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Information on EC 4.3.2.2 - adenylosuccinate lyase and Organism(s) Bacillus subtilis and UniProt Accession P12047
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4.3.2.2 adenylosuccinate lyaseIUBMB Comments
Also acts on 1-(5-phosphoribosyl)-4-(N-succinocarboxamide)-5-aminoimidazole.
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Word Map
- 4.3.2.2
- purine
-
saicar
-
succinyladenosine
-
autistic
- carboxamide
-
psychomotor
- imp
-
succinylaminoimidazole
- amylosucrase
- ribotide
- geothermalis
-
aminoimidazole
- drug development
- medicine
The taxonomic range for the selected organisms is: Bacillus subtilis
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
adenylosuccinate lyase, asase, adenylosuccinase, succino-amp lyase, amps lyase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
adenylosuccinase
-
-
-
-
AMPS lyase
-
-
-
-
ASASE
-
-
-
-
ASL
Glutamyl-tRNA synthetase regulatory factor
-
-
-
-
lyase, adenylosuccinate
-
-
-
-
succino AMP-lyase
-
-
-
-
succino-AMP lyase
-
-
-
-
ASL
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
N6-(1,2-dicarboxyethyl)AMP = fumarate + AMP
uni-bi mechanism, where fumarate is removed by beta-elimination via a general base-general acid mechanism
-
(S)-2-[5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido]succinate = fumarate + 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide
uni-bi mechanism, where fumarate is removed by beta-elimination via a general base-general acid mechanism
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
-
-, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming)
Also acts on 1-(5-phosphoribosyl)-4-(N-succinocarboxamide)-5-aminoimidazole.
CAS REGISTRY NUMBER
COMMENTARY
9027-81-0
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
(S)-2-[5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido]succinate
fumarate + 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide
-
-
-
-
?
5-aminoimidazole-(N-succinylocarboxamide) ribotide
5-aminoimidazole-4-carboxamide ribotide + fumarate
-
-
-
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
adenylosuccinate
AMP + fumarate
-
-
-
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
-
-
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
i.e. SAICAR
i.e. AICAR
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
-
-
-
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
-
i.e. SAICAR
i.e. AICAR
-
?
additional information
?
-
-
adenylosuccinate lyase catalyzes two reactions in the biosynthesis of purine nucleotides
-
-
?
additional information
?
-
-
residues Ser262 and Ser263 in a flexible loop of the enzyme are essential for catalysis
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
-
-
-
?
(S)-2-[5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido]succinate
fumarate + 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide
-
-
-
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
additional information
?
-
-
adenylosuccinate lyase catalyzes two reactions in the biosynthesis of purine nucleotides
-
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
-
-
-
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
-
i.e. SAICAR
i.e. AICAR
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KBr
presence of increasing concentrations of KBr of 0.12.5 M disrupt electrostatic interactions leading to ASL dissociation and loss of catalytic activity
adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate
-
i.e. APBADP, the non-cleavable substrate analogue acts as a competitive inhibitor with respect to either substrate. ASL binds up to 4 mol of APBADP per mole of enzyme tetramer, the enzyme exhibits negative cooperativity. Binding to enzyme mutants, overview
trans-4-hydroxy-2-nonenal
-
10-15 µM, inhibitor reacts both with the free enzyme and the enzyme substrate complex
additional information
as hydrophobic interactions are weakened at 8°C and 4°C, the catalytic activity of ASL decreases strikingly and the enzyme dissociates to a mixture of monomer-dimer-trimer, with small amounts of tetramer
-
additional information
-
as hydrophobic interactions are weakened at 8°C and 4°C, the catalytic activity of ASL decreases strikingly and the enzyme dissociates to a mixture of monomer-dimer-trimer, with small amounts of tetramer
-
additional information
-
dithiothreitol increases inhibition of trans-4-hydroxy-2-nonenal
-
additional information
-
hydroxylamine reverses inhibition of trans-4-hydroxy-2-nonenal
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0029
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
-
pH 7.0, 25°C, wild-type enzyme
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.16
adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate
-
inhibition kinetics, overview
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.068
-
complementation of inactive mutant ASLs, maximum specific activity, T93A + H141Q, 3.0% wild-type activity
0.069
-
mutant I62D/D65R, succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
0.094
-
mutant I62D/D65R/D69E, succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
0.096
-
complementation of inactive mutant ASLs, maximum specific activity, S306A + H141Q, 4.6% wild-type activity
0.18
-
mutant I62D/D65R + I62E/D65R/D69E, adenylsuccinate, 50 mM HEPES, pH 7.0, 25°C
0.21
-
complementation of inactive mutant ASLs, maximum specific activity, T93A + K268Q, 10.1% wild-type activity
0.24
0.32
0.46
-
