Information on EC 4.1.3.38 - aminodeoxychorismate lyase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY
4.1.3.38
-
RECOMMENDED NAME
GeneOntology No.
aminodeoxychorismate lyase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
4-amino-4-deoxychorismate = 4-aminobenzoate + pyruvate
show the reaction diagram
A pyridoxal-phosphate protein; A pyridoxal-phosphate protein.; a pyridoxal-phosphate protein. Forms part of the folate biosynthesis pathway. Acts on 4-amino-4-deoxychorismate, the product of EC 6.3.5.8, aminodeoxychorismate synthase, to form p-aminobenzoate
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-
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4-amino-4-deoxychorismate = 4-aminobenzoate + pyruvate
show the reaction diagram
catalytic mechanism, overview
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
beta-elimination
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
4-aminobenzoate biosynthesis
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tetrahydrofolate metabolism
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Folate biosynthesis
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SYSTEMATIC NAME
IUBMB Comments
4-amino-4-deoxychorismate pyruvate-lyase (4-aminobenzoate-forming)
A pyridoxal-phosphate protein. Forms part of the folate biosynthesis pathway. Acts on 4-amino-4-deoxychorismate, the product of EC 2.6.1.85, aminodeoxychorismate synthase, to form p-aminobenzoate.
SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4-amino-4-deoxychorismate lyase
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-
-
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4-amino-4-deoxychorismate lyase
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4-amino-4-deoxychorismate lyase
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4-amino-4-deoxychorismate lyase
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4-amino-4-deoxychorismate lyase
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-
4-amino-4-deoxychorismate lyase
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ADC lyase
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-
-
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ADCL
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-
-
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enzyme X
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-
-
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TTHA0621 protein
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CAS REGISTRY NUMBER
COMMENTARY
132264-33-6
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
BN117 cells
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-
Manually annotated by BRENDA team
SG-5 cells
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-
Manually annotated by BRENDA team
plasmodial gene PF14_0557 encodes a functional ADCL; gene PF14_0557
UniProt
Manually annotated by BRENDA team
Mill. cv. Micro-Tom
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-
Manually annotated by BRENDA team
PabC-2; strain FR-008
UniProt
Manually annotated by BRENDA team
strain FR-008
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-
Manually annotated by BRENDA team
PabC-2; strain FR-008
UniProt
Manually annotated by BRENDA team
strain FR-008
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-
Manually annotated by BRENDA team
putative 4-amino-4-deoxychorismate lyase; strain HB8
UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
4-amino-4-deoxychorismate lyases can be divided into two classes of dimeric and monomeric enzyme, respectively
physiological function
the enzyme is active in folate biosynthesis and essential for the cell growth of the pathogen
evolution
structure comparisons with related enzymes, overview. PabC enzymes can be classified into two groups depending upon whether an active site and structurally conserved tyrosine is provided from the polypeptide that mainly forms an active site or from the partner subunit in the dimeric assembly
additional information
the catalytic residue Lys251 covalently binds the cofactor pyridoxal 5'-phosphate
additional information
structure-activity relationship of PabC, ligand binding modeling and reaction mechanism, overview. No structure of PabC in complex with ligands is achieved, but a computational model of the catalytic intermediate docked into the enzyme active site is generated. A conserved tyrosine helps to create a hydrophobic wall on one side of the active site that provides important interactions to bind the catalytic intermediate, but it does not appear to participate in interactions with the C atom that undergoes an sp2 to sp3 conversion as pyruvate is produced. An active site threonine hydroxyl contributes a proton used in the reduction of the substrate methylene to pyruvate methyl in the final stage of the mechanism
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
re-face specificity
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
last step of the 4-aminobenzoate branch
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?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
molecular modeling of the catalytic intermediate, overview
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?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
simulation and validation of the substrate-binding model, overview
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?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
the enzyme catalyzes the beta-elimination of pyruvate and the aromatization of the ADC ring to yield 4-aminobenzoate. Substrate synthesis from chorismate and ammonia by chorismate aminase in a coupled assay, the substrate is unstable
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?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
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-
?
