Information on EC 6.3.4.5 - Argininosuccinate synthase

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

EC NUMBER
COMMENTARY
6.3.4.5
-
RECOMMENDED NAME
GeneOntology No.
Argininosuccinate synthase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
mechanism
-
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
rapid-equilibrium random mechanism
-
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
ordered addition of MgATP2-, citrulline, and aspartate, followed by ordered release of argininosuccinate, magnesiumdiphosphate and AMP
-
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
essential Arg in the active site participates in the binding of ATP and diphosphate. The binding of ATP and diphosphate at the same site is mutually exclusive
-
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
detailed catalytic mechanism
-
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
catalytic mechanism
-
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
detailed catalytic mechanism, stereochemistry
P59846, -
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
it is found that argininosuccinate synthetase is the major lipid A-interacting protein in liver. Argininosuccinate synthetase also inhibits the biological activities of natural lipid A and rough-type lipopolysaccharide and but not smooth-type lipopolysaccharide. Argininosuccinate synthetase enzyme activity is inhibited by lipid A and rough-type lipopolysaccharide and smooth-type lipopolysaccharide.
-
ATP + L-citrulline + L-aspartate = AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
rapid-equilibrium random mechanism
Saccharomyces cerevisiae 1278b
-
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
amination
-
-
-
-
PATHWAY
KEGG Link
MetaCyc Link
Alanine, aspartate and glutamate metabolism
-
Arginine and proline metabolism
-
arginine biosynthesis I (via L-ornithine)
-
arginine biosynthesis II (acetyl cycle)
-
arginine biosynthesis III (via N-acetyl-L-citrulline)
-
arginine biosynthesis IV (archaebacteria)
-
Biosynthesis of secondary metabolites
-
canavanine biosynthesis
-
citrulline-nitric oxide cycle
-
Metabolic pathways
-
urea cycle
-
SYSTEMATIC NAME
IUBMB Comments
L-Citrulline:L-aspartate ligase (AMP-forming)
-
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
ARGG
A4I066
-
Arginine succinate synthetase
-
-
-
-
argininosuccinate synthase
-
-
Argininosuccinate synthetase
-
-
-
-
Argininosuccinate synthetase
Q2Z0F6
-
Argininosuccinate synthetase
-
-
Argininosuccinate synthetase
-
-
Argininosuccinate synthetase
-
-
Argininosuccinate synthetase
P00966
-
Argininosuccinate synthetase
A4I066
-
Argininosuccinate synthetase
-
-
Argininosuccinate synthetase
P16460
-
Argininosuccinate synthetase
-
-
Argininosuccinate synthetase
Q0KKQ0
-
Argininosuccinate synthetase
-
-
Argininosuccinate synthetase
-
-
Argininosuccinate synthetase
-
-
Argininosuccinate synthetase
Sulfolobus solfataricus P1
-
-
-
Argininosuccinate synthetase
-
-
Argininosuccinic acid synthetase
-
-
-
-
arininosuccinate synthetase
-
-
ASS
-
-
-
-
ASS
Q2Z0F6
-
ASS
P00966
-
ASS
P16460
-
ASS1
P00966
-
Citrulline--aspartate ligase
-
-
-
-
Citrulline-aspartate ligase
-
-
-
-
Citrulline-aspartate ligase
P00966
-
Elastin-binding protein
-
-
-
-
PyARG1
Q0KKQ0
-
Synthetase, argininosuccinate
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
9023-58-9
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
adult-type citrullinemia with neuro-psychiatric symptoms of late onset, 24-28 years old, caused by ASS abnormalities
-
-
Manually annotated by BRENDA team
ASS1
UniProt
Manually annotated by BRENDA team
citrullinemia is an autosomal recessive disease caused by a deficiency of argininosuccinate synthetase; wild-type and mutant enzyme; wild-type and mutant enzymes
-
-
Manually annotated by BRENDA team
patients with Alzheimer disease and nondemented, age-matched controls
-
-
Manually annotated by BRENDA team
antimonial-sensitive and antimonial-resistant strains
UniProt
Manually annotated by BRENDA team
human tumor necrosis factor-alpha transgenic mice, 4 and 8 weeks old, and age-matched CBA x C57B1/6 wild-type controls
-
-
Manually annotated by BRENDA team
male C3H/He, C57BL/6, and BALB/c mice
-
-
Manually annotated by BRENDA team
male Wistar rats
-
-
Manually annotated by BRENDA team
Sprague-Dawley rats
-
-
Manually annotated by BRENDA team
Wistar rats, 2 days old
-
-
Manually annotated by BRENDA team
strain 1278b, mutant MG409
-
-
Manually annotated by BRENDA team
Saccharomyces cerevisiae 1278b
strain 1278b, mutant MG409
-
-
