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Information on EC 3.5.2.6 - beta-lactamase and Organism(s) Acinetobacter baumannii and UniProt Accession Q8RLA6

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EC Tree
     3 Hydrolases
         3.5 Acting on carbon-nitrogen bonds, other than peptide bonds
             3.5.2 In cyclic amides
                3.5.2.6 beta-lactamase
IUBMB Comments
A group of enzymes of varying specificity hydrolysing beta-lactams; some act more rapidly on penicillins, some more rapidly on cephalosporins. The latter were formerly listed as EC 3.5.2.8, cephalosporinase.
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This record set is specific for:
Acinetobacter baumannii
UNIPROT: Q8RLA6
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The taxonomic range for the selected organisms is: Acinetobacter baumannii
The enzyme appears in selected viruses and cellular organisms
Synonyms
beta-lactamase, carbapenemase, extended-spectrum beta-lactamase, ndm-1, penicillinase, tem-1, blandm-1, ges-1, blactx-m-15, kpc-2, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Beta lactamase OXA-10
-
-
-
-
beta-lactamase
-
-
-
-
beta-lactamase AME I
-
-
-
-
beta-lactamase II
-
-
-
-
BLAIMP
-
-
-
-
carbapenemase
Carbenicillinase
-
-
-
-
cefotaximase
-
-
-
-
ceftazidimase
-
-
-
-
cefurooximase
-
-
-
-
Cefuroximase
-
-
-
-
Cephalosporinase
-
-
-
-
class D beta-lactamase
-
Imipenem-cefoxitin hydrolyzing enzyme
-
-
-
-
imipenemase
-
-
-
-
metallo-beta-lactamase
-
-
-
-
neutrapen
-
-
-
-
New Delhi metallo-beta-lactamase
-
OXA-24 beta-lactamase
-
Oxacillinase
-
-
-
-
penicillinase
-
-
-
-
SHV-2A
-
-
-
-
subclass B1 metallo-?-lactamase
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
a beta-lactam + H2O = a substituted beta-amino acid
show the reaction diagram
overall mechanism for beta-lactamase-inhibitor reaction, Quantum mechanical/molecular mechanical calculations and Raman spectral analysis, overview
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
carboxylic acid amide hydrolysis
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
beta-lactam hydrolase
A group of enzymes of varying specificity hydrolysing beta-lactams; some act more rapidly on penicillins, some more rapidly on cephalosporins. The latter were formerly listed as EC 3.5.2.8, cephalosporinase.
CAS REGISTRY NUMBER
COMMENTARY hide
9073-60-3
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
(5R,6E)-6-[(4H,6H-pyrazolo[1,5-c][1,3]thiazol-2-yl)methylidene]-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one + H2O
(2E)-2-[(2R)-2,3-dihydro-1,3-thiazol-2-yl]-3-(4H,6H-pyrazolo[1,5-c][1,3]thiazol-2-yl)prop-2-enoic acid
show the reaction diagram
-
-
-
?
(5R,6Z)-6-[(1,6,7,8a-tetrahydro-5H-imidazo[2,1-b][1,3]oxazin-2-yl)methylidene]-4-thia-1-azabicyclo[3.2.0]hept-2-en-7-one + H2O
(2Z)-2-[(2R)-2,3-dihydro-1,3-thiazol-2-yl]-3-(1,6,7,8a-tetrahydro-5H-imidazo[2,1-b][1,3]oxazin-2-yl)prop-2-enoic acid
show the reaction diagram
-
-
-
?
ampicillin + H2O
(2R,4S)-2-[(R)-[[(2R)-2-amino-2-phenylacetyl]amino](carboxy)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid
show the reaction diagram
benzylpenicillin + H2O
(2R,4S)-2-[(R)-carboxy(2-phenylacetamido)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid
show the reaction diagram
cephaloridine + H2O
(2R)-2-[(R)-carboxy[(thiophen-2-ylacetyl)amino]methyl]-5-(pyridinium-1-ylmethyl)-3,6-dihydro-2H-1,3-thiazine-4-carboxylate
show the reaction diagram
cephalothin + H2O
(2R)-5-[(acetyloxy)methyl]-2-[(R)-carboxy[(thiophen-2-ylacetyl)amino]methyl]-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid
show the reaction diagram
-
-
-
?
cloxacillin + H2O
(2R,4S)-2-[(R)-carboxy{[3-(2-chlorophenyl)-5-methyl-1,2-oxazole-4-carbonyl]amino}methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid
show the reaction diagram
-
-
-
?
