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Information on EC 4.3.2.2 - adenylosuccinate lyase and Organism(s) Homo sapiens and UniProt Accession P30566
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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: Homo sapiens
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
1-(5-phosphoribosyl)-4-(N-succinocarboxamide)-5-aminoimidazole
5'-phosphoribosyl-5-amino-4-imidazolecarboxamide + fumarate
-
-
-
?
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
-
-
-
-
?
1-(5-phosphoribosyl)-4-(N-succinocarboxamide)-5-aminoimidazole
5'-phosphoribosyl-5-amino-4-imidazolecarboxamide + fumarate
-
-
-
-
?
4-(N-succino)-5-aminoimidazole-4-carboxamide ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
-
reaction in the biosynthesis of AMP
-
-
?
5-aminoimidazole-(N-succinylocarboxamide) ribotide
5-aminoimidazole-4-carboxamide ribotide + fumarate
-
-
-
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
adenylosuccinate 2',3'-acyclic dialcohol
adenylic 2',3'-acyclic dialcohol + fumarate
-
-
-
-
?
phosphoribosylsuccinyl-aminoimidazole carboxamide
phosphoribosylaminoimidazole carboxamide + 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
-
-
-
-
?
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
-
-
ZMP accumulation in the brain of Lesch-Nyhan disease patients induces inhibition of mitochondrial oxidative phosphorylation and adenylosuccinate lyase activity, followed by dowregulation of ATP levels and multifocal cell death in the cerebellum. ZMP is an inhibitor of the bifunctional enzyme adenylosuccinate lyase, a deficiency of this enzyme causes psychomotor and mental retardation in humans, overview, i.e. AICAR or ZMP
-
?
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
-
the 8th step in the purine nucleotide de novo pathway
-
-
?
N6-(1,2-dicarboxyethyl)AMP
fumarate + AMP
-
reaction in the biosynthesis of AMP
-
-
?
succinyladenosine monophosphate
AMP + fumarate
-
-
-
-
?
succinyladenosine monophosphate
AMP + fumarate
-
conversion of adenylosuccinate to adenylate in the purine nucleotide cycle
-
-
?
additional information
?
-
adenylosuccinate lyase catalyzes two reactions in the biosynthesis of purine nucleotides
-
-
?
additional information
?
-
-
adenylosuccinate lyase catalyzes two reactions in the biosynthesis of purine nucleotides
-
-
?
additional information
?
-
adenylosuccinate lyase deficiency is a rare autosomal disorder of de novo purine synthesis, which results in the accumulation of succinylpurines in body fluids. Patients with adenylosuccinate lyase deficiency show a variable combination of mental retardation, epilepsy and autistic features, overview
-
-
?
additional information
?
-
-
adenylosuccinate lyase deficiency is a rare autosomal disorder of de novo purine synthesis, which results in the accumulation of succinylpurines in body fluids. Patients with adenylosuccinate lyase deficiency show a variable combination of mental retardation, epilepsy and autistic features, overview
-
-
?
additional information
?
-
residue Ser289 is essential for catalysis
-
-
?
additional information
?
-
interaction between the enzyme and phosphoribosylsuccinyl-aminoimidazole carboxamide, isothermal titration calorimetry, overview. Modeling of AMPand phosphoribosylaminoimidazole carboxamide, and fumarate binding in the active site of wild-type and R303C mutant enzymes
-
-
?
additional information
?
-
-
interaction between the enzyme and phosphoribosylsuccinyl-aminoimidazole carboxamide, isothermal titration calorimetry, overview. Modeling of AMPand phosphoribosylaminoimidazole carboxamide, and fumarate binding in the active site of wild-type and R303C mutant enzymes
-
-
?
additional information
?
-
-
adenylosuccinate lyase deficiency is an autosomal recessive disorder of the purine de novo synthesis pathway and purine nucleotide cycleby severe neurological involvement including hypotonia, seizures, developmental delay and autistic features. Epilepsy in ADSL deficiency is frequent and occurs in approximately two-thirds of patients, beginning either early in the neonatal period or after the first year of life
-
-
?
additional information
?
-
-
ZMP is an activator of the AMP-activated protein kinase, AMPK, and is toxic in human B lymphocytes and neuroblastoma cell lines, physiological functions of ZMP, overview
-
-
?
additional information
?