mutant I62E/D65R/D69E, succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
0.53
-
mutant I62E/D65R/D69E, succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
0.97
-
mutant I62E/D65R/D69E, adenylsuccinate + succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
1.09
-
mutant I62D/D65R, adenylsuccinate + succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
1.29
-
mutant I62D/D65R + I62E/D65R/D69E, adenylsuccinate + succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
1.3
-
mutant I62D/D65R/D69E, adenylsuccinate + succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
1.4
-
mutant I62E/D65R/D69E, adenylsuccinate + succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
additional information
0.24
-
mutant I62D/D65R + I62E/D65R/D69E, succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
0.24
-
complementation of inactive mutant ASLs, maximum specific activity, T140A + H68Q, 11.5% wild-type activity
0.32
-
complementation of inactive mutant ASLs, maximum specific activity, S306A + K268Q, 15.4% wild-type activity
0.32
-
complementation of inactive mutant ASLs, maximum specific activity, T140A + K268Q, 15.4% wild-type activity
additional information
specific activities of different enzyme variants with different subunit numbers
additional information
-
specific activities of different enzyme variants with different subunit numbers
additional information
-
complementation of inactive mutant ASLs, maximum specific activity, T140A + H141Q, T93A + H68Q, S306A + H68Q 0% wild-type activity
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
147000
-
determined by native polyacrylamide gel electrophoresis, wild-type enzyme
148000
-
determined by native polyacrylamide gel electrophoresis, mutant R310K
152000
-
mutant N270L, light scattering measurements, 0.2 mg/ml enzyme in a filtered 20 mM potassium phosphate buffer at pH 7.0, containing 20 mM potassium chloride
153000
-
wild type, light scattering measurements, 0.2 mg/ml enzyme in a filtered 20 mM potassium phosphate buffer at pH 7.0, containing 20 mM potassium chloride
159000
166000
-
mutant N270D, light scattering measurements, 0.2 mg/ml enzyme in a filtered 20 mM potassium phosphate buffer at pH 7.0, containing 20 mM potassium chloride
173000
174000
-
mutant Q212M, light scattering measurements, 0.2 mg/ml enzyme in a filtered 20 mM potassium phosphate buffer at pH 7.0, containing 20 mM potassium chloride
176000
191000
193000
-
determined by native polyacrylamide gel electrophoresis, mutant S93A
194000
196000
219000
-
mutant R301Q, light scattering measurements, 0.2 mg/ml enzyme in a filtered 20 mM potassium phosphate buffer at pH 7.0, containing 20 mM potassium chloride
50000
159000
-
mutant Q212E, light scattering measurements, 0.2 mg/ml enzyme in a filtered 20 mM potassium phosphate buffer at pH 7.0, containing 20 mM potassium chloride
173000
-
mutant R301K, light scattering measurements, 0.2 mg/ml enzyme in a filtered 20 mM potassium phosphate buffer at pH 7.0, containing 20 mM potassium chloride
194000
-
determined by native polyacrylamide gel electrophoresis, mutant T93A
196000
-
determined by native polyacrylamide gel electrophoresis, wild-type enzyme
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
tetramer
a homotetramer in which three subunits contribute to each of four active sites, analytical ultracentrifugation, gel filtration, circular dichroism spectroscopy, and interaction analysis, overview. ASL is active and exists as 100% tetramer at 25°C, while at 8°C and 4°C, as hydrophobic interactions are weakened, the catalytic activity decreases strikingly and the enzyme dissociates to a mixture of monomer-dimer-trimer, with small amounts of tetramer. In the presence of increasing concentrations of KBr of 0.12.5 M, which disrupts electrostatic interactions, ASL is dissociated initially to monomerdimer, with small amounts of trimer-tetramer, and then the monomer species predominates along with small amounts of trimer-tetramer, analytical ultracentrifugation, homology modelling of wild-type and mutant enzymes, overview
homotetramer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E239M
site-directed mutagenesis, the mutant shows reduced Vmax, increased Km, and lower molecular weight compared to the wild-type enzyme, subunit structure analysis
E239Q
site-directed mutagenesis, the mutant shows reduced Vmax, increased Km, and lower molecular weight compared to the wild-type enzyme, subunit structure analysis
E239R
site-directed mutagenesis, the mutant shows reduced Vmax, increased Km, and lower molecular weight compared to the wild-type enzyme, subunit structure analysis
H299K
site-directed mutagenesis, the mutant shows reduced Vmax, increased Km, and lower molecular weight compared to the wild-type enzyme, subunit structure analysis
H299R
site-directed mutagenesis, the mutant shows reduced Vmax, increased Km, and lower molecular weight compared to the wild-type enzyme, subunit structure analysis
R167E
site-directed mutagenesis, the mutant shows reduced Vmax, increased Km, and lower molecular weight compared to the wild-type enzyme, subunit structure analysis
R167Q
site-directed mutagenesis, the mutant shows reduced Vmax, increased Km, and lower molecular weight compared to the wild-type enzyme, subunit structure analysis
D65R
-
mutant with differences in thermal stability, catalytic activity and substrate binding
D65R/D69E
-
mutant with differences in thermal stability, catalytic activity and substrate binding
