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Information on EC 6.3.3.4 - (carboxyethyl)arginine beta-lactam-synthase
for references in articles please use BRENDA:EC6.3.3.4
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EC Tree 6 Ligases
6.3 Forming carbon-nitrogen bonds
6.3.3 Cyclo-ligases
6.3.3.4 (carboxyethyl)arginine beta-lactam-synthase
IUBMB Comments
Forms part of the pathway for the biosythesis of the β-lactamase inhibitor clavulanate in Streptomyces clavuligerus. It has been proposed that L-N2-(2-carboxyethyl)arginine is first converted into an acyl-AMP by reaction with ATP and loss of diphosphate, and that the β-lactam ring is then formed by the intramolecular attack of the β-nitrogen on the activated carboxy group.
The enzyme appears in viruses and cellular organisms
Reaction Schemes
showSynonyms
betals, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
beta-lactam-forming enzyme
-
-
-
-
bls2
synthetase, beta-lactam
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + L-N2-(2-carboxyethyl)arginine = AMP + diphosphate + deoxyamidinoproclavaminate
overview
ATP + L-N2-(2-carboxyethyl)arginine = AMP + diphosphate + deoxyamidinoproclavaminate
it has been proposed that L-N2-(2-carboxyethyl)arginine is first converted into an acyl-AMP by reaction with ATP and loss of diphosphate, and that the beta-lactam ring is then formed by the intramolecular attack of the beta-nitrogen on the activated carboxy group, in a sequential ordered bi-ter kinetic mechanism
ATP + L-N2-(2-carboxyethyl)arginine = AMP + diphosphate + deoxyamidinoproclavaminate
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
cyclization
-
-
-
-
formation of cyclic amides
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
MetaCyc
clavulanate biosynthesis
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SYSTEMATIC NAME
IUBMB Comments
L-N2-(2-carboxyethyl)arginine cyclo-ligase (AMP-forming)
Forms part of the pathway for the biosythesis of the beta-lactamase inhibitor clavulanate in Streptomyces clavuligerus. It has been proposed [3] that L-N2-(2-carboxyethyl)arginine is first converted into an acyl-AMP by reaction with ATP and loss of diphosphate, and that the beta-lactam ring is then formed by the intramolecular attack of the beta-nitrogen on the activated carboxy group.
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CAS REGISTRY NUMBER
COMMENTARY
68247-54-1
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + (2'R)-methyl-L-N2-(2-carboxyethyl)arginine
?
Substrates: -
Products: -
Products: -
?
ATP + (2'S)-ethyl-L-N2-(2-carboxyethyl)arginine
?
Substrates: -
Products: -
Products: -
?
ATP + (2'S)-methyl-L-N2-(2-carboxyethyl)arginine
?
Substrates: -
Products: -
Products: -
?
additional information
?
-
Substrates: no activity with (2'R)-ethyl-L-N2-(2-carboxyethyl)arginine
Products: -
Products: -
?
ATP + L-N2-(2-carboxyethyl)arginine
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: -
Products: -
Products: -
?
ATP + L-N2-(2-carboxyethyl)arginine
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: the enzyme is involved in clavulanic acid biosynthesis
Products: -
Products: -
?
ATP + L-N2-(2-carboxyethyl)arginine
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: the enzyme is involved in clavulanic acid biosynthesis
Products: -
Products: -
?
N2-(carboxyethyl)-L-arginine + ATP
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: -
Products: -
Products: -
?
N2-(carboxyethyl)-L-arginine + ATP
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: mechanism
Products: -
Products: -
?
N2-(carboxyethyl)-L-arginine + ATP
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: early step in clavulanic acid biosynthesis
Products: -
Products: -
?
N2-(carboxyethyl)-L-arginine + ATP
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: overview on biological role
Products: -
Products: -
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + L-N2-(2-carboxyethyl)arginine
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: -
Products: -
Products: -
?
ATP + L-N2-(2-carboxyethyl)arginine
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: the enzyme is involved in clavulanic acid biosynthesis
Products: -
Products: -
?