-
-
development of a rapid and simple HPLC-based assay method to quantitatively measure ADSL activity with succinyladenosine monophosphate in erythrocytes using isocratic ionpairing reversed-phase HPLC with UV-detection, overview
-
-
?
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
1-(5-phosphoribosyl)-4-(N-succinocarboxamide)-5-aminoimidazole
5'-phosphoribosyl-5-amino-4-imidazolecarboxamide + fumarate
-
-
-
?
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
-
-
-
-
?
1-(5-phosphoribosyl)-4-(N-succinocarboxamide)-5-aminoimidazole
5'-phosphoribosyl-5-amino-4-imidazolecarboxamide + fumarate
-
-
-
-
?
4-(N-succino)-5-aminoimidazole-4-carboxamide ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
-
reaction in the biosynthesis of AMP
-
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
phosphoribosylsuccinyl-aminoimidazole carboxamide
phosphoribosylaminoimidazole carboxamide + 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
-
-
-
-
?
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
-
-
ZMP accumulation in the brain of Lesch-Nyhan disease patients induces inhibition of mitochondrial oxidative phosphorylation and adenylosuccinate lyase activity, followed by dowregulation of ATP levels and multifocal cell death in the cerebellum. ZMP is an inhibitor of the bifunctional enzyme adenylosuccinate lyase, a deficiency of this enzyme causes psychomotor and mental retardation in humans, overview
-
?
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
5-aminoimidazole-4-carboxamide ribonucleotide + fumarate
-
the 8th step in the purine nucleotide de novo pathway
-
-
?
N6-(1,2-dicarboxyethyl)AMP
fumarate + AMP
-
reaction in the biosynthesis of AMP
-
-
?
succinyladenosine monophosphate
AMP + fumarate
-
-
-
-
?
succinyladenosine monophosphate
AMP + fumarate
-
conversion of adenylosuccinate to adenylate in the purine nucleotide cycle
-
-
?
additional information
?
-
adenylosuccinate lyase catalyzes two reactions in the biosynthesis of purine nucleotides
-
-
?
additional information
?
-
-
adenylosuccinate lyase catalyzes two reactions in the biosynthesis of purine nucleotides
-
-
?
additional information
?
-
adenylosuccinate lyase deficiency is a rare autosomal disorder of de novo purine synthesis, which results in the accumulation of succinylpurines in body fluids. Patients with adenylosuccinate lyase deficiency show a variable combination of mental retardation, epilepsy and autistic features, overview
-
-
?
additional information
?
-
-
adenylosuccinate lyase deficiency is a rare autosomal disorder of de novo purine synthesis, which results in the accumulation of succinylpurines in body fluids. Patients with adenylosuccinate lyase deficiency show a variable combination of mental retardation, epilepsy and autistic features, overview
-
-
?
additional information
?
-
-
adenylosuccinate lyase deficiency is an autosomal recessive disorder of the purine de novo synthesis pathway and purine nucleotide cycleby severe neurological involvement including hypotonia, seizures, developmental delay and autistic features. Epilepsy in ADSL deficiency is frequent and occurs in approximately two-thirds of patients, beginning either early in the neonatal period or after the first year of life
-
-
?
additional information
?