Manually annotated by BRENDA team
Sulfolobus solfataricus P1
-
-
-
Manually annotated by BRENDA team
strain HB8
-
-
Manually annotated by BRENDA team
strain HB8
Uniprot
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
mutation results in citrullinemia type I
malfunction
-
malfunction results in citrullinemia type 1 argininosuccinate argininosuccinate synthetase deficiency
malfunction
-
deficiency of the enzyme may result in citrullinemia type I
malfunction
-
epigenetic silencing triggers apoptosis in arginine auxotroph tumours
malfunction
-
enzyme deficency results in congenital urea cycle disorders
metabolism
-
Sulfolobus solfataricus lacks ornithine acetyltransferase and thus forms N-acetylglutamate exclusively via the energetically less favourable reaction catalysed by N-acetylglutamate synthase, investing 1 mol of acetyl CoA per mol of N-acetyl intermediate synthesized
metabolism
Sulfolobus solfataricus P1
-
Sulfolobus solfataricus lacks ornithine acetyltransferase and thus forms N-acetylglutamate exclusively via the energetically less favourable reaction catalysed by N-acetylglutamate synthase, investing 1 mol of acetyl CoA per mol of N-acetyl intermediate synthesized
-
physiological function
-
rate-limiting enzyme in the biosynthesis of arginine
physiological function
-
rate-limiting enzyme in urea and arginine(NO)-citrulline cycles
physiological function
-
part of citrulline-NO cycle, limiting step in NO synthesis
physiological function
P16460
part of citrulline-NO cycle, limiting step in NO synthesis
physiological function
-
involved in urea cycle
physiological function
-
recombinant argininosuccinate synthase reduces lipolysaccharide cytotoxicity, TNF-alpha production, and increases cell viability in cultured mouse macrophages, even when added one h following lipopolysaccharide challenge. Intraperitoneal injection of recombinant argininosuccinate synthase at 5 mg/kg after treatment with a high dose of lipopolysaccharide remarkably increases survival of rodents, with a concomitant decrease of sepsis markers TNF-alpha, C-reactive protein, and lactate dehydrogenase levels in blood
physiological function
-
exogenous expression of either nitric oxide synthase NOS3 or argininosuccinate synthetaseASS1 increases NO production and decreases monocyte adhesion stimulated by tumor necrosis factor-alpha. The latter effect is reduced when human umbilical vein endothelial cells are co-treated with small interfering RNAs for ASS1 or NOS3. SiRNAs of NOS3 and ASS1 attenuate the increase of NO production in human aortic endothelial cells stimulated by laminar shear stress for 24 h
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + citrulline + aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
-
ATP + citrulline + aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
-
ATP + citrulline + aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
-
ATP + citrulline + aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
P16460
assay at pH 7.8, 37C, reaction stopped by addition of molybdate buffer
-
-
?
ATP + L-citrulline + 3-nitro-2-aminopropanoate
?
show the reaction diagram
-
60% of the maximal activity with Asp
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
r
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
r
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
r, D-Asp is inactive as substrate
-
-
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
argininosuccinate synthase catalyzes the rate-limiting step in the recycling of citrulline to arginine, which in endothelial cells, is tighly coupled to the production of nitric oxide. The upstream open reading frame found in the extended, overlapping 5'-untranslated region of argininosuccinate synthase mRNA species suppresses endothelial argininosuccinate expression providing a novel mechanism for regulating endothelial NO production by limiting the availability of arginine
-
-
?
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
argininosuccinate synthase expression is required to maintain nitric oxide production and cell viability in aortic endothelial cells
-
-
?
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
IL-1beta stimulates argininosuccinate synthetase gene expression through NF-kappaB in Caco-2 cells
-
-
?
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
the substrate for NO synthesis, L-arginine can be regenerated from the L-citrulline the coproduct of nitric-oxide synthase. This requires the sequential action of two enzymes, argininosuccinate synthetase and argininosuccinate lyase
-
-
?
