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Information on EC 4.2.1.24 - porphobilinogen synthase and Organism(s) Pseudomonas aeruginosa

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EC Tree
     4 Lyases
         4.2 Carbon-oxygen lyases
             4.2.1 Hydro-lyases
                4.2.1.24 porphobilinogen synthase
IUBMB Comments
The enzyme catalyses the asymmetric condensation and cyclization of two 5-aminolevulinate molecules, which is the first common step in the biosynthesis of tetrapyrrole pigments such as porphyrin, chlorophyll, vitamin B12, siroheme, phycobilin, and cofactor F430. The enzyme is widespread, being essential in organisms that carry out respiration, photosynthesis, or methanogenesis. The enzymes from most organisms utilize metal ions (Zn2+, Mg2+, K+, and Na+) as cofactors that reside at multiple sites, including the active site and allosteric sites. Enzymes from archaea, yeast, and metazoa (including human) contain Zn2+ at the active site. In humans, the enzyme is a primary target for the environmental toxin Pb. The enzymes from some organisms utilize a dynamic equilibrium between architecturally distinct multimeric assemblies as a means for allosteric regulation.
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Pseudomonas aeruginosa
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Word Map
The taxonomic range for the selected organisms is: Pseudomonas aeruginosa
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
Synonyms
delta-aminolevulinic acid dehydratase, ala-d, pbgs, delta-ala-d, delta-aminolevulinate dehydratase, ala dehydratase, porphobilinogen synthase, ala synthetase, 5-aminolevulinic acid dehydratase, delta-alad, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5-aminolevulinate dehydrase
-
-
-
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5-aminolevulinate dehydratase
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-
-
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5-aminolevulinate hydro-lyase (adding 5-aminolevulinate and cyclizing)
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-
-
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5-aminolevulinic acid dehydrase
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-
-
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5-aminolevulinic acid dehydratase
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-
-
-
5-levulinic acid dehydratase
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-
-
-
ALAD
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-
-
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ALADH
-
-
-
-
aminolevulinate dehydrase
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-
-
-
aminolevulinate dehydratase
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-
-
-
aminolevulinic dehydratase
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-
-
-
delta-ALAD
-
-
-
-
delta-aminolevulinate dehydrase
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-
-
-
delta-aminolevulinate dehydratase
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-
-
-
delta-aminolevulinic acid dehydrase
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-
-
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delta-aminolevulinic acid dehydratase
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-
-
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delta-aminolevulinic dehydratase
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-
-
-
gamma-aminolevulinic acid dehydratase
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-
-
-
Porphobilinogen synthase
porphobilinogen synthetase
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-
-
-
synthase, porphobilinogen
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-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
2 5-aminolevulinate = porphobilinogen + 2 H2O
show the reaction diagram
SYSTEMATIC NAME
IUBMB Comments
5-aminolevulinate hydro-lyase (adding 5-aminolevulinate and cyclizing; porphobilinogen-forming)
The enzyme catalyses the asymmetric condensation and cyclization of two 5-aminolevulinate molecules, which is the first common step in the biosynthesis of tetrapyrrole pigments such as porphyrin, chlorophyll, vitamin B12, siroheme, phycobilin, and cofactor F430. The enzyme is widespread, being essential in organisms that carry out respiration, photosynthesis, or methanogenesis. The enzymes from most organisms utilize metal ions (Zn2+, Mg2+, K+, and Na+) as cofactors that reside at multiple sites, including the active site and allosteric sites. Enzymes from archaea, yeast, and metazoa (including human) contain Zn2+ at the active site. In humans, the enzyme is a primary target for the environmental toxin Pb. The enzymes from some organisms utilize a dynamic equilibrium between architecturally distinct multimeric assemblies as a means for allosteric regulation.
CAS REGISTRY NUMBER
COMMENTARY hide
9036-37-7
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
5-aminolevulinate
?
show the reaction diagram
5-aminolevulinate + 5-aminolevulinate
porphobilinogen + 2 H2O
show the reaction diagram
5-aminolevulinic acid + 5-aminolevulinic acid
porphobilinogen + 2 H2O
show the reaction diagram
-
-
-
?
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
5-aminolevulinate
?