-
-
ZMP is an activator of the AMP-activated protein kinase, AMPK, and is toxic in human B lymphocytes and neuroblastoma cell lines, physiological functions of ZMP, overview
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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 positive cooperativity
5-aminoimidazole-4-carboxamide riboside 5'-monophosphate
-
i.e. ZMP or AICAR, product inhibition, accumulation in the brain of Lesch-Nyhan disease patients induces inhibition of mitochondrial oxidative phosphorylation and adenylosuccinate lyase activity, followed by dowregulation of ATP levels and multifocal cell death in the cerebellum
trans-4-hydroxy-2-nonenal
-
10-15 µM, inhibitor reacts both with the free enzyme and the enzyme substrate complex
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
0.0003
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
pH 7.0, 25°C, mutant S290A
0.0016
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide
pH 7.0, 25°C, wild-type enzyme
0.0007
phosphoribosylsuccinyl-aminoimidazole carboxamide
-
recombinant His-tagged mutant R426H, pH 7.4, 25°C
0.00174
phosphoribosylsuccinyl-aminoimidazole carboxamide
-
recombinant His-tagged wild-type enzyme, pH 7.4, 25°C
0.009
phosphoribosylsuccinyl-aminoimidazole carboxamide
-
recombinant His-tagged mutant R303C, pH 7.4, 25°C
0.0014
succinyladenosine monophosphate
-
recombinant His-tagged mutant R426H, pH 7.4, 25°C
0.0021
succinyladenosine monophosphate
-
recombinant His-tagged wild-type enzyme, pH 7.4, 25°C
0.0027
succinyladenosine monophosphate
-
recombinant His-tagged mutant R303C, pH 7.4, 25°C
additional information
additional information
the enzyme shows cooperativity and does not follow simple Michaelis-Menten kinetics, kinetic analysis, overview
-
additional information
additional information
-
the enzyme shows cooperativity and does not follow simple Michaelis-Menten kinetics, kinetic analysis, overview
-
additional information
additional information
-
non-linear dependence of the activities on the substrate ratios due to competitive binding. The enzyme does not follow simple Michaelis-Menten kinetics, kinetic analysis of wild-type and mutant enzymes, overview. Wild-type enzyme and mutant R426H appear to have equivalent cooperative binding on both substrates, while mutant R303C demonstrates no cooperativity
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
pH-dependence of turnover-numbers
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
3640
phosphoribosylsuccinyl-aminoimidazole carboxamide
-
recombinant His-tagged mutant R303C, pH 7.4, 25°C
37500
phosphoribosylsuccinyl-aminoimidazole carboxamide
-
recombinant His-tagged mutant R426H, pH 7.4, 25°C
50900
phosphoribosylsuccinyl-aminoimidazole carboxamide
-
recombinant His-tagged wild-type enzyme, pH 7.4, 25°C
915
succinyladenosine monophosphate
-
recombinant His-tagged mutant R303C, pH 7.4, 25°C
17800
succinyladenosine monophosphate
-
recombinant His-tagged mutant R426H, pH 7.4, 25°C
25200
succinyladenosine monophosphate
-
recombinant His-tagged wild-type enzyme, pH 7.4, 25°C
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.21
adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate
inhibition kinetics, overview
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
1.07
-
adenylsuccinate and succinylaminoimidazole carboxamide, 50 mM HEPES, pH 7.0, 25°C
13.9
-
purified recombinant His-tagged wild-type enzyme, substrate succinyladenosine monophosphate, pH 7.4, 25°C
23.3
-
purified recombinant His-tagged wild-type enzyme, substrate phosphoribosylsuccinyl-aminoimidazole carboxamide, pH 7.4, 25°C
3.6
6.4
-
purified recombinant His-tagged mutant R426H enzyme, substrate phosphoribosylsuccinyl-aminoimidazole carboxamide, pH 7.4, 25°C
6.7
-
purified recombinant His-tagged mutant R426H enzyme, substrate succinyladenosine monophosphate, pH 7.4, 25°C
7.5
-
His-tagged mutant L311V, after treatment with guanidiniumHCl, pH 7.4, 25°C
8.9
-
His-tagged mutant R194C, after treatment with guanidiniumHCl, pH 7.4, 25°C
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
the enzyme executes two non-sequential steps in the de novo synthesis of AMP: the conversion of phosphoribosylsuccinyl-aminoimidazole carboxamide to phosphoribosylaminoimidazole carboxamide, which occurs in the de novo synthesis of IMP, and the conversion of adenylosuccinate to AMP, which occurs in the de novo synthesis of AMP and also in the purine nucleotide cycle, using the same active site
malfunction
metabolism
malfunction
phenotypic severity in ADSL deficiency is correlated with residual enzymatic activity and structural stability of the corresponding mutant ADSL complexes and does not result from genotype-specific disproportional catalytic activities toward one of the enzyme substrates
malfunction
enzyme mutation R303C is involved in ADSL deficiency, a rare autosomal recessive disorder, which causes a defect in purine metabolism resulting in neurological and physiological symptoms. The R303C mutation potentially has a disproportional decrease in activity toward its substrates
