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Catalytic Site Atlas

CSA LITERATURE entry for 1xa8

E.C. nameS-(hydroxymethyl)glutathione synthase
SpeciesParacoccus denitrificans (Bacteria)
E.C. Number (IntEnz) 4.4.1.22
CSA Homologues of 1xa8
CSA Entries With UniProtID Q51669
CSA Entries With EC Number 4.4.1.22
PDBe Entry 1xa8
PDBSum Entry 1xa8
MACiE Entry 1xa8

Literature Report

IntroductionGlutathione-dependent formaldehyde-activating enzyme (Gfa) is a carbon-sulphur lyase enzyme that catalyses the first step of a pathway that metabolises toxic formaldehyde to yield formate as a product. Gfa catalyses the condensation of formaledhyde and glutathione to form an adduct, S-hydroxymethylglutathione.
MechansimCatalysis uses a zinc redox switch mechanism, in which a zinc molecule moves in a ping-pong fashion between its coordination state and its dislocated state. Formation of a disulphide bond between a glutathione molecule in its oxidised form (GSSG) and a zinc-coordinating thiol (Cys56) releases zinc into its dislocated state. In its dislocated state, zinc exerts its actual catalytic function by activating the coordinated formaldehyde and glutathione (GSH) for nucleophilic addition.
The proposed mechanism involves the GSSG reacting with Cys56, resulting in the formation of a disulphide-bonded Gfa-glutathione intermediate and the displacement of zinc. The zinc-glutathione complex acts as a formaldehyde scavenger.
In this complex, the carbonyl bond of the formaldehyde and the sulfinyl bond of GSH are polarised by zinc and activated for the final nucleophilic addition to form S-hydroxymethylglutathione, relocate zinc into the catalytic site and regenerate GSSG.
Reaction

Catalytic Sites for 1xa8

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
CysA5654macie:sideChainCys 56 forms a ligand interaction with zinc and also forms a disulphide bridge with GSSG, which is important in the displacement of zinc forming a highly dynamic zinc redox switch which is crucial for the reaction. Sulphur ligands, such as Cys56, are needed to create an oxidoreductive environment in which the ligands (not the metal) are oxidised and reduced with concomitant release and binding of zinc.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
CysB5654macie:sideChainCys 56 forms a ligand interaction with zinc and also forms a disulphide bridge with GSSG, which is important in the displacement of zinc forming a highly dynamic zinc redox switch which is crucial for the reaction. Sulphur ligands, such as Cys56, are needed to create an oxidoreductive environment in which the ligands (not the metal) are oxidised and reduced with concomitant release and binding of zinc.

Annotated By Reference To The Literature - Site 3 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
CysC5654macie:sideChainCys 56 forms a ligand interaction with zinc and also forms a disulphide bridge with GSSG, which is important in the displacement of zinc forming a highly dynamic zinc redox switch which is crucial for the reaction. Sulphur ligands, such as Cys56, are needed to create an oxidoreductive environment in which the ligands (not the metal) are oxidised and reduced with concomitant release and binding of zinc.

Annotated By Reference To The Literature - Site 4 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
CysD5654macie:sideChainCys 56 forms a ligand interaction with zinc and also forms a disulphide bridge with GSSG, which is important in the displacement of zinc forming a highly dynamic zinc redox switch which is crucial for the reaction. Sulphur ligands, such as Cys56, are needed to create an oxidoreductive environment in which the ligands (not the metal) are oxidised and reduced with concomitant release and binding of zinc.

Literature References

Notes:
Neculai AM
A dynamic zinc redox switch.
J Biol Chem 2005 280 2826-2830
PubMed: 15548539
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