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CSA entry for 1x9h
Original Entry
Title:
Isomerase
Compound:
Glucose-6-phosphate isomerase
Mutant:
No
UniProt/Swiss-Prot:
Q8ZWV0-PGMI_PYRAE
EC Class:
5.3.1.8
5.3.1.9
Other CSA Entries:
Overview of all sites for 1x9h
Homologues of 1x9h
Entries for UniProt/Swiss-Prot: Q8ZWV0
Entries for EC: 5.3.1.8
Entries for EC: 5.3.1.9
Other Databases:
PDB entry: 1x9h
PDBsum entry: 1x9h
UniProt/Swiss-Prot: Q8ZWV0
IntEnz entry: 5.3.1.8
IntEnz entry: 5.3.1.9
Literature Report:
Introduction:
Several aerobic crenarcheaons, including Pyrobaculum aerophilum, contain an isomerase that converts both glucose-6-phosphate and mannose-6-phosphate (G6P and M6P, which are C2 epimers) into fructose-6-phosphate. Most organisms contain only highly specific phosphoglucose and phosphomannose isomerases (PGIs and PMIs), which only accept either glucose or mannose as a substrate.

These dual specificity isomerases share very low sequence identity with 'conventional' PGIs or PMIs, but structure is conserved, especially at the active site, supporting a common mechanism.

Mechanism:
1) Lys 248 is deprotonated in the active site and deprotonates the C1 hydroxyl group. This leads to concomitant ring opening and protonation of the ring oxygen by His 219.

2) Rotation takes place around the C3-C4 bond, and also C2-C3 for the M6P mechanism (this is forbidden in conventional PGIs by a glutamate residue).

3) Glu 203 abstracts the C2 proton, leading to cis-enediolate formation. In the PGI mechanism, this cis-enediolate is stabilised by Arg 135.

4) The C1 enolate oxygen deprotonates the C2 enol. Glu 203 protonates C1, reducing the C1=C2 bond while the C2 hydroxyl is oxidised to a carbonyl.

5) Rotation about the C3-C4 bond occurs.

6) His 219 deprotonates the C5 hydroxyl (formerly the ring oxygen). This is concomitant with the attack of the C5 hydroxyl oxygen on the new C2 carbonyl, which is protonated by Lys 248 (ring closure).

7) The product is fructose-6-phosphate.

Sites:

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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ARGA 135 135Sidechain
ElectrostaticSubstrate
ElectrostaticTransition state
In the PGI mechanism, Arg 135 stabilises the charge on the enediolate and the transition states leading to and from the intermediate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 15518558 Current protein Structural similarity to homologue of known mechanism
PubMed ID 15518558 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
GLUA 203 203Sidechain
Acid/baseSubstrate
Glu 203 abstracts the C2 proton, which leads to enolisation to give a enediolate. After bond rotation, Glu 203 then returns the proton to the other side of the enediolate.
Evidence from paper Evidence concerns Evidence type
PubMed ID 15518558 Current protein Residue is positioned appropriately (ligand position known)
PubMed ID 15518558 Current protein Structural similarity to homologue of known mechanism

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
HISA 219 219Sidechain
Acid/baseSubstrate
His 219 protonates the ring oxygen in the first, ring opening, step in the mechanism. His 219 later abstracts the same proton in the last, ring closing, step.
Evidence from paper Evidence concerns Evidence type
PubMed ID 15518558 Current protein Structural similarity to homologue of known mechanism
PubMed ID 15518558 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
LYSA 298 298Sidechain
Acid/baseSubstrate
Lys 298 deprotonates the C2 hydroxyl group in the first, ring opening, step in the mechanism. The proton is later redonated to the C2 carbonyl in the last, ring closing, step.
Evidence from paper Evidence concerns Evidence type
PubMed ID 15518558 Current protein Structural similarity to homologue of known mechanism
PubMed ID 15518558 Current protein Residue is positioned appropriately (ligand position known)
Notes:

References:
1
Structural basis for phosphomannose isomerase activity in phosphoglucose isomerase from Pyrobaculum aerophilum: a subtle difference between distantly related enzymes.
M. K. Swan and T. Hansen and P. Schönheit and C. Davies
Biochemistry 43, (44) 14088-95, (2004).
15518558
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