain diminishes the affinity of vancomycin by 1000-fold.
MechansimAn incoming peptide displaces a zinc-bound water molecule towards Glu181, giving a six-coordinated metal ion. The nucleophilic hydroxide is generated by zinc and Glu181 from the water molecule, and the nucleophile attacks the polarised carbonyl to form a tetrahedral intermediate. This forms a bidentate complex with the zinc and is stabilised further by interactions with Arg71. It is likely that Glu181 donates a proton to the scissile nitrogen, completing the reaction and yielding D-ala, although it is possible that the source of the proton may be from the nucleophile or another active site residue.
Reaction

Catalytic Sites for 1r44

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluA181181macie:sideChainGlu181 acts as a catalytic base, deprotonating the water molecule to form the nucleophile. The residue is thought to donate a proton to the scissile nitrogen to complete the reaction.
ArgA7171macie:sideChainArg71 is a key residue in stabilising the tetrahedral transition state by formation of a salt link to one of the phosphonate oxygens.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluB181181macie:sideChainGlu181 acts as a catalytic base, deprotonating the water molecule to form the nucleophile. The residue is thought to donate a proton to the scissile nitrogen to complete the reaction.
ArgB7171macie:sideChainArg71 is a key residue in stabilising the tetrahedral transition state by formation of a salt link to one of the phosphonate oxygens.

Annotated By Reference To The Literature - Site 3 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluC181181macie:sideChainGlu181 acts as a catalytic base, deprotonating the water molecule to form the nucleophile. The residue is thought to donate a proton to the scissile nitrogen to complete the reaction.
ArgC7171macie:sideChainArg71 is a key residue in stabilising the tetrahedral transition state by formation of a salt link to one of the phosphonate oxygens.

Annotated By Reference To The Literature - Site 4 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluD181181macie:sideChainGlu181 acts as a catalytic base, deprotonating the water molecule to form the nucleophile. The residue is thought to donate a proton to the scissile nitrogen to complete the reaction.
ArgD7171macie:sideChainArg71 is a key residue in stabilising the tetrahedral transition state by formation of a salt link to one of the phosphonate oxygens.

Annotated By Reference To The Literature - Site 5 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluE181181macie:sideChainGlu181 acts as a catalytic base, deprotonating the water molecule to form the nucleophile. The residue is thought to donate a proton to the scissile nitrogen to complete the reaction.
ArgE7171macie:sideChainArg71 is a key residue in stabilising the tetrahedral transition state by formation of a salt link to one of the phosphonate oxygens.

Annotated By Reference To The Literature - Site 6 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
GluF181181macie:sideChainGlu181 acts as a catalytic base, deprotonating the water molecule to form the nucleophile. The residue is thought to donate a proton to the scissile nitrogen to complete the reaction.
ArgF7171macie:sideChainArg71 is a key residue in stabilising the tetrahedral transition state by formation of a salt link to one of the phosphonate oxygens.

Literature References

Notes:
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