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
Saccharomyces cerevisiae 1278b
-
r
-
-
ATP + L-citrulline + L-Asp
?
show the reaction diagram
-
mechanism to recycle citrulline, formed in the nervous system via nitric oxide synthetase, EC 1.14.13.39, activity, back to the nitric oxide precursor, L-Arg
-
-
-
ATP + L-citrulline + L-Asp
?
show the reaction diagram
-
third reaction of urea cycle
-
-
-
ATP + L-citrulline + L-Asp
?
show the reaction diagram
-
anabolic function in biosynthesis of Arg and catabolic function as the first enzyme of citrulline utilization as nitrogen source
-
-
-
ATP + L-citrulline + L-Asp
?
show the reaction diagram
-
urea-cycle enzyme
-
-
-
ATP + L-citrulline + L-Asp
?
show the reaction diagram
Saccharomyces cerevisiae 1278b
-
anabolic function in biosynthesis of Arg and catabolic function as the first enzyme of citrulline utilization as nitrogen source
-
-
-
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
ATP induces conformational changes in the nucleotide binding domain, each monomer of tetrameric EAS consists of a nucleotide binding domain and a novel catalytic/multimerization domain, detailed catalytic mechanism via adenylated citrulline intermediate, active site structure
-
r
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
P59846, -
ATP-dependent condensation of citrulline with aspartate, detailed mechanism via citrullyl-AMP intermediate, stereochemistry of catalysis, no conformational change upon binding of ATP, active site structure
-
r
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
ATP-dependent condensation of citrulline with aspartate, no conformational change upon binding of substrates, mechanism via citrullyl-AMP intermediate, active site structure
-
r
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
ATP-dependent ligation of citrulline and aspartate
-
r
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
catalyzes the coupling reaction between citrulline and arginine to form argininosuccinic acid
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
mediates transformation of L-citrulline to L-arginine in the ureum cycle in hepatocytes, first step in L-citrulline recycling pathway
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
penultimate step in the biosnthesis of arginine, rate-limiting enzyme of both the urea and arginine-citrulline cycles
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
second step of urea cycle
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
P59846, -
seventh step of the arginine biosynthesis, second step of the urea cycle
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
the rate-limiting enzyme for converting citrulline to arginine
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
P00966
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
argininosuccinate synthase is essential for endothelial nitric oxide production, vascular NO production is regulated by dynamic argininosuccinate synthase phosphorylation
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-, P00966
citrulline-aspartate ligase is the rate-limiting enzyme in the synthesis of the amino acid arginine. Type I citrullinaemia is a disorder caused by mutations in the ASS gene leading to reduced or abolished activity of the ASS enzyme
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
P00966
rate-limiting enzyme in nitric oxide synthesis, negative feedback mechanism, overview
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
rate-limiting enzyme of the urea cycle
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
the caveolar-localized endothelial argininosuccinate synthase catalyzes the rate-limiting step of the citrulline-NO cycle, involving not only the regulation of endothelial nitric oxide synthase, but also regulation of cycle, overview
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
the key enzyme in the urea cycle participates in many metabolic processes including arginine biosynthesis and the citrulline-nitric oxide cycle
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-, P00966
substrate binding structures, overview
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
Sulfolobus solfataricus lacks ornithine acetyltransferase and thus forms N-acetylglutamate exclusively via the energetically less favourable reaction catalysed by N-acetylglutamate synthase, investing 1 mol of acetyl CoA per mol of N-acetyl intermediate synthesized
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
Sulfolobus solfataricus P1
-
-, Sulfolobus solfataricus lacks ornithine acetyltransferase and thus forms N-acetylglutamate exclusively via the energetically less favourable reaction catalysed by N-acetylglutamate synthase, investing 1 mol of acetyl CoA per mol of N-acetyl intermediate synthesized
-
-
?
ATP + L-citrulline + threo-beta-hydroxy-DL-Asp
?
show the reaction diagram
-
-
-
-
-
ATP + L-citrulline + threo-beta-methyl-L-Asp
?
show the reaction diagram
-
-
-
-
-
dATP + L-citrulline + L-Asp
dAMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
2.6% as active as ATP
-
-
-
additional information
?
-
-
citrullinemia is an autosomal recessive disease caused by a deficiency of argininosuccinate synthetase
-
-
-
additional information
?
-
-
adult-type citrullinemia with neuro-psychiatric symptoms of late onset, 24-28 years old, caused by argininosuccinate synthetase abnormalities
-
-
-
additional information
?
-
-
urea cycle
-
?
additional information
?
-
-
involved in L-arginine synthesis from L-citrulline, urea cycle, rate-limiting enzyme for high output NO generation, inducible enzyme, AS synthesis is more strictly regulated at the posttranscriptional than the transcriptional level in vivo
-
?
additional information
?
-
-
involved in the recycling of L-citrulline to L-arginine
-
?
additional information
?