malfunction
-
adenylosuccinate lyase deficiency causes encephalopathy with epilepsy and marked psychomotor retardation
malfunction
-
adenylosuccinate lyase deficiency is characterized by the accumulation of 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide and succinyladenosine in tissue and body fluids
malfunction
-
ADSL deficiency is an autosomal recessive disorder, characterized by severe neurologic involvement including seizures, developmental delay, hypotonia, and autistic features
malfunction
-
ADSL enzyme deficiency is a disorder of purine metabolism with a broad clinical spectrum. The enzyme deficit causes a highly variable clinical presentation varying from a relatively mild presentation with slight motor retardation and severe muscle hypotonia to severe neonatal onset convulsions accompanied by severe mental retardation
malfunction
-
missense mutations in the protein lead to enzyme deficiency, an inborn error of purine metabolism characterized by neurological and physiological symptoms. Enzyme deficiency is biochemically diagnosed by elevated levels of succinylaminoimidazolecarboxamide riboside and succinyladenosine, the dephosphorylated derivatives of the substrates. Succinyladenosine/succinylaminoimidazolecarboxamide riboside ratios are associated with three phenotypic groups
metabolism
-
adenylosuccinate lyase is involved in the de novo purine biosynthesis pathway and purine nucleotide cycle
metabolism
-
the enzyme is a bifunctional protein that is involved in both purine de novo synthesis and purine interconversion. It catalyzes the formation of phosphoribosylaminoimidazole carboxamide and succinate from phosphoribosylsuccinyl-aminoimidazole carboxamide in the biosynthesis of IMP from phosphoribosylpyrophosphate. Alternatively, the enzyme catalyzes the synthesis of AMP and succinate from succinyl-AMP in the interconversion of IMP into AMP
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). PUR8_HUMAN
484
0
54889
Swiss-Prot
other Location (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
227000
57000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homotetramer
tetramer
homotetramer
recombinant His-tagged wild-type and R303C mutant enzymes, static light scattering
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified wild-type apo-enzyme and enzyme mutant R303C, high throughput screening by sitting drop method, method optimization, mixing of 0.004 ml of protein solution with 0.004 ml of reservoir solution and equilibration against 0.5 ml of reservoir solution, with a precipitant gradient for the native enzyme of 18-28% w/v PEG 6000, 0.1 M Tris, pH 8.0, and 12.5 mM MgCl2 hexahydrate, and for enzyme mutant R303C, a precipitant gradient of 18-28% w/v PEG 8000, 0.1 M Tris, pH 8.5, and 12.5 mM spermine tetrahydrochloride, X-ray diffraction structure determination and analysis at 2.7 A and 2.6 A resolution, respectively
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D215H
the mutation is associated with ADSL deficiency and shows 92% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
D268H
the mutation is associated with ADSL deficiency and shows 20% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
D430N
the mutation is associated with ADSL deficiency and shows 151% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
D87E
the mutation is associated with ADSL deficiency and shows 91% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
E376D
the mutation is associated with ADSL deficiency and shows 49% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
E80D
the mutation is associated with ADSL deficiency and shows 102% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
I351T
the mutation is associated with ADSL deficiency and shows 151% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
K246E
the mutation is associated with adenylosuccinate lyase deficiency, the Vmax for the K246E mutant enzyme is about 2% that of the wild type enzyme, K246E exists mainly as dimer or monomer
L311V
the mutation is associated with adenylosuccinate lyase deficiency, the Vmax for the L311V mutant enzyme is 72% about 2% that of the wild type enzyme
R190Q
the mutation is associated with ADSL deficiency and shows 119% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
R194C
R303C
naturally occuring type II mutation, observed as a homozygous mutation in two unrelated patients, the mutant shows reduced activity compared to the wild-type enzyme, KM values of R303C enzyme mutant increase 4fold for phosphoribosylsuccinyl-aminoimidazole carboxamide compared to that of wild-type enzyme, for succinyladenosine monophosphate the change is almost negligible, substrate binding of the enzyme is latered compared to the wild-type
R396C
R396H
the mutation is associated with adenylosuccinate lyase deficiency, Vmax (at 25°C) for R194C is considerably reduced and affinity for adenylosuccinate is retained
R426H
