2.3.2.B14: L,D-transpeptidase
This is an abbreviated version!
For detailed information about L,D-transpeptidase, go to the full flat file.
Word Map on EC 2.3.2.B14
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2.3.2.B14
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tuberculosis
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mycobacterium
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carbapenems
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penicillin-binding
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d,d-transpeptidases
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enterococcus
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faecium
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ldtmt2
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transpeptidases
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imipenem
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ertapenem
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muropeptides
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acylenzyme
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clavulanate
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transpeptidation
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d-ala
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lineage-determining
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doripenem
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d,d-carboxypeptidase
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analysis
- 2.3.2.B14
- tuberculosis
- mycobacterium
- carbapenems
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penicillin-binding
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d,d-transpeptidases
- enterococcus
- faecium
- ldtmt2
- transpeptidases
- imipenem
- ertapenem
- muropeptides
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acylenzyme
- clavulanate
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transpeptidation
- d-ala
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lineage-determining
- doripenem
- d,d-carboxypeptidase
- analysis
Reaction
Generates 3->3 cross-links in peptidoglycan, catalyzing the cleavage of the mDap(3)-D-Ala4 bond of a tetrapeptide donor stem and the formation of a bond between the carbonyl of mDap3 of the donor stem and the side chain of mDap3 of the acceptor stem. =
Synonyms
CLIBASIA_01175, IprQ, L,D-transpeptidase, L,D-transpeptidase 2, L,D-transpeptidase 5, LdtB, LdtBS, LdtF, Ldtfm, Ldtfm217, Ldtfs, LdtMt1, LdtMt2, LdtP, MAB_1530, MAB_3165c, MT0125, MT0501, MT2594, Rv1433, Rv2518c, transpeptidase, YcbB
ECTree
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Inhibitors
Inhibitors on EC 2.3.2.B14 - L,D-transpeptidase
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(4R,5S,6S)-3-[[(3S,5R)-5-(aminomethyl)oxolan-3-yl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
compound identified by virtual screening, interacts with residues Arg242 and Gly304
(4R,6S)-3-[[(3R,5R)-5-(aminomethyl)oxolan-3-yl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
2-[(2S,3S)-2-(2H-1,3-benzodioxol-5-yl)-1-(3-fluoro-4-methylphenyl)-4-oxoazetidin-3-yl]-5-nitro-1H-isoindole-1,3(2H)-dione
inhibitor identified by virtual screening, demonstrates close hydrogen bond interaction between the ligand and two active site residues Asn303 and Cys305, shows the highest binding free energy observed
2-[(2S,3S)-2-(4-fluorophenyl)-1-(3-methylphenyl)-4-oxoazetidin-3-yl]-5-nitro-1H-isoindole-1,3(2H)-dione
6-aminopenicillanic acid
high degree of Cys354 modification, occurrence of a possible coupling reaction
cefapirin
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formation of a covalent comple that undergoes non-hydrolytic fragmentation, resulting in an adduct in which the C3' leaving group is lost
cefdinir
doripenem and cefdinir exhibit synergy against Mycobacterium abscessus
faropenem daloxate
high degree of Cys354 modification, fast degradation following the initial acylation event
panipenem
panipenem is not degraded after binding. The presence of the 1-beta-methyl group in carbapenems is related to the ligand affinity of LdtB and the presence of the Y308 and Y318 residues in LdtB stabilizes the conformation of the LdtB-carbepenem adduct
sulopenem
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formation of a covalent comple that undergoes non-hydrolytic fragmentation, yielding LdtB acylated with a 3-hydroxybutanoate fragment
ticarcillin
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formation of a covalent comple that undergoes non-hydrolytic fragmentation
ZINC02475683
simulation of complex with isoform IprQ. The DELTAG# for the acylation is calculated as 28.26 kcal/mol
ZINC03784242
