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Catalytic Site Atlas Version 2.2.12
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CSA entry for 1e7q
Original Entry
Title:
Epimerase/reductase
Compound:
Gdp-fucose synthetase
Mutant:
Yes
UniProt/Swiss-Prot:
P32055-FCL_ECOLI
EC Class:
1.1.1.271
Other CSA Entries:
Overview of all sites for 1e7q
Homologues of 1e7q
Entries for UniProt/Swiss-Prot: P32055
Entries for EC: 1.1.1.271
Other Databases:
PDB entry: 1e7q
PDBsum entry: 1e7q
UniProt/Swiss-Prot: P32055
IntEnz entry: 1.1.1.271
Literature Report:
Introduction:
GDP-4-keto-6-deoxy-D-mannose epimerase/reductase (GMER) is a bifunctional enzyme, catalysing the last 2 steps, epimerisation and reduction, in the biosynthesis of GDP-L-fucose, the substrate of fucosyl transferases.

In bacteria, fucose is a component of the capsular polysaccharides and lipopolysaccharides which function as antigenic determinants. In human, fucose is a Lewis system antigen. It is a ligand to selectin and is involved in leukocytes and tumour cell adhesion to the endothelium. Human deficient in the biosynthesis of GDP fucose suffer from immune disorder adhesion deficiency type II, which cna lead to serious symptoms, for instance, immunodeficiency and psychomotor retardation.
Mechanism:
GDP-4-keto-6-deoxy-D-mannose reductase belongs to the family of short-chain dehydrogenase/reductases (SDRs). It shares the same catalytic triad (Ser, Tyr and Lys) with the other members of the family in reduction of the 4-keto.

Tyr136, with pKa altered by electrostatic effect from Lys140, acts as a general acid to protonate the C4 oxygen in concomitant to hydride transfer to C4 from NADPH. Ser 107 acts as the proton shuttle between the sugar and the phenolic side chain of Tyr 136.
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Found by:
Literature reference 

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
ALAA 107 107Sidechain
ElectrostaticSubstrate
It acts as a proton shuttle between the sugar and the phenolic side chain of Tyr 136.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11021971 Current protein Conservation of residue
PubMed ID 11021971 Current protein Structural similarity to homologue of known mechanism
PubMed ID 11021971 Current protein Mutagenesis of residue

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
TYRA 136 136Sidechain
Acid/baseSubstrate
It acts as a general acid to protonate the C4 oxygen in concomitant to hydride transfer to C4 from NADPH.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11021971 Current protein Conservation of residue
PubMed ID 11021971 Current protein Mutagenesis of residue
PubMed ID 11021971 Current protein Structural similarity to homologue of known mechanism

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
LYSA 140 140Sidechain
ElectrostaticResidue
It lowers the pKa of Tyr 136 by electrostatic effects.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11021971 Current protein Structural similarity to homologue of known mechanism
PubMed ID 11021971 Current protein Mutagenesis of residue
PubMed ID 11021971 Current protein Conservation of residue
PubMed ID 9862812 Current protein Residue is positioned appropriately (ligand position known)

ResidueChainNumberUniProt numberFunctional part FunctionTargetDescription
NAPA1317 0
It transfer a hydrides to sugar C4 to reduce the sugar.
Evidence from paper Evidence concerns Evidence type
PubMed ID 11021971 Current protein Ligand is essential for catalysis
Notes:
The epimerase activity is described in another csa entry under 1e7q.
References:
1
Probing the catalytic mechanism of GDP-4-keto-6-deoxy-d-mannose Epimerase/Reductase by kinetic and crystallographic characterization of site-specific mutants.
C. Rosano and A. Bisso and G. Izzo and M. Tonetti and L. Sturla and A. De Flora and M. Bolognesi
J Mol Biol 303, (1) 77-91, (2000).
11021971
2
GDP-fucose synthetase from Escherichia coli: structure of a unique member of the short-chain dehydrogenase/reductase family that catalyzes two distinct reactions at the same active site.
W. S. Somers and M. L. Stahl and F. X. Sullivan
Structure 6, (12) 1601-12, (1998).
9862812
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