show the reaction diagram
5-aminolevulinate + 5-aminolevulinate
porphobilinogen + 2 H2O
show the reaction diagram
porphobilinogen synthase catalyzes the first committed step of the tetrapyrrole biosynthesis pathway
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Co2+
-
partially restores activity after inhibition with EDTA
K+
-
stimulates
Li+
-
stimulates
Na+
-
stimulates
Ni2+
-
partially restores activity after inhibition with EDTA
Zn2+
-
partially restores activity after inhibition with EDTA
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2,2-difluorosuccinic acid
-
competitive
5,5'-iminobis(4-oxopentanoic acid)
5,5'-oxybis(4-oxopentanoic acid)
5,5'-sulfinylbis(4-oxopentanoic acid)
5,5'-sulfonylbis(4-oxopentanoic acid)
5,5'-thiobis(4-oxopentanoic acid)
5-fluorolevulinic acid
both inhibitor molecules are covalently bound to two conserved, active-site lysine residues, Lys205 and lys260, through Schiff bases
5-hydroxylevulinic acid
-
alaremycin
porphobilinogen synthase is cocrystallized with the alaremycin. At 1.75 A resolution, the crystal structure reveals that the antibiotic efficiently blocks the active site of porphobilinogen synthase. The antibiotic binds as a reduced derivative of 5-acetamido-4-oxo-5-hexenoic acid. The corresponding methyl group is not coordinated by any amino acid residues of the active site, excluding its functional relevance for alaremycin inhibition. Alaremycin is covalently bound by the catalytically important active-site lysine residue 260 and is tightly coordinated by several active-site amino acids
diethyl dicarbonate
-
-
EDTA
-
activity can be completely restored by addition of Mg2+ or Mn2+. Co2+, Zn2+, and Ni2+ partially restore EDTA-inhibited activity
levulinic acid
-
-
protoporphyrin IX
-
-
pyridoxal phosphate
-
-
succinic acid
-
noncompetitive
succinic acid monomethyl ester
-
competitive
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
NH4+
-
stimulates
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.33
5-aminolevulinate
-
pH 8.6 in Na-Hepes buffer
0.00032
5-aminolevulinic acid
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
16.1
5-aminolevulinic acid
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
50300
5-aminolevulinic acid
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
7
2,2-difluorosuccinic acid
-
-
0.2 - 0.313
5,5'-iminobis(4-oxopentanoic acid)
0.098 - 0.963
5,5'-oxybis(4-oxopentanoic acid)
9.94 - 10.8
5,5'-sulfinylbis(4-oxopentanoic acid)
0.342 - 11
5,5'-sulfonylbis(4-oxopentanoic acid)
0.06 - 38.4
5,5'-thiobis(4-oxopentanoic acid)
4.05
5-hydroxylevulinic acid
37°C, pH 8.5
0.03
diethyl dicarbonate
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-
1.5
levulinic acid
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-
0.0025
protoporphyrin IX
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-
0.03
pyridoxal phosphate
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-
9
succinic acid
-
-
1.9
succinic acid monomethyl ester
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-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.31
5,5'-iminobis(4-oxopentanoic acid)
Pseudomonas aeruginosa
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-
0.96
5,5'-oxybis(4-oxopentanoic acid)
Pseudomonas aeruginosa
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-
38
5,5'-sulfinylbis(4-oxopentanoic acid)
Pseudomonas aeruginosa
-
-
9.9
5,5'-sulfonylbis(4-oxopentanoic acid)
Pseudomonas aeruginosa
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-
0.34
5,5'-thiobis(4-oxopentanoic acid)
Pseudomonas aeruginosa
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-
1.33
alaremycin
Pseudomonas aeruginosa
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8.6
-
in presence of Mg2+ and K+
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5 - 9.8
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pH 7.5: about 35% of maximal activity, pH 9.8: about 50% of maximal activity
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.4
-
isoelectric focusing, pH-range 3-10
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
A0A072ZJ09_PSEAI
337
0
37037
TrEMBL
-
A0A8G5GD65_PSEAI
337
0
37065
TrEMBL
-
A0A8G3V8L5_PSEAI
337
0
37065
TrEMBL
-
Q9R7M4_PSEAI
43
0
4721
TrEMBL
-
A0A431X5J4_PSEAI
337
0
37067
TrEMBL
-
A0A2R3IW84_PSEAI
337
0
37113
TrEMBL
-
Q9S645_PSEAI
75
0
8511
TrEMBL
-
A0A8G6DU24_PSEAI
337
0
37035
TrEMBL
-
A0A8G4DXD3_PSEAI
337
0
36988
TrEMBL
-
A0A4P0TG86_PSEAI
352
0
39066
TrEMBL
-
A0A659C2G9_PSEAI
337
0
37065
TrEMBL
-
A0A8G2RS58_PSEAI
337
0
37067
TrEMBL
-
A0A8G4DZB3_PSEAI
337
0
36977
TrEMBL
-
A0A8G6EGX7_PSEAI
337
0
37049
TrEMBL
-
A0A6B1YHV8_PSEAI
337
0
37064
TrEMBL
-
A0A8G6I5W4_PSEAI
337
0
36977
TrEMBL
-
A0A8G6V065_PSEAI
337
0
37095
TrEMBL
-
A0A6A9JRE6_PSEAI
337
0
37051
TrEMBL
-
A0A8G7BVK4_PSEAI
337
0
37024
TrEMBL
-
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
280000
-
gel filtration
37832
-
6 * 37832, electrospray ionization mass spectrometry
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
octamer
-
6 * 37832, electrospray ionization mass spectrometry
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop vapor-diffusion method. Crystal structures of the active site of Pseudomonas aeruginosa PBGS with the various inhibitors 5-hydroxylevulinic acid, 5,5'-oxybis(4-oxopentanoic acid), 5,5'-iminobis(4-oxopentanoic acid), 5,5'-thiobis(4-oxopentanoic acid), 5,5'-sulfinylbis(4-oxopentanoic acid) or 5,5'-sulfonylbis(4-oxopentanoic acid)
hanging drop vapour diffusion method, crystals of the enzyme complex with levulinic acid solved at 1.67 A resolution, crystals belong to space group P42(1)2 with cell dimensions of a = b = 129.8 A, c = 86.7 A
-
porphobilinogen synthase is cocrystallized with the alaremycin
structure of the active-site variant D139N of the Mg2+-dependent enzyme in complex with the inhibitor 5-fluorolevulinic acid
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
using affinity chromatography and anion-exchange chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli as a His-tagged fusion protein
expression in Escherichia coli
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Frankenberg, N.; Kittel, T.; Hungerer, C.; Rrnemann, D.