the mutation is associated with ADSL deficiency and shows 89% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
S23R
the mutation is associated with ADSL deficiency and shows 108% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
S289A
site-directed mutagenesis, the mutant shows no activity, and altered molecular weight and binding of inhibitory substrate analogue adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate compared to the wild-type enzyme
S289H
site-directed mutagenesis, the mutant shows no activity, and altered molecular weight and binding of inhibitory substrate analogue adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate compared to the wild-type enzyme
S290A
site-directed mutagenesis, the mutant shows altered molecular weight and binding of inhibitory substrate analogue adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate compared to the wild-type enzyme
S290H
site-directed mutagenesis, the mutant shows no activity, and altered molecular weight and binding of inhibitory substrate analogue adenosine phosphonobutyric acid, 2'(3'),5'-diphosphate compared to the wild-type enzyme
T242I
the mutation is associated with ADSL deficiency and shows 108% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
T450S
the mutation is associated with ADSL deficiency and shows 68% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
Y114H
the mutation is associated with ADSL deficiency and shows 37% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
D215H
-
naturally occuring mutation, two homozygous and two compound heterozygous mutant variants
D268H
-
naturally occuring mutation, two homozygous and two compound heterozygous mutant variants
I351T
-
naturally occuring mutation, two homozygous and two compound heterozygous mutant variants
P100A/D422Y
-
the mutation leads to a defective enzyme which is inhibited by micromolar concentrations of trans-4-hydroxy-2-nonenal
R303C
R426H
S23R
-
naturally occuring mutation, two homozygous and two compound heterozygous mutant variants
S413P
-
the mutation leads to structural instability of the mutant enzyme, this instability lowers the enzyme level in lymphocytes. The mutation segregates with mental retardation in the affected family
T242I
-
naturally occuring mutation, two homozygous and two compound heterozygous mutant variants
Y114H
-
naturally occuring mutation, two homozygous and two compound heterozygous mutant variants
additional information
R194C
the mutation is associated with adenylosuccinate lyase deficiency,Vmax (at 25°C) for R194C is comparable to that of wild type, R194C is rapidly inactivated at 60°C
R194C
the mutation is associated with ADSL deficiency and shows 101% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
R396C
the mutation is associated with adenylosuccinate lyase deficiency the Vmax for the R396C mutant enzyme is about 16% that of the wild type enzyme
R396C
the mutation is associated with ADSL deficiency and shows 32% activity using 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide as substrate at 25°C compared to the wild type enzyme
R303C
-
naturally occuring mutation, causing the mild form, Type II, of enzyme deficiency, the mutant shows reduced activity compared to the wild-type enzyme, mutation R303C increases the KM value
R426H
-
naturally occuring mutation, two homozygous and two compound heterozygous mutant variants
R426H
-
naturally occuring mutation, causing the severe form, Type I, of enzyme deficiency, the mutant shows reduced activity compared to the wild-type enzyme, mutation R426H reduces the KM value
additional information
enzyme deficiency due to homozygous missense mutation T674C leading to the amino acid exchange M225T in the exon 6 of the ADSL gene causes a phenotype with global developmental delay, motor apraxia, severe speech deficits, seizures and behavioural features, which combines excessive laughter, a very happy disposition, hyperactivity, a short attention span, the mouthing of objects, tantrums and stereotyped movements that give a behavioural profile mimicking Angelman syndrome, the patients have an increased succinyladenosine/5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide ratio of 1.6 compared to wild-type humans, overview
additional information
-
enzyme deficiency due to homozygous missense mutation T674C leading to the amino acid exchange M225T in the exon 6 of the ADSL gene causes a phenotype with global developmental delay, motor apraxia, severe speech deficits, seizures and behavioural features, which combines excessive laughter, a very happy disposition, hyperactivity, a short attention span, the mouthing of objects, tantrums and stereotyped movements that give a behavioural profile mimicking Angelman syndrome, the patients have an increased succinyladenosine/5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide ratio of 1.6 compared to wild-type humans, overview
additional information
-
the review gives an overview of the characteristics of patients with ADSL deficiency in dependence of amino acid changes
