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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1pd2
Original Entry
Title:
Ligase
Compound:
Hematopoietic prostagladin d synthase
Mutant:
No
UniProt/Swiss-Prot:
O35543-PGD_RAT
EC Class:
5.3.99.2
Other CSA Entries:
Overview of all sites for 1pd2
Homologues of 1pd2
Entries for UniProt/Swiss-Prot: O35543
Entries for EC: 5.3.99.2
Other Databases:
PDB entry: 1pd2
PDBsum entry: 1pd2
UniProt/Swiss-Prot: O35543
IntEnz entry: 5.3.99.2
Literature Report:
Introduction:
Hematopoietic prostaglandin-D synthase (H-PGDS) is a homodimer in an asymmetric unit. Each monomer is complexed with one glutathione (GTT or GSH) molecule. H-PGDS is one of two types of prostaglandin-D synthase (PGDS) that catalyses the isomerisation of PGH2 to PGD2. PGD2 is a lipid mediator produced by a variety of cells of the immune system, including Th2 and mast cells, that accelerates allergic and inflammatory responses, regulates body temperature, inhibits platelet aggregation, promotes sleep and numerous other physiological functions. H-PGDS is also a member of the glutathione S-transferase (GST) gene family, a group of enzymes that catalyse the conjugation of GSH to an electrophilic substrate.
Mechanism:

Bound GSH is deprotonated by the formation of a hydrogen bond of gamma-S (of GSH) to O atom of Tyr8. Isomerization is initiated when PGH2 binds to the cleft in H-PGDS (formed by 3 active site pockets), the thiolic anion of the (bound) deprotonated GSH performs nucleophilic attack on the C-11 oxygen of PGH2. Successive base attack on C-11 hydrogen by a deprotonated GSH found free in solution (GS-) causes O-S bond cleavage, forming C-11 carbonyl in a concerted, sterically-restricted manner. Hydrogen transfer to C-9 hydroxyanion from GSH results in the completion of PGD2 formation and in the recycling of GSH.
The presence of Mg2+ can increase the affinity of H-PGDS for GSH and cause a four-fold decrease of the Km.
Sites:

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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
TYR1 8 8Sidechain
ElectrostaticCofactor
Essential for GSH thiol activation for nucleophilic attack on PGH2 peroxide. H-bonding of (bound) GSH S atom to Tyr8 O atom considered to decrease pKa of thiol group resulting in deprotonated S- anion at neutral pH.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10871602 Current protein Kinetic studies
PubMed ID 10871602 Current protein Mutagenesis of residue
PubMed ID 12895599 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ARG1 14 14Sidechain
ElectrostaticSubstrate
ElectrostaticCofactor
Assists GSH activation for nucleophilic attack by forming salt bridge with alpha-glutamyl carboxyanion of (bound) GSH, neutralising negative charge and maintaining active configuration of GSH. Also facilitates PGH2 binding by H-bonding to the omega chain at C-15 of PGH2.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10871602 Current protein Ligand is essential for catalysis
PubMed ID 10871602 Current protein Mutagenesis of residue
PubMed ID 12895599 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 10871602 Current protein Kinetic studies

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
TRP1 104 104Sidechain
ElectrostaticSubstrate
The indole ring forms van der Waals interactions with hydrophobic PGH2 substrate for binding. Trp104 is important in the structural integrity of the catalytic site by creating the 'kinked' backbone responsible for the formation of the deep and wide pocket for the substrate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 10871602 Current protein Ligand is essential for catalysis
PubMed ID 10871602 Current protein Kinetic studies
PubMed ID 12895599 Current protein Residue is positioned appropriately (ligand position known)
Notes:

References:
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