-
-
rate-limiting enzyme in the metabolic pathway leading from L-citrulline to L-arginine, urea cycle
-
?
additional information
?
-
-
urea cycle, enzyme of citrulline-arginine recycling, which is important for high output production of NO in activated microglial cells, inducible enzyme
-
?
additional information
?
-
-
ASS binds to and inactivates lipopolysaccharide and lipid A, overview
-
-
-
additional information
?
-
-
factors like diets, hormones and pro-inflammatory stimuli regulate ASS gene expression primarily at the transcription level
-
-
-
additional information
?
-
-, P00966
in mammals, the urea-cycle enzymes ASS and argininosuccinatelyase are part of an additional pathway together with the enzyme nitric oxide synthase, forming the arginine-citrulline cycle
-
-
-
additional information
?
-
-
pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase
-
-
-
additional information
?
-
P00966
the enzyme interacts and cooperates with NADPH sensor protein, HSCARG, in downregulation of nitric oxide synthesis, the enzyme interacts with the dimerization region of HSCARG, amino acid residues 153-189, HSCARG regulation of AS activity is crucial for maintaining the intracellular balance between redox state and nitric oxide levels, overview
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
argininosuccinate synthase catalyzes the rate-limiting step in the recycling of citrulline to arginine, which in endothelial cells, is tighly coupled to the production of nitric oxide. The upstream open reading frame found in the extended, overlapping 5'-untranslated region of argininosuccinate synthase mRNA species suppresses endothelial argininosuccinate expression providing a novel mechanism for regulating endothelial NO production by limiting the availability of arginine
-
-
?
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
argininosuccinate synthase expression is required to maintain nitric oxide production and cell viability in aortic endothelial cells
-
-
?
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
IL-1beta stimulates argininosuccinate synthetase gene expression through NF-kappaB in Caco-2 cells
-
-
?
ATP + L-citrulline + L-Asp
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
the substrate for NO synthesis, L-arginine can be regenerated from the L-citrulline the coproduct of nitric-oxide synthase. This requires the sequential action of two enzymes, argininosuccinate synthetase and argininosuccinate lyase
-
-
?
ATP + L-citrulline + L-Asp
?
show the reaction diagram
-
mechanism to recycle citrulline, formed in the nervous system via nitric oxide synthetase, EC 1.14.13.39, activity, back to the nitric oxide precursor, L-Arg
-
-
-
ATP + L-citrulline + L-Asp
?
show the reaction diagram
-
third reaction of urea cycle
-
-
-
ATP + L-citrulline + L-Asp
?
show the reaction diagram
-
anabolic function in biosynthesis of Arg and catabolic function as the first enzyme of citrulline utilization as nitrogen source
-
-
-
ATP + L-citrulline + L-Asp
?
show the reaction diagram
-
urea-cycle enzyme
-
-
-
ATP + L-citrulline + L-Asp
?
show the reaction diagram
Saccharomyces cerevisiae 1278b
-
anabolic function in biosynthesis of Arg and catabolic function as the first enzyme of citrulline utilization as nitrogen source
-
-
-
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
mediates transformation of L-citrulline to L-arginine in the ureum cycle in hepatocytes, first step in L-citrulline recycling pathway
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
penultimate step in the biosnthesis of arginine, rate-limiting enzyme of both the urea and arginine-citrulline cycles
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
second step of urea cycle
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
P59846, -
seventh step of the arginine biosynthesis, second step of the urea cycle
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + L-argininosuccinate
show the reaction diagram
-
the rate-limiting enzyme for converting citrulline to arginine
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
-
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
argininosuccinate synthase is essential for endothelial nitric oxide production, vascular NO production is regulated by dynamic argininosuccinate synthase phosphorylation
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-, P00966
citrulline-aspartate ligase is the rate-limiting enzyme in the synthesis of the amino acid arginine. Type I citrullinaemia is a disorder caused by mutations in the ASS gene leading to reduced or abolished activity of the ASS enzyme
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
P00966
rate-limiting enzyme in nitric oxide synthesis, negative feedback mechanism, overview
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
rate-limiting enzyme of the urea cycle
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
the caveolar-localized endothelial argininosuccinate synthase catalyzes the rate-limiting step of the citrulline-NO cycle, involving not only the regulation of endothelial nitric oxide synthase, but also regulation of cycle, overview
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
-
the key enzyme in the urea cycle participates in many metabolic processes including arginine biosynthesis and the citrulline-nitric oxide cycle
-
-
?