ATP + L-N2-(2-carboxyethyl)arginine
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: the enzyme is involved in clavulanic acid biosynthesis
Products: -
Products: -
?
N2-(carboxyethyl)-L-arginine + ATP
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: -
Products: -
Products: -
?
N2-(carboxyethyl)-L-arginine + ATP
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: early step in clavulanic acid biosynthesis
Products: -
Products: -
?
N2-(carboxyethyl)-L-arginine + ATP
AMP + diphosphate + deoxyamidinoproclavaminate
Substrates: overview on biological role
Products: -
Products: -
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
N2-(carboxymethyl)-L-arginine
competitive to N2-(carboxyethyl)-L-arginine
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.04
(2'R)-methyl-L-N2-(2-carboxyethyl)arginine
wild type enzyme, pH and temperature not specified in the publication
0.33
(2'R)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446A, pH and temperature not specified in the publication
1.9
(2'R)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446G, pH and temperature not specified in the publication
0.04
(2'S)-ethyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446A, pH and temperature not specified in the publication
0.06
(2'S)-ethyl-L-N2-(2-carboxyethyl)arginine
wild type enzyme, pH and temperature not specified in the publication
0.06
(2'S)-methyl-L-N2-(2-carboxyethyl)arginine
wild type enzyme, pH and temperature not specified in the publication
0.08
(2'S)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme H447A, pH and temperature not specified in the publication
0.46
(2'S)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446A, pH and temperature not specified in the publication
1.2
(2'S)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446G, pH and temperature not specified in the publication
0.037
L-N2-(2-carboxyethyl)arginine
wild type enzyme, pH and temperature not specified in the publication
0.36
L-N2-(2-carboxyethyl)arginine
mutant enzyme V446A, pH and temperature not specified in the publication
0.6 - 1
L-N2-(2-carboxyethyl)arginine
mutant enzyme V446G, pH and temperature not specified in the publication
0.9
L-N2-(2-carboxyethyl)arginine
mutant enzyme H447A, pH and temperature not specified in the publication
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.014
(2'R)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446A, pH and temperature not specified in the publication
0.032
(2'R)-methyl-L-N2-(2-carboxyethyl)arginine
wild type enzyme, pH and temperature not specified in the publication
0.07
(2'R)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446G, pH and temperature not specified in the publication
0.0023
(2'S)-ethyl-L-N2-(2-carboxyethyl)arginine
wild type enzyme, pH and temperature not specified in the publication
0.004
(2'S)-ethyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446A, pH and temperature not specified in the publication
0.013
(2'S)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme H447A, pH and temperature not specified in the publication
0.023
(2'S)-methyl-L-N2-(2-carboxyethyl)arginine
wild type enzyme, pH and temperature not specified in the publication
0.13
(2'S)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446G, pH and temperature not specified in the publication
0.34
(2'S)-methyl-L-N2-(2-carboxyethyl)arginine
mutant enzyme V446A, pH and temperature not specified in the publication
0.016
L-N2-(2-carboxyethyl)arginine
mutant enzyme H447A, pH and temperature not specified in the publication
0.13
L-N2-(2-carboxyethyl)arginine
mutant enzyme V446G, pH and temperature not specified in the publication
0.28
L-N2-(2-carboxyethyl)arginine
mutant enzyme V446A, pH and temperature not specified in the publication
0.87
L-N2-(2-carboxyethyl)arginine
wild type enzyme, pH and temperature not specified in the publication
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
Uniprot
brenda
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
metabolism