Cloning, mapping and functional characterization of the hemB gene of Pseudomonas aeruginosa, which encodes a magnesium-dependent 5-aminolevulinic acid dehydratase
Mol. Gen. Genet.
257
485-489
1998
Pseudomonas aeruginosa
Manually annotated by BRENDA team
Frankenberg, N.; Jahn, D.; Jaffe, E.K.
Pseudomonas aeruginosa contains a novel type V porphobilinogen synthase with no required catalytic metal ions
Biochemistry
38
13976-13982
1999
Pseudomonas aeruginosa
Manually annotated by BRENDA team
Jaffe, E.K.
The porphobilinogen synthase family of metalloenzymes
Acta Crystallogr. Sect. D
56
115-128
2000
Actinobacillus sp., Synechocystis sp., Aquifex sp., Archaeoglobus sp., Bordetella sp., Bradyrhizobium sp., Campylobacter sp., Candida sp. (in: Saccharomycetales), Caulobacter sp., Streptomyces sp., Chlamydia sp., Chlamydomonas sp., Clostridium sp., Deinococcus sp., Escherichia coli, Helicobacter sp., Homo sapiens, Methanobacterium sp., Methanococcus sp., Methanothermus sp., Mycobacterium sp., Neisseria sp., Physcomitrella sp., Pisum sativum, Propionibacterium sp., Rattus norvegicus, Rhodobacter sp., Rickettsia sp., Salmonella sp., Schizosaccharomyces sp., Shewanella sp., Vibrio sp., Yersinia sp., Saccharomyces cerevisiae (P05373), Pseudomonas aeruginosa (Q59643)
Manually annotated by BRENDA team
Frere, F.; Schubert, W.D.; Stauffer, F.; Frankenberg, N.; Neier, R.; Jahn, D.; Heinz, D.W.
Structure of porphobilinogen synthase from Pseudomonas aeruginosa in complex with 5-fluorolevulinic acid suggests a double Schiff base mechanism
J. Mol. Biol.
320
237-247
2002
Pseudomonas aeruginosa (Q59643), Pseudomonas aeruginosa
Manually annotated by BRENDA team
Frankenberg, N.; Heinz, D.W.; Jahn, D.
Production, purification, and characterization of a Mg2+-responsive porphobilinogen synthase from pseudomonas aeruginosa
Biochemistry
38
13968-13975
1999
Pseudomonas aeruginosa
Manually annotated by BRENDA team
Frere, F.; Nentwich, M.; Gacond, S.; Heinz, D.W.; Neier, R.; Frankenberg-Dinkel, N.
Probing the active site of Pseudomonas aeruginosa porphobilinogen synthase using newly developed inhibitors
Biochemistry
45
8243-8253
2006
Pseudomonas aeruginosa (Q59643), Pseudomonas aeruginosa
Manually annotated by BRENDA team
Gacond, S.; Frere, F.; Nentwich, M.; Faurite, J.P.; Frankenberg-Dinkel, N.; Neier, R.
Synthesis of bisubstrate inhibitors of porphobilinogen synthase from Pseudomonas aeruginosa
Chem. Biodivers.
4
189-202
2007
Pseudomonas aeruginosa
Manually annotated by BRENDA team
Heinemann, I.U.; Schulz, C.; Schubert, W.D.; Heinz, D.W.; Wang, Y.G.; Kobayashi, Y.; Awa, Y.; Wachi, M.; Jahn, D.; Jahn, M.
Structure of the heme biosynthetic Pseudomonas aeruginosa porphobilinogen synthase in complex with the antibiotic alaremycin
Antimicrob. Agents Chemother.
54
267-272
2010
Pseudomonas aeruginosa (Q59643), Pseudomonas aeruginosa
Manually annotated by BRENDA team