additional information
-
genotype is related to severity of the mental retardation phenotype, overview
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
60
wild type and mutant enzymes R396H and R396C are relatively stable at 60°C for about 4 h, the R194C mutant enzyme loses most of its activity within about 1 h of incubation at 60 °C
25
-
enzyme is stable for at least 5 days at 25°C, and upon rapid freezing and thawing
37
-
t1/2 for enzyme from mutant cell line 1751: 0.23 min, t1/2 for enzyme from mutant cell line 1753: 0.2 min, t1/2 for enzyme from the normal cell lines: 9.65 h
60
-
t1/2 for enzyme from mutant cell line 1751: 7.35 h, t1/2 for enzyme from mutant cell line 1753: 6.25 h, t1/2 for enzyme from the normal lines: 2.18 min
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
dialysis for 24 h at 5°C, activity in mutant lysates is decreased by 95% while 50-60% of the initial activity remains in the normal cell lysates
-
freezing at -80°C, followed by thawing, 20-40% loss of enzyme activity in extract
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-70°C, 10% glycerol, 1 mM dithiothreitol, 0.01 M Tris, pH 7.4, activity in lysates from all cell lines is stable for more than 6 weeks
-
-80°C or -20°C, recombinant enzyme is very unstable regardless of salt or glycerol concentration
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain Rosetta 2(DE3)pLysS by nickel affinity chromatography, dialysis, cleavage of the His-tag through thrombin, and gel filtration, to homogeneity
recombinant His-tagged wild-type and mutant enzymes from Escherichia coli strain Rosetta 2(DE3)pLysS by nickel affinity chromatography
-
using a Ni-NTA column, the 6-histidine tag is removed by cleavage with thrombin, separation of thrombin and histidine-tag from the enzyme is achieved by using a Sephadex G-100 column
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli DH5alphaF'IQ cells as recombinant maltose binding protein-ADSL fusion protein
expression of His-tagged wild-type and mutant enzymes in Escherichia coli strain Rosetta 2(DE3)pLysS
ADSL gene, genotyping in Polish patients with adenylosuccinate lyase deficiency compared to the wild-type, overview
-
expression of N-terminally His-tagged wild-type and mutant enzymes in Escherichia coli strain Rosetta 2(DE3)pLysS
-
into the pET-14b vector for expression in Escherichia coli Rosetta 2DE3pLysS cells
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
additional information
-
participates in the purine biosynthetic pathway, enzyme defects result in psychomotor retardation, epilepsy, muscle wasting and autistic features
medicine
-
adenylosuccinate lyase deficiency causes serious neurological and physiological symptoms
medicine
-
generation of in vitro hybrids that mimic compound heterozygote ASL for studies on disease-associated mutant enzymes. His-tagged wild-type/non-His-tagged wild-type, His-tagged wild-type/non-His-tagged R396C, His-tagged wild-type/non-His-tagged R396H, His-tagged R194C/non-His-tagged R396C, and His-tagged L311V/non-His-tagged R396H enzyme pairs are used in various hybrids generated by denaturing pairs of enzymes in 1 M guanidinium chloride and renaturing them by removing the denaturant. The hybrids have predominant amounts of heterotetramers. Analysis of the Vmax values of the hybrids indicates that most of the subunits behave independently. However, the hybrid tetramers retain weak positive cooperativity
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Stone, R.L.; Zalkin, H.; Dixon, J.E.
Expression, purification, and kinetic characterization of recombinant human adenylosuccinate lyase
J. Biol. Chem.
268
19710-19716
1993
Homo sapiens
Barshop, B.A.; Alberts, A.S.; Gruber, H.E.
Kinetic studies of mutant human adenylosuccinase
Biochim. Biophys. Acta
999
19-23
1989
Homo sapiens
Crifo, C.; Lomonte, A.; Salerno, C.
Inhibition of adenylosuccinate lyase by 2,3 -acyclic substrate analogs
Adv. Exp. Med. Biol.
431
245-248
1998
Homo sapiens
Van den Bergh, F.; Vincent, M.F.; Jaeken, J.; van den Berghe, G.
Radiochemical assay of adenylosuccinase: demonstration of parallel loss of activity toward both adenylosuccinate and succinylaminoimidazole carboxamide ribotide in liver of patients with the enzyme defect
Anal. Biochem.
193
287-291
1991
Homo sapiens
Stone, R.L.; Aimi, J.; Barshop, B.A.; Jaeken, J.; van den Berghe, G.; Zalkin, H.; Dixon, J.E.
A mutation in adenylosuccinate lyase associated with mental retardation and autistic features
Nature Genet.
1
59-63
1992
Homo sapiens
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)
Lee, P.; Colman, R.F.
Expression, purification, and characterization of stable, recombinant human adenylosuccinate lyase
Protein Expr. Purif.
51
227-234
2007
Homo sapiens
Gitiaux, C.; Ceballos-Picot, I.; Marie, S.; Valayannopoulos, V.; Rio, M.; Verrieres, S.; Benoist, J.F.; Vincent, M.F.; Desguerre, I.; Bahi-Buisson, N.
Misleading behavioural phenotype with adenylosuccinate lyase deficiency
Eur. J. Hum. Genet.