imipenem + H2O
(5R)-5-[(1S,2R)-1-carboxy-2-hydroxypropyl]-3-([2-[(iminomethyl)amino]ethyl]sulfanyl)-4,5-dihydro-1H-pyrrole-2-carboxylic acid
show the reaction diagram
the enzyme catalyzes the hydrolysis of the C-N bond of the beta-lactam ring
-
-
?
imipenem + H2O
(5R)-5-[(1S,2R)-1-carboxy-2-hydroxypropyl]-3-({2-[(iminomethyl)amino]ethyl}sulfanyl)-4,5-dihydro-1H-pyrrole-2-carboxylic acid
show the reaction diagram
meropenem + H2O
(4R,5S)-5-[(1S,2R)-1-carboxy-2-hydroxypropyl]-3-{[(3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-4-methyl-4,5-dihydro-1H-pyrrole-2-carboxylic acid
show the reaction diagram
-
-
-
?
nitrocefin + H2O
(2R)-2-[(R)-carboxy[2-(thiophen-2-yl)acetamido]methyl]-5-[(E)-2-(2,4-dinitrophenyl)ethenyl]-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid
show the reaction diagram
-
-
-
?
nitrocefin + H2O
(2R)-2-{(R)-carboxy[2-(thiophen-2-yl)acetamido]methyl}-5-[(E)-2-(2,4-dinitrophenyl)ethenyl]-3,6-dihydro-2H-1,3-thiazine-4-carboxylic acid
show the reaction diagram
-
-
-
?
oxacillin + H2O
(2R,4S)-2-{(R)-carboxy[(5-methyl-3-phenyl-1,2-oxazole-4-carbonyl)amino]methyl}-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid
show the reaction diagram
piperacillin + H2O
(2R,4S)-2-[(R)-carboxy[[(2R)-2-[[(4-ethyl-2,3-dioxopiperazin-1-yl)carbonyl]amino]-2-phenylacetyl]amino]methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid
show the reaction diagram
-
-
-
?
ticarcillin + H2O
(2R,4S)-2-[(R)-carboxy[[(2R)-2-carboxy-2-(thiophen-3-yl)acetyl]amino]methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid
show the reaction diagram
-
-
-
?
additional information
?
-
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
benzylpenicillin + H2O
(2R,4S)-2-[(R)-carboxy(2-phenylacetamido)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid
show the reaction diagram
the enzyme catalyzes the hydrolysis of the C-N bond of the beta-lactam ring
-
-
?
imipenem + H2O
(5R)-5-[(1S,2R)-1-carboxy-2-hydroxypropyl]-3-([2-[(iminomethyl)amino]ethyl]sulfanyl)-4,5-dihydro-1H-pyrrole-2-carboxylic acid
show the reaction diagram
the enzyme catalyzes the hydrolysis of the C-N bond of the beta-lactam ring
-
-
?
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4,7-dichloro benzothien-2-yl sulfonylaminomethyl boronic acid
inhibitor synergizes with imipenem against Acintobacter baumannii
clavulanate
0.1 mM, 50% inhibition
clavulanic acid
-
-
Cloxacillin
0.398 mM, 50% inhibition
Imipenem
2.5 mM, 50% inhibition
meropenem
0.000004 mM, 50% inhibition
NaCl
3.2 mM, 50% inhibition
nitrocefin
substrate inhibition, NaHCO3 can reactivate the enzyme
penem 1
a 6-methylidene penem, the carboxylated Lys84 in the active site of OXA-24 utilizes a catalytic water molecule to deacylate the Ser81, resulting in hydrolysis of the penem 1 inhibitor, and the enzyme is regenerated because Lys84 is not decarboxylated and hydrolyzes the next arriving inhibitor molecule, proposed mechanism for penem 1 and OXA-24, overview
penem 3
a 6-methylidene penem
SA-1-204
a penam sulfone inhibitor, can effectively inhibit OXA-24 by decarboxylating the Lys84 in the active site
Sulbactam
tazobactam
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.024 - 0.24
ampicillin
0.71
benzylpenicillin
30°C, pH 7.0
0.077 - 2.5
cephaloridine
0.19
cephalothin
30°C, pH 7.0
0.129
Cloxacillin
37°C, pH 7.0
0.011 - 3.6
Imipenem
4.5
meropenem
30°C, pH 7.0
0.028 - 0.13
nitrocefin
0.531 - 3.7
Oxacillin
4
piperacillin
30°C, pH 7.0
2.8
ticarcillin
30°C, pH 7.0
additional information
additional information
steady-state kinetics
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.06
ampicillin
30°C, pH 7.0
0.2
benzylpenicillin
30°C, pH 7.0
0.05
cephaloridine
30°C, pH 7.0
0.004
cephalothin
30°C, pH 7.0
0.1
Imipenem
30°C, pH 7.0
0.06
meropenem
30°C, pH 7.0
0.4
nitrocefin
30°C, pH 7.0
0.2
Oxacillin
30°C, pH 7.0
0.2
piperacillin
30°C, pH 7.0
0.3
ticarcillin
30°C, pH 7.0
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00003
penem 1
pH 7.2, temperature not specified in the publication, recombinant enzyme
0.00015
penem 3
pH 7.2, temperature not specified in the publication, recombinant enzyme
additional information
additional information
inhibition kinetics
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0056
4,7-dichloro benzothien-2-yl sulfonylaminomethyl boronic acid
Acinetobacter baumannii
pH not specified in the publication, temperature not specified in the publication
0.00015
penem 1
