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Information on EC 5.1.1.7 - diaminopimelate epimerase and Organism(s) Haemophilus influenzae and UniProt Accession P44859

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EC Tree
     5 Isomerases
         5.1 Racemases and epimerases
             5.1.1 Acting on amino acids and derivatives
                5.1.1.7 diaminopimelate epimerase
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Haemophilus influenzae
UNIPROT: P44859 not found.
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The taxonomic range for the selected organisms is: Haemophilus influenzae
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
diaminopimelate epimerase, dap epimerase, diaminopimelic acid epimerase, mtdapf, cgdapf, dapfct, dap-epimerase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
diaminopimelate epimerase
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DAP epimerase
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DAP-epimerase
diaminopimelate epimerase
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Diaminopimelic acid epimerase
Diaminopimelic epimerase
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Epimerase, diaminopimelate
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LL-Diaminopimelate epimerase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
LL-2,6-diaminoheptanedioate = meso-diaminoheptanedioate
show the reaction diagram
molecular dynamics simulations show that the configuration of the distal carbon C–6 of L,L-DAP is critical for complex formation since both amino and carboxylate groups are involved in H–bonding interactions with the active site residues. Furthermore, the interactions occurring between the functional groups bonded to the C–2 and some residues of the binding cavity immobilize the ligand in a position appropriate for the epimerization reaction, i.e., exactly in the middle of the two catalytic residues Cys73 and Cys217 as confirmed by DFT (density-functional theory) quantum mechanical computation of the Michaelis complex
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
epimerization
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SYSTEMATIC NAME
IUBMB Comments
LL-2,6-diaminoheptanedioate 2-epimerase
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CAS REGISTRY NUMBER
COMMENTARY hide
9024-22-0
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SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
LL-2,6-Diaminoheptanedioate
meso-Diaminoheptanedioate
show the reaction diagram
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-
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?
LL-2,6-diaminoheptanedioate
meso-diaminopimelate
show the reaction diagram
stereo-conversion, the product complex (Enzyme/meso-diaminopimelate) is less stable than the reactant complex (Enzyme/LL-diaminopimelate)
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-
r
LL-oxa-diaminopimelic acid
meso-oxa-diaminopimelic acid
show the reaction diagram
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-
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?
(2S,6S)-2,6-diaminoheptanedioate
meso-diaminoheptanedioate
show the reaction diagram
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-
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?
DL-3-fluoro-2,6-diaminopimelic acid
tetrahydrodipicolinic acid + HF
show the reaction diagram
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rapid elimination, enamine product is formed which spontaneously cyclizes to tetrahydrodipicolinic acid
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?
LL-2,6-Diaminoheptanedioate
meso-Diaminoheptanedioate
show the reaction diagram
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-
-
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?
LL-3-fluoro-2,6-diaminopimelic acid
tetrahydrodipicolinic acid + HF
show the reaction diagram
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slow elimination of HF
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
LL-2,6-diaminoheptanedioate
meso-diaminopimelate
show the reaction diagram
stereo-conversion, the product complex (Enzyme/meso-diaminopimelate) is less stable than the reactant complex (Enzyme/LL-diaminopimelate)
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r
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(2-(4-amino-4-carboxybutyl) aziridine-2-carboxylic acid)
AziDAP
DL-aziridino analogues of diaminoheptanedioate
DL-aziridino diaminopimelic acid, irreversible inhibitor
DL-aziridino-diaminopimelate
product-like inhibitor, inhibitor mimics the natural substrate, the methylene carbon of the aziridine ring of the 2 diastereomeric inhibitors is covalently bonded to the sulfur atom of Cys73 or Cys217 after the nucleophilic attack of the sulfur on the aziridine ring that irreversibly inhibits the enzyme
LL-aziridino analogues of diaminoheptanedioate
LL-aziridino diaminopimelic acid, irreversible inhibitor
LL-aziridino-diaminopimelate
reactant-like inhibitor, inhibitor mimics the natural substrate, the methylene carbon of the aziridine ring of the 2 diastereomeric inhibitors is covalently bonded to the sulfur atom of Cys73 or Cys217 after the nucleophilic attack of the sulfur on the aziridine ring that irreversibly inhibits the enzyme
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
128
LL-2,6-Diaminoheptanedioate
forward reaction
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
enzyme belongs to the group of isomerases which are capable of inverting the absolute configuration of a carbon atom in substrates containing one (racemases) or more stereocenters
