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Catalytic Site Atlas

CSA LITERATURE entry for 1z9h

E.C. nameprostaglandin-E synthase
SpeciesMacaca fascicularis (Crab-eating macaque)
E.C. Number (IntEnz) 5.3.99.3
CSA Homologues of 1z9h
CSA Entries With UniProtID Q9N0A4
CSA Entries With EC Number 5.3.99.3
PDBe Entry 1z9h
PDBSum Entry 1z9h
MACiE Entry M0192

Literature Report

IntroductionMicrosomal Prostaglandin E Synthase Type 2 (mPGES-2), sourced from Macaca fascicularis catalyses the isomerization reaction of PGH2 (Prostaglandin H2) to PGE2 (Prostaglandin E2). PGH2 is formed from arachidonic acid. It is an unstable intermediate and so is converted into PGE2. PGE2 exerts control over various biological activities such as relaxation/ contraction of smooth muscle, excretion of Na+, body temperature and the physiological sleep/ wake cycle.
Mechansim1. The pKa of Cys 110 is lowered by hydrogen bonds from Phe 112 and Cys 113. Cys 110 protonates O11 of PGH2, causing O11 to become positively charged. The deprotonated Cys 110 residue then nucleophilically attacks the O9 of PGH2. This results in formation of a covalent O9-gamma S bond between PGH2 and Cys 110 and breaking of the O9-O11 bond. 2. Water is polarised through hydrogen bonding to Tyr 107. The water molecule then acts as a base to abstract the hydrogen atom attached to C9. This causes elimination of Cys 110. The C9=O9 carbonyl group forms and the O9-gamma S bond is broken.
Reaction

Catalytic Sites for 1z9h

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrA107107macie:sideChainTyr 107 polarises a water molecule through hydrogen bonding, causing it to become basic.
CysA113113macie:sideChainLowers pKa of Cys 110, allowing it to act as a proton donor and then a nucleophile.
PheA112112macie:mainChainAmideLowers pKa of Cys 110, allowing it to act as a proton donor and then a nucleophile.
CysA110110macie:sideChainCys 110 protonates O11 of PGH2, causing O11 to become positive. The deprotonated Cys 110 residue then nucleophilically attacks the O9 of PGH2.

Annotated By Reference To The Literature - Site 2 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrB107107macie:sideChainTyr 107 polarises a water molecule through hydrogen bonding, causing it to become basic.
CysB113113macie:sideChainLowers pKa of Cys 110, allowing it to act as a proton donor and then a nucleophile.
PheB112112macie:mainChainAmideLowers pKa of Cys 110, allowing it to act as a proton donor and then a nucleophile.
CysB110110macie:sideChainCys 110 protonates O11 of PGH2, causing O11 to become positive. The deprotonated Cys 110 residue then nucleophilically attacks the O9 of PGH2.

Annotated By Reference To The Literature - Site 3 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrC107107macie:sideChainTyr 107 polarises a water molecule through hydrogen bonding, causing it to become basic.
CysC113113macie:sideChainLowers pKa of Cys 110, allowing it to act as a proton donor and then a nucleophile.
PheC112112macie:mainChainAmideLowers pKa of Cys 110, allowing it to act as a proton donor and then a nucleophile.
CysC110110macie:sideChainCys 110 protonates O11 of PGH2, causing O11 to become positive. The deprotonated Cys 110 residue then nucleophilically attacks the O9 of PGH2.

Annotated By Reference To The Literature - Site 4 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
TyrD107107macie:sideChainTyr 107 polarises a water molecule through hydrogen bonding, causing it to become basic.
CysD113113macie:sideChainLowers pKa of Cys 110, allowing it to act as a proton donor and then a nucleophile.
PheD112112macie:mainChainAmideLowers pKa of Cys 110, allowing it to act as a proton donor and then a nucleophile.
CysD110110macie:sideChainCys 110 protonates O11 of PGH2, causing O11 to become positive. The deprotonated Cys 110 residue then nucleophilically attacks the O9 of PGH2.

Literature References

Notes:Upon addition of an R-SH reagent to mPGES-2, the catalytic activity is increased two -four fold. An alternative catalytic mechanism is also described in the paper, based upon different assumptions.
Yamada T
Crystal structure and possible catalytic mechanism of microsomal prostaglandin E synthase type 2 (mPGES-2).
J Mol Biol 2005 348 1163-1176
PubMed: 15854652
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