the enzyme is involved in clavulanic acid biosynthesis
metabolism
-
the enzyme is involved in clavulanic acid biosynthesis
-
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). BLS_STRCL
513
0
54530
Swiss-Prot
Chloroplast (Reliability: 2)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H447A
the mutant shows severely reduced turnover number compared to the wild type enzyme
V446A
the mutant shows reduced turnover number compared to the wild type enzyme
V446G
the mutant shows strongly reduced turnover number compared to the wild type enzyme
additional information
disruption mutant, complete loss of clavulanic acid production, accumulation of N2-(carboxyethyl)-L-arginine, but no effect on synthesis of penicillin or cephamycin
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, 50 mM Tris-HCl, 10% glycerol, 2 mM dithiothreitol, 0.01 mM EDTA, pH 7.5, stable
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
Streptomyces venezuelae YJ028 is utilized as the heterologous host for the expression of four structural clavulanic acid biosynthesis genes, which encode carboxyethylarginine synthase (ceas2), beta-lactam synthetase (bls2), clavaminate synthase (cas2), and proclavaminate amidinohydrolase (pah2). The genes are cloned into pIBR25 expression vector containing ermE promoter to generate pBS4. The cas2 gene is also cloned into pSET152 to generate pCas2. It is then integrated into the genome of Streptomyces venezuelae YJ028
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
synthesis
synthesis
clavulanic acid intermediates: deoxygaunidinoproclavaminic acid, guanidinoproclavaminic acid, and dihydroclavaminic acid are heterologously produced in Streptomyces venezuelae recombinant using four sets of early genes from the clavulanic acid biosynthetic pathway
synthesis
-
clavulanic acid intermediates: deoxygaunidinoproclavaminic acid, guanidinoproclavaminic acid, and dihydroclavaminic acid are heterologously produced in Streptomyces venezuelae recombinant using four sets of early genes from the clavulanic acid biosynthetic pathway
-
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Bachmann, B.O.; Li, R.; Townsend, C.A.
beta-Lactam synthetase: a new biosynthetic enzyme
Proc. Natl. Acad. Sci. USA
95
9082-9086
1998
Streptomyces clavuligerus (P0DJQ7)
brenda
Bachmann, B.O.; Townsend, C.A.
Kinetic mechanism of the beta-Lactam synthetase of Streptomyces clavuligerus
Biochemistry
39
11187-11193
2000
Streptomyces clavuligerus (P0DJQ7)
brenda
Miller, M.T.; Bachmann, B.O.; Townsend, C.A.; Rosenzweig, A.C.
The catalytic cycle of beta-lactam synthetase observed by X-ray crystallographic snapshots
Proc. Natl. Acad. Sci. USA
99
14752-14757
2002
Streptomyces clavuligerus (P0DJQ7)
brenda
Miller, M.T.; Bachmann, B.O.; Townsend, C.A.; Rosenzweig, A.C.
Structure of beta-lactam synthetase reveals how to synthesize antibiotics instead of asparagine
Nat. Struct. Biol.
8
684-689
2001
Streptomyces clavuligerus (P0DJQ7)
brenda
McNaughton, H.J.; Thirkettle, J.E.; Zhang, Z.; Schofield, C.J.; Jensen, S.E.; Barton, B.; Greaves, P.
beta-Lactam synthetase: implications for beta-lactamase evolution
Chem. Commun. (Camb.)
1998
2325-2326
1998
Streptomyces clavuligerus (P0DJQ7)
-
brenda
Townsend, C.A.
New reactions in clavulanic acid biosynthesis
Curr. Opin. Chem. Biol.
6
583-589
2002
Streptomyces clavuligerus (P0DJQ7)
brenda
Labonte, J.W.; Kudo, F.; Freeman, M.F.; Raber, M.L.; Townsend, C.A.
Engineering the synthetic potential of beta-lactam synthetase and the importance of catalytic loop dynamics
MedChemComm
3
960-966
2012
Streptomyces clavuligerus (P0DJQ7)
brenda
Shrestha, B.; Dhakal, D.; Darsandhari, S.; Pandey, R.; Pokhrel, A.; Jnawali, H.; Sohng, J.
Heterologous production of clavulanic acid intermediates in Streptomyces venezuelae
Biotechnol. Bioprocess Eng.
22
359-365
2017
Streptomyces clavuligerus (B5GLC7), Streptomyces clavuligerus DSM 738 (B5GLC7)
-
brenda
EXTERNAL LINKS (specific for EC-Number 6.3.3.4)
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