D-alanine + pyridoxal 5'-phosphate
pyridoxamine 5'-phosphate + pyruvate
show the reaction diagram
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L-alanine and other D- and L-amino acids tested are inert as substrates of transamination
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r
additional information
?
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the enzyme also shows a pyridoxal 5'-phosphate-dependent transamination activity with D-asparate, EC 2.6.1.1, but PF14_0557 is unable to transaminate branched-chain amino acids L-leucine, L-isoleucine and L-valine. The enzyme also fails completely to carry out a transamination reaction between L-glutamate and 4-methyl 2-oxovalerate
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
-
-
?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
Q9HZN6
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?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
Q8IKP7
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?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
Q03266
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?
4-amino-4-deoxychorismate
4-aminobenzoate + pyruvate
show the reaction diagram
-
last step of the 4-aminobenzoate branch
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?
D-alanine + pyridoxal 5'-phosphate
pyridoxamine 5'-phosphate + pyruvate
show the reaction diagram
-
L-alanine and other D- and L-amino acids tested are inert as substrates of transamination
-
r
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pyridoxal 5'-phosphate
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tightly bound
pyridoxal 5'-phosphate
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-
pyridoxal 5'-phosphate
dependent on
pyridoxal 5'-phosphate
;
pyridoxal 5'-phosphate
dependent on
pyridoxal 5'-phosphate
dependent on, one molecule of cofactor is deeply buried in the cleft between domains I and II, pyridoxal 5'-phosphate adopts the re-face specificity facing the protein side and is covalently linked to the catalytic residue Lys251 by forming an internal aldimine bond, Schiff base linkage
pyridoxal 5'-phosphate
dependent on, the PLP methyl group makes van der Waals interactions with Gln147 and is positioned 3.2 A distant from the carbonyl oxygen of Val175, Ser237 interacts with the pyridoxal 5'-phosphate phosphate
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
D-glutamate
complete inhibition of the transamination activity of the enzyme
additional information
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no feedback inhibition by physiological concentrations of 4-aminobenzoate, its glucose ester, or folates
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30
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assay at
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Pseudomonas aeruginosa (strain ATCC 15692 / PAO1 / 1C / PRS 101 / LMG 12228)
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
50000
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gel filtration
644227
50000
gel filtration
644228
50000
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gel filtration
644229
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
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2 * 25000, SDS-PAGE
dimer
2 * 29700, most likely dimeric, SDS-PAGE
dimer
-
2 * 29715
dimer
sequence comparisons, structure modeling of the catalytic intermediate and ligand-bound enzyme, overview
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
small yellow prisms crystals in the unliganded form obtained using the sparse-matrix method along with the hanging-drop vapor-difussion method
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purified recombinant detagged enzyme, hanging drop vapour diffusion method, mixing of 0.001 ml of 33 mg/mL prrotein in 100 mM HEPES, pH 7.5, 500 mM NaCl, 0.1 mM pyridoxal 5'-phosphate, and 10 mM 4-aminobenzoate, with 0001 ml of reservoir solution containing 10% w/v PEG 400, 1.8 M ammonium sulfate and 100 mM MES, pH 6.5, 20°C, 1 week, X-ray diffraction structure dtermination and analysis at 1.75 A resolution
purified recombinant selenomethionine-labeled enzyme and of purified recombinant wild-type enzyme in complex with cofactor pyridoxal 5'-phosphate, hanging drop vapor diffusion method, mixing of 0.001 ml of 10 mg/ml protein in 100 mM NaCl, 20 mM Tris-Cl, pH 8.0, with an equal volume of reservoir solution containing 20% w/v PEG monomethyl ether 5000, 0.1 M Bis-Tris, pH 6.2, 1-2 days to 1 week, 16°C, X-ray diffraction structure determination and analysis at 1.90-2.20 A resolution