simulation of complex with isoform IprQ. The DELTAG# for the acylation is calculated as 27.86 kcal/mol
ZINC03788344
simulation of complex with isoform IprQ. The DELTAG# for the acylation is calculated as 13.67 kcal/mol
ZINC03791246
simulation of complex with isoform IprQ. The DELTAG# for the acylation is calculated as 22.88 kcal/mol
(4R,6S)-3-[[(3R,5R)-5-(aminomethyl)oxolan-3-yl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
simulation of complex with isoform IprQ. The DELTAG# for the acylation is calculated as 24.29 kcal/mol
(4R,6S)-3-[[(3R,5R)-5-(aminomethyl)oxolan-3-yl]sulfanyl]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
compound identified by virtual screening, interacts with residues Arg242 and Gly304
2-[(2S,3S)-2-(4-fluorophenyl)-1-(3-methylphenyl)-4-oxoazetidin-3-yl]-5-nitro-1H-isoindole-1,3(2H)-dione
simulation of complex with isoform IprQ. The DELTAG# for the acylation is calculated as 20.9 kcal/mol
2-[(2S,3S)-2-(4-fluorophenyl)-1-(3-methylphenyl)-4-oxoazetidin-3-yl]-5-nitro-1H-isoindole-1,3(2H)-dione
compound identified by virtual screening, interacts with the residue Asn263 and a water molecule which is within the active site
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isoform Ldt2, formation of acylenzyme, half-life of 2.0 min
biapenem
investigation of the binding interactions using a two-layered ONIOM model
biapenem
decreasing order of inhibition is biapenem > doripenem > ertapenem > tebipenem; decreasing order of inhibition is biapenem > doripenem > ertapenem > tebipenem
cefotaxime
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formation of a covalent comple that undergoes non-hydrolytic fragmentation, resulting in an adduct in which the C3' leaving group is lost
cephalothin
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formation of a covalent comple that undergoes non-hydrolytic fragmentation, resulting in an adduct in which the C3' leaving group is lost
doripenem
doripenem and cefdinir exhibit synergy against Mycobacterium abscessus
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formation of a covalent comple that undergoes non-hydrolytic fragmentation, yielding LdtB acylated with a 3-hydroxybutanoate fragment
faropenem
high degree of Cys354 modification, fast degradation following the initial acylation event
faropenem
best inhibition among beta-lactams tested; best inhibition among beta-lactams tested
faropenem
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formation of an acyl adduct. In competition experiments, both faropenem and meropenem initially acylate LdtF, then faropenem is hydrolyzed off the enzyme at a faster rate than meropenem
Imipenem
treatment leads to full and irreversible acylation of the protein
Imipenem
irreversible inhibition, imipenem binds only the catalytically active enzyme with apparent submicromolar affinity
Imipenem
investigation of the binding interactions using a two-layered ONIOM model
Imipenem
modeling of the reaction pathways. A 6-membered ring model best describes the inhibition mechanism of acylation. The electrostatic potential and the natural bond orbital analysis show stronger interactions in 6-membered ring transition state mechanism involving water in the active site of the enzyme
meropenem
treatment leads to full and irreversible acylation of the protein
meropenem
meropenem binds only the catalytically active enzyme with apparent submicromolar affinity
meropenem
investigation of the binding interactions using a two-layered ONIOM model
meropenem
modeling of the reaction pathways. A 6-membered ring model best describes the inhibition mechanism of acylation. The electrostatic potential and the natural bond orbital analysis show stronger interactions in 6-membered ring transition state mechanism involving water in the active site of the enzyme
meropenem
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complete formation of an acyl adduct. In competition experiments, both faropenem and meropenem initially acylate LdtF, then faropenem is hydrolyzed off the enzyme at a faster rate than meropenem
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formation of a covalent comple that undergoes non-hydrolytic fragmentation. Cleavage of the C5-C6 bond of the penicillin-derived LdtB acyl-enzyme complex yields LdtB modified by an acetyl group bearing the penicillin C6 side chain
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formation of a covalent comple that undergoes non-hydrolytic fragmentation. Cleavage of the C5-C6 bond of the penicillin-derived LdtB acyl-enzyme complex yields LdtB modified by an acetyl group bearing the penicillin C6 side chain
tebipenem
investigation of the binding interactions using a two-layered ONIOM model
