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Catalytic Site Atlas

CSA LITERATURE entry for 1a4i

E.C. namemethylenetetrahydrofolate dehydrogenase (NADP+)
SpeciesHomo sapiens (Human)
E.C. Number (IntEnz) 1.5.1.5
CSA Homologues of 1a4iThere are 10 Homologs
CSA Entries With UniProtID P11586
CSA Entries With EC Number 1.5.1.5
PDBe Entry 1a4i
PDBSum Entry 1a4i
MACiE Entry 1a4i

Literature Report

IntroductionEnzymes involved in tetrahydrofolate metabolism are of particular pharmaceutical interest, as their function is crucial for amino acid and DNA biosynthesis. This particular enzyme is trifunctional, but the structure for this entry contains only the dehydrogenase (D) and cyclohydrolase (C) domains, which have an overlapping active site (as determined by chemical modification and kinetic studies). In the complete enzyme there is also a tetrahydrofolate synthetase domain.
MechansimDehydrogenase: 5,10-methylene-tetrahydrofolate is converted to 5,10-methenyltetrahydrofolate. The mechanism involves hydride transfer from the substrate to NADP+.
Cyclohydrase: A water molecule, positioned by Gln100 and activated by Lys56, attacks the substrate. It is then deprotonated by Lys56, which transfers the proton to elsewhere on the substrate. Lys56 then deprotonates the newly formed alcohol group on the intermediate, causing it to be reduced to a ketone and break open one of the rings in the substrate. Lys56 is restored to its original state by protonating a water molecule.
Reaction

Catalytic Sites for 1a4i

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysA5656macie:sideChainD: Activates substrate for its internal reaction. C: General base.
GlnA100100macie:sideChainLowers pKa of Lys56.

Literature References

Notes:
Schmidt A
Structures of three inhibitor complexes provide insight into the reaction mechanism of the human methylenetetrahydrofolate dehydrogenase/cyclohydrolase.
Biochemistry 2000 39 6325-6335
PubMed: 10828945
Allaire M
The 3-D structure of a folate-dependent dehydrogenase/cyclohydrolase bifunctional enzyme at 1.5 A resolution.
Structure 1998 6 173-182
PubMed: 9519408
Sundararajan S
Residues involved in the mechanism of the bifunctional methylenetetrahydrofolate dehydrogenase-cyclohydrolase: the roles of glutamine 100 and aspartate 125.
J Biol Chem 2002 277 18703-18709
PubMed: 11904299
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