ATP + L-citrulline + L-aspartate
AMP + diphosphate + 2-(Nomega-L-arginino)succinate
show the reaction diagram
Sulfolobus solfataricus, Sulfolobus solfataricus P1
-
Sulfolobus solfataricus lacks ornithine acetyltransferase and thus forms N-acetylglutamate exclusively via the energetically less favourable reaction catalysed by N-acetylglutamate synthase, investing 1 mol of acetyl CoA per mol of N-acetyl intermediate synthesized
-
-
?
additional information
?
-
-
citrullinemia is an autosomal recessive disease caused by a deficiency of argininosuccinate synthetase
-
-
-
additional information
?
-
-
adult-type citrullinemia with neuro-psychiatric symptoms of late onset, 24-28 years old, caused by argininosuccinate synthetase abnormalities
-
-
-
additional information
?
-
-
urea cycle
-
?
additional information
?
-
-
involved in L-arginine synthesis from L-citrulline, urea cycle, rate-limiting enzyme for high output NO generation, inducible enzyme, AS synthesis is more strictly regulated at the posttranscriptional than the transcriptional level in vivo
-
?
additional information
?
-
-
involved in the recycling of L-citrulline to L-arginine
-
?
additional information
?
-
-
rate-limiting enzyme in the metabolic pathway leading from L-citrulline to L-arginine, urea cycle
-
?
additional information
?
-
-
urea cycle, enzyme of citrulline-arginine recycling, which is important for high output production of NO in activated microglial cells, inducible enzyme
-
?
additional information
?
-
-
ASS binds to and inactivates lipopolysaccharide and lipid A, overview
-
-
-
additional information
?
-
-
factors like diets, hormones and pro-inflammatory stimuli regulate ASS gene expression primarily at the transcription level
-
-
-
additional information
?
-
-, P00966
in mammals, the urea-cycle enzymes ASS and argininosuccinatelyase are part of an additional pathway together with the enzyme nitric oxide synthase, forming the arginine-citrulline cycle
-
-
-
additional information
?
-
-
pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase
-
-
-
additional information
?
-
P00966
the enzyme interacts and cooperates with NADPH sensor protein, HSCARG, in downregulation of nitric oxide synthesis, the enzyme interacts with the dimerization region of HSCARG, amino acid residues 153-189, HSCARG regulation of AS activity is crucial for maintaining the intracellular balance between redox state and nitric oxide levels, overview
-
-
-
COFACTOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
ATP
P00966
binding structure, conformational change upon ATP binding
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Mg2+
-
essential for catalysis
Mg2+
P59846, -
required for maximal activity, in octahedral coordination with 3 oxygen atoms of the triphosphate group and 3 water molecules
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1,2-Cyclohexanedione
-
magnesiumdiphosphate and analogues protect
2,3-Butanedione
-
magnesiumdiphosphate and analogues protect
2-aminopentanoic acid
-
competitive to L-citrulline
5,5'-dithiobis(2-nitrobenzoate)
-
-
alpha-methyl-D,L-aspartate
-
-
AMP
-
competitive with respect to ATP
diphosphate
-
-
diphosphoryl lipid A (DPL)
-
DPL from Escherichia coli, inhibits argininosuccinate synthetase in a dose-dependent manner, concentration for half inhibition of argininosuccinate synthetase enzyme activity: 0.039 mg/ml
-
erythro-3-Hydroxy-3-methylaspartate
-
-
Glyoxal
-
magnesiumdiphosphate and analogues protect
IL-1beta
-
a long-term 24 h exposure of ASS to IL-1beta in Caco-2 cells inhibits its activity. The inhibiting effect of IL-1beta is linked to the production of nitric oxide (NO) induced by IL-1beta. The inhibiting effect is totally blocked in the presence of N-methyl-L-arginine an inhibitor of the inducible nitric oxide synthase or by culturing the cells in an arginine-deprived medium
-
L-Arg
-
non-competitive with respect to Asp and MgATP2-
L-Arg
-
competitive to L-Asp; competitive with L-citrulline
L-argininosuccinate
-
competitive with respect to citrulline, Asp, and ATP
L-argininosuccinate
-
-
L-argininosuccinate
-
competitive to L-Asp
L-argininosuccinate
-
-
L-Ile
-
competitive to L-citrulline
L-Val
-
competitive to L-citrulline
Methylaspartate
-
-
NO
-
mediates reversible S-nitrosylation and inactivation of argininosuccinate synthetase in vitro and in lipopolysaccharide-treated cells and mice. S-nitrosylation of Cys132 is noth necessary and sufficient for the inhibition of argininosuccinate synthase by NO donors