sitting drop vapor diffusion method, using 0.1 M HEPES buffer pH 8.0 containing 1.3 M Li2SO4 and 2% (v/v) PEG 200
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
DEAE-Sephacel, phenyl-Sepharose column, Superose 6 gel filtration column, Mono Q, Superose 12 column, yield 400-800fold
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fractionation with ammonium sulfate pH 7.5, DEAE-Sephacel column, butyl-Sepharose 4B column, Gigapite column
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fractionation with ammonium sulfate, DEAE-Toyopearl column, butyl-Toyopearl column and Mono Q column
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reactive yellow 3-agarose column, Mono Q HR 5/5 FPLC column, Superose 12HR 10/30 FPLC column, Mono Q HR 5/20 FPLC column, Aquapore RP-300 C8 HPLC column: 4100fold to near homogeneity
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recombinant His6-tagged enzyme from Escherichia coli by metal affinity chromatography
recombinant His6-tagged enzyme from Escherichia coli strain BL21(DE3) GOLD by nickel affinity chromatography, cleavage of the tag by TEV protease, and gel filtration
recombinant His-tagged wild-type and selenomethionine-labeled enzymes from Escherichia coli strain BL21(DE3) and B834(DE3), respectively, by nickel affinity chromatography
nickel affinity column chromatography; nickel affinity column chromatography
Resource ISO column chromatography, ammonium sulfate precipitation, Resource Q column chromatography, and Superdex 75 gel filtration
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cDNAs are shown to encode functional enzymes by complementation of an Escherichia coli pabC mutant, and by demonstrating that the partially purified recombinant proteins convert 4-amino-4-deoxychorismate to 4-aminobenzoate. The full-length Arabidopsis ADC lyase polypeptide is translocated into isolated pea chloroplasts and, when fused to green fluorescent protein, directed the passenger protein to Arabidopsis chloroplasts in transient expression experiments
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expression in Escherichia coli JM109
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expression in Escherichia coli MC1000 cells
gene PF14_0557, functional overexpression as His6-tagged protein in Escherichia coli cells
gene pabC, expression of His6-tagged enzyme with TEV protease cleavage site in Escherichia coli strain BL21(DE3) GOLD
recombinant expression of His-tagged wild-type and selenomethionine-labeled enzymes in Escherichia coli strain BL21(DE3) and B834(DE3), respectively
cDNAs are shown to encode functional enzymes by complementation of an Escherichia coli pabC mutant, and by demonstrating that the partially purified recombinant proteins convert 4-amino-4-deoxychorismate to 4-aminobenzoate
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expressed in Escherichia coli BL21(DE3) cells; expressed in Escherichia coli BL21(DE3) cells
expressed in Escherichia coli B834 (DE3) cells
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K180A
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
N360A
site-directed mutagenesis, inactive mutant
N360D
site-directed mutagenesis, inactive mutant
T30A
site-directed mutagenesis, the mutant shows reduced activity compared to the wild-type enzyme
additional information
a mutant with pabC-1 inactivated still retains about 20% of the wild type level of antibiotic FR-008 production, pabC-1/pabC-2 double mutation severely reduces antibiotic FR-008 production and renders the mutant p-aminobenzoic acid-auxotrophic; pabC-1/pabC-2 double mutation severely reduces antibiotic FR-008 production and renders the mutant p-aminobenzoic acid-auxotrophic
additional information
-
a mutant with pabC-1 inactivated still retains about 20% of the wild type level of antibiotic FR-008 production, pabC-1/pabC-2 double mutation severely reduces antibiotic FR-008 production and renders the mutant p-aminobenzoic acid-auxotrophic; pabC-1/pabC-2 double mutation severely reduces antibiotic FR-008 production and renders the mutant p-aminobenzoic acid-auxotrophic
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
the absence of the enzyme in humans and its essentiality in various microbes suggests that inhibition of PabC offers the possibility of therapeutics targeting a range of microbial infections, potential of this protein for early stage drug discovery