D69E
D69N
H141Q
-
site-directed mutagenesis, the mutant shows altered binding of inhibitory substrate analogue adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate compared to the wild-type enzyme
H68A
-
site-directed mutagenesis, the mutant shows altered binding of inhibitory substrate analogue adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate compared to the wild-type enzyme
H89Q
-
site-directed mutagenesis, the mutant shows altered binding of inhibitory substrate analogue adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate compared to the wild-type enzyme
H89R
-
site-directed mutagenesis, the mutant shows altered binding of inhibitory substrate analogue adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate compared to the wild-type enzyme
I62D
-
mutant with differences in thermal stability, catalytic activity and substrate binding
I62D/D65R
-
mutant with differences in thermal stability, catalytic activity and substrate binding
I62D/D65R/D69E
-
mutant with differences in thermal stability, catalytic activity and substrate binding
I62D/D69E
-
mutant with differences in thermal stability, catalytic activity and substrate binding
I62E
-
mutant with differences in thermal stability, catalytic activity and substrate binding
I62E/D65R/D69E
-
mutant with differences in thermal stability, catalytic activity and substrate binding
I62E/D69E
-
mutant with differences in thermal stability, catalytic activity and substrate binding
S262A
-
site-directed mutagenesis, the mutant shows no activity and altered molecular weight compared to the wild-type enzyme
S262H
-
site-directed mutagenesis, the mutant shows no activity and altered molecular weight compared to the wild-type enzyme
S263A
-
site-directed mutagenesis, the mutant shows no activity and altered molecular weight compared to the wild-type enzyme
S263H
-
site-directed mutagenesis, the mutant shows no activity and altered molecular weight compared to the wild-type enzyme
S306A
-
conserved amino acid in all adenylosuccinate lyases, mutant for testing the involvement of the residue in the enzyme function
S94A
-
conserved amino acid in all adenylosuccinate lyases, mutant for testing the involvement of the residue in the enzyme function
T140A
-
conserved amino acid in all adenylosuccinate lyases, mutant for testing the involvement of the residue in the enzyme function
T93A
-
conserved amino acid in all adenylosuccinate lyases, mutant for testing the involvement of the residue in the enzyme function
D69E
-
mutant with differences in thermal stability, catalytic activity and substrate binding
D69N
-
site-directed mutagenesis, the mutant shows altered binding of inhibitory substrate analogue adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate compared to the wild-type enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His6-tagged wild-type and mutant enzymes from Escherichia coli strain Bl21 by nickel affinity chromatography
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of His6-tagged wild-type and mutant enzymes in Escherichia coli strain BL21
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
participates in the purine biosynthetic pathway, enzyme defects result in psychomotor retardation, epilepsy, muscle wasting and autistic features
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ebbole, D.J.; Zalkin, H.
Cloning and characterization of a 12-gene cluster from Bacillus subtilis encoding nine enzymes for de novo purine nucleotide synthesis
J. Biol. Chem.
262
8274-8287
1987
Bacillus subtilis
Redinbo, M.R.; Eide, S.M.; Stone, R.L.; Dixon, J.E.; Yeates, T.O.
Crystallization and preliminary structural analysis of Bacillus subtilis adenylosuccinate lyase, an enzyme implicated in infantile autism
Protein Sci.
5
786-788
1996
Bacillus subtilis
Segall, M.L.; Colman, R.F.
Gln212, Asn270, and Arg301 are critical for catalysis by adenylosuccinate lyase from Bacillus subtilis
Biochemistry
43
7391-7402
2004
Bacillus subtilis
Crifo, C.; Siems, W.; Soro, S.; Salerno, C.
Inhibition of defective adenylosuccinate lyase by HNE: a neurological disease that may be affected by oxidative stress
Biofactors
24
131-136
2005
Bacillus subtilis, Homo sapiens, Pyrobaculum aerophilum, Thermotoga maritima
Sivendran, S.; Patterson, D.; Spiegel, E.; McGown, I.; Cowley, D.; Colman, R.F.
Two novel mutant human adenylosuccinate lyases (ASLs) associated with autism and characterization of the equivalent mutant Bacillus subtilis ASL
J. Biol. Chem.
279
53789-53797
2004
Bacillus subtilis, Homo sapiens
Spiegel, E.K.; Colman, R.F.; Patterson, D.
Adenylosuccinate lyase deficiency
Mol. Genet. Metab.
89
19-31
2006
Bacillus subtilis, Homo sapiens, Mus musculus, Pyrobaculum aerophilum, Thermotoga maritima (Q9X0I0)
Sivendran, S.; Segall, M.L.; Rancy, P.C.; Colman, R.F.
Effect of Asp69 and Arg310 on the pK of His68, a key catalytic residue of adenylosuccinate lyase
Protein Sci.
16
1700-1707
2007
Bacillus subtilis
Segall, M.L.; Cashman, M.A.; Colman, R.F.
Important roles of hydroxylic amino acid residues in the function of Bacillus subtilis adenylosuccinate lyase
Protein Sci.
16
441-448
2007
Bacillus subtilis
De Zoysa Ariyananda, L.; Colman, R.F.
Evaluation of types of interactions in subunit association in Bacillus subtilis adenylosuccinate lyase
Biochemistry
47
2923-2934
2008
Bacillus subtilis (P12047), Bacillus subtilis
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