p-chloromercuribenzoate
-
-
Phenylglyoxal
-
ATP and diphosphate protect
Phenylglyoxal
-
magnesiumdiphosphate and analogues protect
phosphate
-
competitive with respect to citrulline and Asp
R-lipopolysaccharide (LPS)
-
rough-type LPS from Escherichia coli, inhibits argininosuccinate synthetase in a dose-dependent manner, concentration for half inhibition of argininosuccinate synthetase enzyme activity: 0.230 mg/ml
-
recombinant mycoplasma arginine deiminase
-
36% decrease in AS activity after rADI treatment
-
S-lipopolysaccharide (LPS)
-
smooth-type-LPS from Escherichia coli, inhibits argininosuccinate synthetase in a dose-dependent manner, concentration for half inhibition of argininosuccinate synthetase enzyme activity: 0.024 mg/ml
-
sodium 2-deoxy-2-(3S-(9-phenyl-nonanoyl-oxy) tetradecanoyl) amino-3-O-(9-phenyl-nonanoyl)-D-glucopyranose 4-sulfate
-
synthesized lipid A analog, inhibits argininosuccinate synthetase in a dose-dependent manner, concentration for half inhibition of argininosuccinate synthetase enzyme activity: 0.0065 mg/ml
threo-3-Hydroxy-3-methylaspartate
-
-
monophosphoryl lipid A (MPL)
-
MPL from Escherichia coli, inhibits argininosuccinate synthetase in a dose-dependent manner, concentration for half inhibition of argininosuccinate synthetase enzyme activity: 0.270 mg/ml
-
additional information
-
study of the effect of recombinant mycoplasma arginine deiminase on cell proliferation, correlation of the low resistance to this treatment with a low AS activity in the sensitive cell line
-
additional information
-
study of the effect of recombinant mycoplasma arginine deiminase on cell proliferation, good correlation of the high resistance to this treatment with a high AS activity in the cell line
-
additional information
-
1-D-ribofuranosylbenzimidazole suppresses enzyme expression
-
additional information
-
HNF4 mutations influence enzyme expression activity
-
additional information
-
pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
IL-1beta
-
ASS is rapidly induced by a short time exposure of IL-1beta to Caco-2 cells. By contrast, a long-term 24 h exposure to IL-1beta inhibited the ASS activity despite an increase in both specific mRNA-level and protein amount, demonstrating a post-translational effect
-
recombinant mycoplasma arginine deiminase
-
350% increase in AS activity in HeLa cells after rADI treatment, no activity change in umbilical vein endothelial cells
-
lipopolysaccharide
-
argininosuccinate synthase accumulates in circulation within 1 h after treatment with both lipopolysaccharide alone and hepatotoxic combination of lipopolysaccharide and D-Galactosamine. Enzyme physically binds to lipopolysaccharide
additional information
-
study of the effect of recombinant mycoplasma arginine deiminase on cell proliferation, good correlation of the resistance to this treatment with the AS activity in the cell lines
-
additional information
-
inducible enzyme, immunostimulation of AS synthesis with lipopolysaccharide or cytokines, such as TNF-alpha, interleukin 1 and interferon-gamma
-
additional information
-
AS mRNA is 4-6fold induced by Escherichia coli lipopolysaccharide and mouse interferon-gamma, kinetics of induction
-
additional information
-
AS mRNA is induced by Escherichia coli lipopolysaccharide and mouse interferon-gamma
-
additional information
-
expression of argininosuccinate synthetase mRNA is inducible by lipopolysaccharides
-
additional information
-
troglitazone, a PPARgamma ligand, and thiazolidinedione up-regulate vascular endothelial argininosuccinate synthase expression, quantitative real time RT-PCR, overview
-
additional information
-
CRE-1 is the cis-element responsible for liver-specific cAMP induction of the human ASS gene
-
additional information
-
interaction with Bj-BPP-10c, snake venom anti-hypertensive peptide of Botrops jararaca, activates the catalytic activity of argininosuccinate snythetase in a dose-dependent manner
-
additional information
P16460
interaction with Bj-BPP-10c, snake venom anti-hypertensive peptide of Botrops jararaca, activates the catalytic activity of argininosuccinate snythetase in a dose-dependent manner
-
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.022
-
AMP
-
-
0.022
-
AMP