17
133-136
2009
Homo sapiens (P30566), Homo sapiens
Lopez, J.M.
Is ZMP the toxic metabolite in Lesch-Nyhan disease?
Med. Hypotheses
71
657-663
2008
Homo sapiens
Jurecka, A.; Zikanova, M.; Tylki-Szymanska, A.; Krijt, J.; Bogdanska, A; Gradowska, W.; Mullerova, K.; Sykut-Cegielska, J.; Kmoch, S.; Pronicka, E.
Clinical, biochemical and molecular findings in seven Polish patients with adenylosuccinate lyase deficiency
Mol. Genet. Metab.
94
435-442
2008
Homo sapiens
Sivendran, S.; Colman, R.F.
Effect of a new non-cleavable substrate analog on wild-type and serine mutants in the signature sequence of adenylosuccinate lyase of Bacillus subtilis and Homo sapiens
Protein Sci.
17
1162-1174
2008
Bacillus subtilis, Homo sapiens (P30566), Homo sapiens
Jurecka, A.; Tylki-Szymanska, A.; Zikanova, M.; Krijt, J.; Kmoch, S.
D-Ribose therapy in four Polish patients with adenylosuccinate lyase deficiency: absence of positive effect
J. Inherit. Metab. Dis.
31
S329-332
2008
Homo sapiens
Ariyananda, L.d.e..Z.; Lee, P.; Antonopoulos, C.; Colman, R.F.
Biochemical and biophysical analysis of five disease-associated human adenylosuccinate lyase mutants
Biochemistry
48
5291-5302
2009
Homo sapiens (P30566), Homo sapiens
Mierzewska, H.; Schmidt-Sidor, B.; Jurkiewicz, E.; Bogdanska, A.; Kusmierska, K.; Stepien, T.
Severe encephalopathy with brain atrophy and hypomyelination due to adenylosuccinate lyase deficiency--MRI, clinical, biochemical and neuropathological findings of Polish patients
Folia Neuropathol.
47
314-320
2009
Homo sapiens
Zikanova, M.; Skopova, V.; Hnizda, A.; Krijt, J.; Kmoch, S.
Biochemical and structural analysis of 14 mutant ADSL enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency
Hum. Mutat.
31
445-455
2010
Homo sapiens (P30566), Homo sapiens
Chen, B.C.; McGown, I.N.; Thong, M.K.; Pitt, J.; Yunus, Z.M.; Khoo, T.B.; Ngu, L.H.; Duley, J.A.
Adenylosuccinate lyase deficiency in a Malaysian patient, with novel adenylosuccinate lyase gene mutations
J. Inherit. Metab. Dis.
33
S159-162
2010
Homo sapiens
Camici, M.; Micheli, V.; Ipata, P.L.; Tozzi, M.G.
Pediatric neurological syndromes and inborn errors of purine metabolism
Neurochem. Int.
56
367-378
2010
Homo sapiens
Henneke, M.; Dreha-Kulaczewski, S.; Brockmann, K.; van der Graaf, M.; Willemsen, M.A.; Engelke, U.; Dechent, P.; Heerschap, A.; Helms, G.; Wevers, R.A.; Gaertner, J.
In vivo proton MR spectroscopy findings specific for adenylosuccinate lyase deficiency
NMR Biomed.
23
441-445
2010
Homo sapiens
De Zoysa Ariyananda, L.; Antonopoulos, C.; Currier, J.; Colman, R.F.
In vitro hybridization and separation of hybrids of human adenylosuccinate lyase from wild-type and disease-associated mutant enzymes
Biochemistry
50
1336-1346
2011
Homo sapiens
Ray, S.P.; Deaton, M.K.; Capodagli, G.C.; Calkins, L.A.; Sawle, L.; Ghosh, K.; Patterson, D.; Pegan, S.D.
Structural and biochemical characterization of human adenylosuccinate lyase (ADSL) and the R303C ADSL deficiency-associated mutation
Biochemistry
51
6701-6713
2012
Homo sapiens (P30566), Homo sapiens
Ray, S.P.; Duval, N.; Wilkinson, T.G.; Shaheen, S.E.; Ghosh, K.; Patterson, D.
Inherent properties of adenylosuccinate lyase could explain S-Ado/SAICAr ratio due to homozygous R426H and R303C mutations
Biochim. Biophys. Acta
1834
1545-1553
2013
Homo sapiens
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