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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1g0d
Original Entry
Title:
Transferase
Compound:
Protein-glutamine gamma-glutamyltransferase
Mutant:
No
UniProt/Swiss-Prot:
P52181-TGLC_PAGMA
EC Class:
2.3.2.13
Other CSA Entries:
Overview of all sites for 1g0d
Homologues of 1g0d
Entries for UniProt/Swiss-Prot: P52181
Entries for EC: 2.3.2.13
Other Databases:
PDB entry: 1g0d
PDBsum entry: 1g0d
UniProt/Swiss-Prot: P52181
IntEnz entry: 2.3.2.13
Literature Report:
Introduction:
Fish transglutaminase is able to catalyse the Ca2+ dependent acyl transfer between glutamine and the side chain amino group of lysine. It is unknown what the biological function of this is in fish, but the human homologue is blood clotting factor XIII which forms cross-links between these two residues in fibrin, thus plays a key role in the clotting cascade. The activation of the clotting factor is a subject of study in the hope of designing inhibitors which could be of pharmacological importance.
Mechanism:
The reaction proceeds in a manner analogous to a cysteine protease: the catalytic Cys 272 acts as the initial nucleophile to attack the carbonyl of the glutamine side chain, resulting in a tetrahedral intermediate. Protonation of the leaving group by His 332, assisted by Asp 355 allows the collapse of this tetrahedral intermediate to form a thiolacyl enzyme intermediate. This intermediate is protected by a Tyr 560 residue in the active form so that Cys 333 cannot form a disulphide to Cys 272 as would otherwise happen. Subsequent nucleophilic attack on the intermediate from a Lysine, activated by deprotonation by His 332, leads to the formation of the product and the release of the Cysteine residue.
Sites:

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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
CYSA 272 272Sidechain, Backbone amide
NucleophileSubstrate
Acts as the nucleophile to attack the substrate forming the oxyanion intermediate which collapses to form the thioacyl enzyme intermediate. This in turn breaks down to release the Cysteine, through attack of a Lysine residue from the substrate, forming a crosslinkage.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11080504 Current protein Structural similarity to homologue of known mechanism
PubMed ID 11080504 Current protein Residue is covalently bound to intermediate, based on structural data

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 332 332Sidechain
Acid/baseSubstrate
Protonates the leaving group to allow collapse of the tetrahedral intermediate. Then deprotonates the lysine residue from the protein to allow it to act as a nucleophile to break down the covalent intermediate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11080504 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 11080504 Current protein Structural similarity to homologue of known mechanism

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ASPA 355 355Sidechain
ElectrostaticResidue
Forms the third part of the catalytic triad, thus alters the pKa of His 332 so that it can act as an acid-base.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11080504 Current protein Structural similarity to homologue of known mechanism

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
TYRA 515 515Sidechain
ElectrostaticTransition state
ElectrostaticResidue
In the active form, Ca2+ causes Tyr 515 to move so that it prevents Cys 333 from forming a disulphide to the nucleophilic Cys 272; thus can be described as stabilising the thioacyl enzyme intermediate or as activating Cys 272.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11080504 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 11080504 Current protein Conservation of residue
References:
1
Crystal structure of red sea bream transglutaminase.
K. Noguchi and K. Ishikawa and Yokoyama Ki and T. Ohtsuka and N. Nio and E. Suzuki
J Biol Chem 276, (15) 12055-9, (2001).
11080504
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