-
citrulline, enzyme form ASSII
0.12
-
argininosuccinate
-
-
0.017
-
Asp
-
-
0.019
-
Asp
-
reaction with 5 mM citrulline
0.027
-
Asp
-
wild-type enzyme
0.078
-
Asp
-
MGL8B2 enzyme and MGL8D1 enzyme
0.083
-
Asp
-
reaction with 0.5 mM citrulline
1.5
-
Asp
-
mutant A192V
4.3
-
Asp
-
mutant R272C
0.12
-
aspartate
P16460
in presence of 0.0005 mM Bj-BPP-10c
0.17
-
aspartate
P16460
in presence of 0.1 mM Bj-BPP-10c
0.18
-
aspartate
P16460
-
0.041
-
ATP
-
-
0.051
-
ATP
-
wild-type enzyme
0.077
-
ATP
-
citrulline
0.081
-
ATP
-
mutant enzyme A192V
0.11
-
ATP
-
enzyme form ASSI
0.14
-
ATP
-
mutant R272C
0.15
-
ATP
P16460
in presence of 0.0005 mM Bj-BPP-10c
0.17
-
ATP
-
enzyme form ASSII
0.18
-
ATP
-
normal liver and from patients with citrullinemia
0.44
-
ATP
-
mutant R304W
0.61
-
ATP
P16460
in presence of 0.1 mM Bj-BPP-10c
0.66
-
ATP
P16460
-
0.02
-
citrulline
-
-
0.02
-
citrulline
-
-
0.024
-
citrulline
-
reaction with 5 mM Asp
0.042
-
citrulline
-
reaction with 0.5 mM Asp
0.044
-
citrulline
-
-
0.044
-
citrulline
-
Asp
0.056
-
citrulline
-
wild-type enzyme
0.061
-
citrulline
-
MGL8B2 enzyme
0.089
-
citrulline
-
MGL8D1 enzyme
0.18
-
citrulline
P16460
in presence of 0.0005 mM Bj-BPP-10c
0.29
-
citrulline
P16460
in presence of 0.1 mM Bj-BPP-10c
0.36
-
citrulline
P16460
-
4.2
-
citrulline
-
mutant R272C
15
-
citrulline
-
mutant A192V
56
-
citrulline
-
mutant R304W
190
-
citrulline
-
mutant R304W
0.016
-
diphosphate
-
-
0.016
-
diphosphate
-
citrulline
0.025
-
L-Asp
-
-
0.029
-
L-Asp
-
normal liver and from patients with citrullinemia
0.035
-
L-Asp
-
-
0.037
-
L-Asp
-
enzyme form ASSII
0.038
-
L-Asp
-
enzyme form ASSI
0.026
-
L-citrulline
-
enzyme form ASSI
4.5
-
threo-beta-hydroxy-L-Asp
-
-
0.88
-
threo-beta-methyl-L-Asp
-
-
0.03
-
L-citrulline
-
normal liver
additional information
-
additional information
-
ATP: biphasic double-reciprocal plot
-
additional information
-
additional information
-
-
-
Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.25
-
L-arginine
-
pH 8.7, 70C
IC50 VALUE [mM]
IC50 VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
additional information
-
additional information
-
substrate: diphosphoryl lipid A, IC50: 0.039 mg/ml; substrate: monophosphoryl lipid A, IC50: 0.270 mg/ml; substrate: R-lipopolysaccharide, IC50: 0.230 mg/ml; substrate: S-lipopolysaccharide, IC50: 0.024 mg/ml; substrate: sodium 2-deoxy-2-(3S-(9-phenyl-nonanoyl-oxy) tetradecanoyl) amino-3-O-(p-phenyl-nonanoyl)-D-glucopyranose 4-sulfate (ONO-4007), IC50: 0.0065 mg/ml
-
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
1e-06
-
-
37C, cell homogenate
6e-06
-
-
37C, A-549 cell homogenate
1.3e-05
-
-
37C, LNCaP cell homogenate
1.9e-05
-
-
37C, MCF-7 cell homogenate
4.8e-05
-
-
37C, HeLa cell homogenate
0.000174
-
-
37C, cell homogenate
0.0002
-
-
pH 8.7, 70C, activity in cell culture in growth medium 0.5% peptone and 0.1% yeast extract
0.00045
-
-
pH 8.7, 70C, activity in cell culture in growth medium with 0.2% yeast extract
0.0007
-
-
pH 8.7, 70C, activity in cell culture in minimal growth medium with 20 mM glucose and 5 mM NH4+
0.002
-
-
in the presence of 5 mM (NH4)2SO4 and after addition of 20 mM L-norvaline in root-free compartments
0.0028
-
-
in the presence of 5 mM (NH4)2SO4 and after addition of 20 mM L-norvaline in the root-free compartments
0.0071
-
-
in the presence of 5 mM (NH4)2SO4 and after addition of 0.5 mM phenyl phosphorodiamidate in root-free compartments
0.0085
-
-
in the presence of 5 mM (NH4)2SO4 in root-free compartments
0.0166
-
-
in the absence of (NH4)2SO4 in root-free compartments
0.0166
-
-
in the absence of (NH4)2SO4 in the root-free compartments
0.049
-
-
in the presence of 5 mM (NH4)2SO4 and after addition of 0.5 mM phenyl phosphorodiamidate in the root-free compartments; in the presence of 5 mM (NH4)2SO4 in the root-free compartments
0.06
-
P59846, -
20C
0.14
-
-
purification step: liver homogenate supernatant
0.27
-
-
purification step: 45-55% saturated ammonium sulfate precipitate
0.92
-
P59846, -
70C
0.95
-
-
-
0.99
-
-
purification step: DE-52 fraction
1
-
-
specific activity of ASS in Caco-2 cells after long time exposure (24h) to 1 ng/ml IL-1beta
1.27
-
-
specific activity of ASS in Caco-2 cells after the addition of 0.5 mM S-nitroso-acetylpenicillamine for 24h, an NO donor. This clearly demonstrates that NO induces an inhibition of the ASS activity in Caco-2 cells.