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
co-crystals of the inhibitors LL- and DL-aziridino diaminopimelic acid with diaminopimelate epimerase from Haemophilus influenzae are grown at room temperature by the hanging-drop vapor-diffusion method. Crystals of both complexes are obtained in 2.8 M sodium acetate /0.1 M Hepes (pH 7.0) at a protein concentration of approx. 10 mg/ml in 25 mM Hepes, 5 mM DTT (pH 8.0)
comparisons of the mutant structures with the structures of the AziDAP inhibitor-bound form reveal that the enzyme adopts an open conformation in the absence of substrates or inhibitors with the two active site cysteines existing as a thiol–thiolate pair. Substrate binding to the C-terminal domain triggers the closure of the N-terminal domain coupled with tight encapsulation of the ligand, stabilization of the conformation of an active site loop containing Cys73 and expulsion of water molecules with concomitant desolvation of the thiolate base
crystal structures of diaminopimelate epimerase from Haemophilus influenzae with two different isomers of the irreversible inhibitor and substrate mimic aziridino diaminopimelic acid at 1.35- and 1.70-A resolution are analysed. These structures permit a detailed description of this pyridoxal 5’-phosphate-independent amino acid racemase active site and delineate the electrostatic interactions that control the exquisite substrate selectivity of DAP epimerase. Moreover, the active site shows how deprotonation of the substrates’nonacidic hydrogen at the alpha-carbon by a seemingly weakly basic cysteine residue is facilitated by interactions with two buried alpha-helices
crystallization of C73S and C217S mutant diaminopimelate epimerase enzymes of Haemophilus influenzae are obtained by the hanging-drop vapor diffusion method and submitted to X-ray structure analysis
hanging-drop vapour-diffusion method, space group C222(1), unit cell parameters a = 98.64 A, b = 113.87 A, c = 64.48 A, 1.75 A resolution
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C73S/C217S
in order to prevent C73 and C217 of DAP epimerase from oxidation to a disulfide prior to crystallization, DAP epimerase mutants C73S and C217S from Haemophilus influenzae are generated by site-directed mutagenesis
C217A
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mutant enzyme is inactive as epimerase, catalyzes elimination of HF via abstraction of the C-2 hydrogen from L,L-3-fluoro-2,6-diaminopimelate, incapable of catalyzing HF elimination from D,L-3-fluoro-2,6-diaminopimelate
C217S
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catalyzes epimerization of L,L-diaminopimelate at 2% of the activity of the wild-type enzyme,catalyzes HF elimination from L,L-3-fluoro-2,6-diaminopimelate and D,L-3-fluoro-2,6-diaminopimelate
C73A
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mutant enzyme is inactive as epimerase, catalyzes elimination of HF via abstraction of the C-2 hydrogen. Mutant enzyme is able to rapidly catalyze elimination of the D,L-3-fluoro-2,6-diaminopimelate and is unable to catalyze elimination with the L,L-3-fluoro-2,6-diaminopimelate
C73S
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epimerization of L,L-diaminopimelate at 3% of the activity of the wild-type enzyme, catalyzes HF elimination from L,L-3-fluoro-2,6-diaminopimelate and D,L-3-fluoro-2,6-diaminopimelate
C73S/C217S
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mutant enzyme is inactive as epimerase, slow elimination of HF from D,L-3-fluoro-2,6-diaminopimelate and L,L-3-fluoro-2,6-diaminopimelate
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
DAP epimerase mutants C73S and C217S from Haemophilus influenzae are cloned and purified
expression in Escherichia coli BL21(DE3)
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Koo, C.W.; Sutherland, A.; Vederas, J.C.; Blanchard, J.S.
Identification of active site cysteine residues that function as general bases: diaminopimelate epimerase
J. Am. Chem. Soc.
122
6122-6123
2000
Haemophilus influenzae
-
Manually annotated by BRENDA team
Lloyd, A.J.; Huyton, T.; Turkenburg, J.; Roper, D.I.
Refinement of Haemophilus influenzae diaminopimelic acid epimerase (DapF) at 1.75 A resolution suggests a mechanism for stereocontrol during catalysis
Acta Crystallogr. Sect. D
60
397-400
2004
Haemophilus influenzae
Manually annotated by BRENDA team
Pillai, B.; Cherney, M.; Diaper, C.M.; Sutherland, A.; Blanchard, J.S.; Vederas, J.C.; James, M.N.
Dynamics of catalysis revealed from the crystal structures of mutants of diaminopimelate epimerase
Biochem. Biophys. Res. Commun.
363
547-553
2007
Haemophilus influenzae (P44859), Haemophilus influenzae
Manually annotated by BRENDA team
Brunetti, L.; Galeazzi, R.; Orena, M.; Bottoni, A.
Catalytic mechanism of l,l-diaminopimelic acid with diaminopimelate epimerase by molecular docking simulations
J. Mol. Graph. Model.
26
1082-1090
2008
Haemophilus influenzae
Manually annotated by BRENDA team
Pillai, B.; Cherney, M.M.; Diaper, C.M.; Sutherland, A.; Blanchard, J.S.; Vederas, J.C.; James, M.N.
Structural insights into stereochemical inversion by diaminopimelate epimerase: an antibacterial drug target
Proc. Natl. Acad. Sci. USA
103
8668-8673
2006
Haemophilus influenzae (P44859), Haemophilus influenzae
Manually annotated by BRENDA team
Stenta, M.; Calvaresi, M.; Alto, P.; Spinelli, D.; Garavelli, M.; Galeazzi, R.; Bottoni, A.
Catalytic mechanism of diaminopimelate epimerase: A QM/MM investigation
J. Chem. Theory Comput.
5
1915-1930
2009
Haemophilus influenzae (P44859)
Manually annotated by BRENDA team