spacer
View the latest EBI news stories and important announcements...
more

spacer
Search The CSA
PDB ID
UNIPROT ID
EC Number

Catalytic Site Atlas

CSA LITERATURE entry for 1dhp

E.C. namedihydrodipicolinate synthase
SpeciesEscherichia coli (Bacteria)
E.C. Number (IntEnz) 4.2.1.52
CSA Homologues of 1dhpThere are 43 Homologs
CSA Entries With UniProtID P0A6L2
CSA Entries With EC Number 4.2.1.52
PDBe Entry 1dhp
PDBSum Entry 1dhp
MACiE Entry M0267

Literature Report

IntroductionDihydrodipicolinate synthase (DHDPS) catalyses the aldol-like condensation of pyruvate and L-aspartate beta semi-aldehyde (S-ASA). It is an enzyme involved in the lysine biosynthetic pathway of procaryotes, some Phycomycetes and higher plants. Since this pathway is not present in animals, pathway members such as DHDPS have become attractive targets for rational antibiotic and herbicide drug design.
MechansimIn the first step, the E-amino group of the active site Lys161 acts as a nucleophile towards the keto group of pyruvate, forming an internal Schiff base adduct. Tyr133 is aligned to form a hydrogen bond with the keto oxygen of pyruvate which accelerates the dehydration of the tetrahedral intermediate during Schiff base formation. The enamine tautomer of the Schiff base adds to the dehydrated (S)-ASA, and this species then undergoes cyclisation to form HTPA.
This cyclisation could occur outside of the active site, with water acting as the nucleophile and displacing Lys161 from the Schiff base adduct. A conserved strained peptide carbonyl is thought to enhance the reactivity of the active site by polarizing the pyruvate substrate. Also, the release of strain in the peptide conformation, triggered by the binding of (S)-ASA may couple to the condensation reaction and increase the free energy associated with catalysis.
Reaction

Catalytic Sites for 1dhp

Annotated By Reference To The Literature - Site 1 (Perform Site Search)
ResidueChainNumberUniProtKB NumberFunctional PartFunctionTargetDescription
LysA161161macie:sideChainThe side chain amine group acts as a nucleophile towards the pyruvate keto functionality, forming a Schiff base linkage. The linkage is broken either in the active site by intramolecular 6-exo-tet cyclisation followed by elimination or outside of the active site by hydrolysis followed by cyclisation.
TyrA133133macie:sideChainThe residue's phenolic oxygen forms a hydrogen bond to the reacting pyruvate carbonyl, activating the group towards nucleophilic attack by Ly161. It is also thought to encourage the collapse of the tetrahedral intermediate during Schiff base formation.
IleA203203macie:sideChainThe backbone carbonyl adopts a strained conformation within the active site. The binding of (S)-SAS releases the carbonyl, and so increases the free energy available to the reaction. The carbonyl is also thought to polarise the pyruvate substrate towards attack by Lys161.

Literature References

Notes:
Blickling S
Reaction mechanism of Escherichia coli dihydrodipicolinate synthase investigated by X-ray crystallography and NMR spectroscopy.
Biochemistry 1997 36 24-33
PubMed: 8993314
Dobson RC
Conserved main-chain peptide distortions: a proposed role for Ile203 in catalysis by dihydrodipicolinate synthase.
Protein Sci 2008 17 2080-2090
PubMed: 18787203
spacer
spacer