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isoform Ldt3 does not form any covalent adduct with the five beta-lactams tested
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additional information
computation of the ring strain energy, force constant of amide, acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of beta-lactam derivatives. The calculated DELTAG# values from the acylation reaction of the lactams reveal a faster rate of C-N cleavage in the five-membered ring lactams especially in the 1-2 derivatives. Electronic factors may play more of a role on reactivity of the beta-lactam ring, than ring strain
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additional information
the intact catalytic site is required for the acylation by beta-lactams
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additional information
investigation of the binding interactions carbapenems (biapenem, imipenem, meropenem, and tebipenem) using a two-layered ONIOM model. The carbapenems exhibit reasonable binding interactions towards LdtB. Increasing the number of amino acid residues that form hydrogen bond interactions in the QM layer shows significant impact in binding interaction energy differences and the stabilities of the carbapenems inside the active pocket. The hydrogen bond interactions and charge transfer from the bonding to anti-bonding orbitals between catalytic residues of the enzyme and selected ligands enhances the binding and stability of carbapenem-LdtB complexes
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additional information
virtual screening of compounds from the ZINC database against Ldt5 investigated with AutoDock Vina and Schrödinger Maestro software programs. A set of compounds from four antibiotic classes with less than 30 kcal/mol molecular mechanics/generalized born surface area binding free energies is characterized
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additional information
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virtual screening of compounds from the ZINC database against Ldt5 investigated with AutoDock Vina and Schrödinger Maestro software programs. A set of compounds from four antibiotic classes with less than 30 kcal/mol molecular mechanics/generalized born surface area binding free energies is characterized
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additional information
all of the tested penicillins exhibit moderate inhibition of Ldt2. The greatest to least inhibition is observed in the following order: carbenicillin = oxacillin = amoxicillin > methicillin > ampicillin. Cephalosporin cephalexin is not inhibitory, inhibition by cephalosporins in decreasing order is cefdinir > ceftriaxone >cefotaxime > cefoxitin. Carbapenems are the most potent inhibitors of Ldt2, with the following decreasing inhibition profile: doripenem = biapenem >ertapenem > tebipenem >meropenem; doripenem and cefdinir exhibit synergy against Mycobacterium abscessus; not inhibitory: penicillins amoxicillin, ampicillin, carbenicillin, methicillin, and oxacillin, nor carbapenems meropenem or imipenem
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additional information
all of the tested penicillins exhibit moderate inhibition of Ldt2. The greatest to least inhibition is observed in the following order: carbenicillin = oxacillin = amoxicillin > methicillin > ampicillin. Cephalosporin cephalexin is not inhibitory, inhibition by cephalosporins in decreasing order is cefdinir > ceftriaxone >cefotaxime > cefoxitin. Carbapenems are the most potent inhibitors of Ldt2, with the following decreasing inhibition profile: doripenem = biapenem >ertapenem > tebipenem >meropenem; doripenem and cefdinir exhibit synergy against Mycobacterium abscessus; not inhibitory: penicillins amoxicillin, ampicillin, carbenicillin, methicillin, and oxacillin, nor carbapenems meropenem or imipenem
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additional information
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all of the tested penicillins exhibit moderate inhibition of Ldt2. The greatest to least inhibition is observed in the following order: carbenicillin = oxacillin = amoxicillin > methicillin > ampicillin. Cephalosporin cephalexin is not inhibitory, inhibition by cephalosporins in decreasing order is cefdinir > ceftriaxone >cefotaxime > cefoxitin. Carbapenems are the most potent inhibitors of Ldt2, with the following decreasing inhibition profile: doripenem = biapenem >ertapenem > tebipenem >meropenem; doripenem and cefdinir exhibit synergy against Mycobacterium abscessus; not inhibitory: penicillins amoxicillin, ampicillin, carbenicillin, methicillin, and oxacillin, nor carbapenems meropenem or imipenem
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