Acinetobacter baumannii
pH 7.2, temperature not specified in the publication, recombinant enzyme
0.00016
penem 3
Acinetobacter baumannii
pH 7.2, temperature not specified in the publication, recombinant enzyme
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
comparison of the structures of subclass B1 metallo-beta-lactamases IMP-1 and IMP-2, which have an 85% amino acid identity, suggests that the amino acid substitution at position 68 on a beta-strand (beta3) (Pro in IMP-1 versus Ser in IMP-2) may be a staple factor affecting the flexibility of loop 1 (comprising residues at positions 60-66, EVNGWGV). In the IMP-1 structure, loop 1 adopts an open, disordered conformation. Comparison of the active site structure between IMP-1 and IMP-2, loop 1 of IMP-2 forms a closed conformation in which the side chain of Trp64, involved in substrate binding, is oriented so as to cover the active site, even though there is an acetate ion in the active site of both IMP-1 and IMP-2. Loop 1 of IMP-2 has a more flexible structure in comparison to IMP-1 due to having a Ser residue instead of the Pro residue at position 68, indicating that this difference in sequence may be a trigger to induce a more flexible conformation in loop 1
physiological function
the enzyme is involved in antibiotic resistance, catalyzing the hydrolysis of antibiotics such as benzylpenicillin and imipenem
additional information
different genotypes of the New Delhi metallo beta-lactamase are identified: the substitutions do not affect the overall folds of the enzyme variants, within limits of detection. Differences in thermal stabilities are observed. kcat/KM values are similar for carbapenem and penicillin substrates for NDM variants, but differences in kinetics are observed for cephalosporin substrates. Apparent substrate inhibition is observed with nitrocefin for variants containing the M154L substitution. In all cases, cefoxitin and ceftazidime are poorly hydrolysed. Clinically observed substitutions can make substantial differences in thermodynamic stability, suggesting that this may be a factor in metallo beta-lactamase evolution. Comparative analysis of the beta-lactam susceptibility of the NDM variants in Escherichia coli, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
Q8RLA6_ACIBA
275
0
30939
TrEMBL
-
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
35500
x * 35500, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 35500, SDS-PAGE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified enzyme IMP-2 MBL, hanging drop vapour diffusion metod, mixxing of 0.003 ml of 5 mg/ml protein in 20 mM HEPES-NaOH, pH 7.5, with 0.003 ml of reservoir solution containing 30% w/v PEG 4000, 0.1 M citric acid/sodium citrate, and 0.2 M sodium acetate, pH 6.0, equilibration against 0.35 ml reservori solution, 20°C, X-ray diffraction structure determination and analysis at 2.3 A resolution, modeling and structure comparisons
purified recombinant enzyme, hanging drop vapor diffusion method, mixing of 6 mg/ml protein in 10 mM HEPES, pH 7.5, with crystallization solution containing 0.1 M HEPES, pH 7.5, 0.1 M sodium acetate, and 28% PEG 2000, X-ray diffraction structure determination and analysis
structure of the class D beta-lactamase OXA-1 as an acyl complex with doripenem, determined to 1.4 A resolution
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
P28A
naturally occuring genetic variation, the P28A substitution occurs in the predicted N-terminal periplasmic signal peptide
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme IMP-2 from Escherichia coli strain HB101 harboring pBC SK(+) by cation exchange chromatography, ultrafiltration and gel filtration, to over 95% purity
recombinant N-terminally His6-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, cleavage of the N-terminal His6-tag using recombinant human Rhinovirus 3C protease, and further purification of the untagged protein by affinity chromatography, followed by ultrafiltration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli
-
gene blaIMP-2, recombinant expression in Escherichia coli strain HB101 harboring pBC SK(+)
gene blaNDM-2, genotyping, recombinant expression of His6-tagged enzyme in Escherichia coli strain BL21(DE3)
gene OXA24, recombinant expression in Escerichia coli strain BL21(DE3)
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Higgins, P.G.; Wisplinghoff, H.; Stefanik, D.; Seifert, H.
In vitro activities of the beta-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam alone or in combination with beta-lactams against epidemiologically characterized multidrug-resistant Acinetobacter baumannii strains
Antimicrob. Agents Chemother.
48
1586-1592
2004
Acinetobacter baumannii
Manually annotated by BRENDA team
Heritier, C.; Poirel, L.; Fournier, P.E.; Claverie, J.M.; Raoult, D.; Nordmann, P.
Characterization of the naturally occurring oxacillinase of Acinetobacter baumannii
Antimicrob. Agents Chemother.
49
4174-4179
2005
Acinetobacter baumannii (Q5I2N2), Acinetobacter baumannii
Manually annotated by BRENDA team
Brown, S.; Young, H.K.; Amyes, S.G.
Characterisation of OXA-51, a novel class D carbapenemase found in genetically unrelated clinical strains of Acinetobacter baumannii from Argentina
Clin. Microbiol. Infect.
11
15-23
2005
Acinetobacter baumannii (Q5QT35), Acinetobacter baumannii
Manually annotated by BRENDA team
Schneider, K.D.; Karpen, M.E.; Bonomo, R.A.; Leonard, D.A.; Powers, R.A.
The 1.4 A crystal structure of the class D beta-lactamase OXA-1 complexed with doripenem
Biochemistry
48
11840-11847
2009
Acinetobacter baumannii
Manually annotated by BRENDA team
Tan, Q.; Ogawa, A.M.; Painter, R.E.; Park, Y.W.; Young, K.; DiNinno, F.P.
4,7-Dichloro benzothien-2-yl sulfonylaminomethyl boronic acid: first boronic acid-derived beta-lactamase inhibitor with class A, C, and D activity
Bioorg. Med. Chem. Lett.
20
2622-2624
2010
Klebsiella pneumoniae (P0A3M1), Pseudomonas aeruginosa (Q6LBN9), Acinetobacter baumannii (Q8RLA6), Acinetobacter baumannii
Manually annotated by BRENDA team
Yamaguchi, Y.; Matsueda, S.; Matsunaga, K.; Takashio, N.; Toma-Fukai, S.; Yamagata, Y.; Shibata, N.; Wachino, J.; Shibayama, K.; Arakawa, Y.; Kurosaki, H.
Crystal structure of IMP-2 metallo-beta-lactamase from Acinetobacter spp.: comparison of active-site loop structures between IMP-1 and IMP-2
Biol. Pharm. Bull.
38
96-101
2015
Acinetobacter baumannii (Q9KVZ2)
Manually annotated by BRENDA team
Makena, A.; Brem, J.; Pfeffer, I.; Geffen, R.E.; Wilkins, S.E.; Tarhonskaya, H.; Flashman, E.; Phee, L.M.; Wareham, D.W.; Schofield, C.J.
Biochemical characterization of New Delhi metallo-beta-lactamase variants reveals differences in protein stability
J. Antimicrob. Chemother.
70
463-469
2015
Escherichia coli (A0A024FRL9), Escherichia coli (A0A0F6N6D4), Escherichia coli (H6WET3), Escherichia coli (H6WZS9), Escherichia coli (I3VKD5), Escherichia coli (J7I0S9), Escherichia coli (M1VE66), Klebsiella pneumoniae (C7C422), Klebsiella pneumoniae (S5ZIP8), Klebsiella pneumoniae (T2A6Y2), Acinetobacter baumannii (F2YZ26)
Manually annotated by BRENDA team
Che, T.; Bethel, C.R.; Pusztai-Carey, M.; Bonomo, R.A.; Carey, P.R.
The different inhibition mechanisms of OXA-1 and OXA-24 beta-lactamases are determined by the stability of active site carboxylated lysine
J. Biol. Chem.
289
6152-6164
2014
Acinetobacter baumannii (J9XTR7), Escherichia coli (P13661)
Manually annotated by BRENDA team