1.3
-
-
-
1.39
-
-
purification step: S-300 fraction
2.5
-
-
specific activity of ASS in Caco-2 cells after short time exposure (4h) to 1 ng/ml IL-1beta
3.8
-
-
-
3.83
-
-
-
4.2
-
-
-
5.16
-
-
purification step: UNO S-1 fraction
12.8
-
-
-
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
6
6.5
-
reaction of AMP + diphosphate + L-argininosuccinate
6
-
-
reaction of AMP + diphosphate + L-argininosuccinate
6.2
6.3
-
reaction of AMP + diphosphate + L-argininosuccinate
7.5
7.8
-
reaction of ATP + citrulline + L-argininosuccinate
7.5
-
-
assay at
7.8
-
-
assay at
7.8
-
P16460
assay at
7.9
-
-
-
8.4
8.8
-
-
8.4
-
-
reaction of ATP + citrulline + L-Asp
8.5
-
P59846, -
assay at
8.6
-
-
reaction of ATP + citrulline + L-Asp, enzyme forms ASSI and ASSII
8.7
-
-
reaction of ATP + L-citulline + L-Asp
pH RANGE
pH RANGE MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
5.5
7
-
about 60% of maximal activity at pH 5.5 and 7
6.5
8.5
-
6.5: about 55% of maximal activity, 8.5: about 70% of maximal activity, reaction of ATP + citrulline + L-argininosuccinate
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37
-
-
assay at
37
-
-
assay at
37
-
-
assay at
37
-
P16460
assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
human adenocarcinoma cell line Caco-2/TC7
Manually annotated by BRENDA team
-
endothelial cell
Manually annotated by BRENDA team
-
pancreatic cancer cell line, low ASS expression level
Manually annotated by BRENDA team
-, Q2Z0F6
Northern analyses of ass during fruiting body formation and post-harvest development reveals that expression is significantly up-regulated from developmental stage 3 on for all the tissues studied (gills, stip and cap). The expression reaches a maximum at the later stages of fruiting body growth, stages 6 and 7
Manually annotated by BRENDA team
-
pancreatic cancer cell line, low ASS expression level
Manually annotated by BRENDA team
-
in a rat ischemia model the striatum is examined at 24, 72 and 144 h after reperfusion and compared with rats in normal conditions. At 24 h after reperfusion, the number of the nitric oxide synthase-positive neurons and the percentage of those co-expressing argininosuccinate synthetase and argininsuccinate lyase and nitric oxide synthase are significantly increased in the animals with a longer survival
Manually annotated by BRENDA team
-
expression analysis is performed in bovine aortic endothelial cells (BAEC)
Manually annotated by BRENDA team
-, Q2Z0F6
Northern analyses of ass during fruiting body formation and post-harvest development reveals that expression is significantly up-regulated from developmental stage 3 on for all the tissues studied (gills, stip and cap). The expression reaches a maximum at the later stages of fruiting body growth, stages 6 and 7
Manually annotated by BRENDA team
-
pancreatic cancer cell line, low ASS expression level
Manually annotated by BRENDA team
-
pancreatic cancer cell line, low ASS expression level
Manually annotated by BRENDA team
-
a human hepatoma cell line
Manually annotated by BRENDA team
-
proximal tubules
Manually annotated by BRENDA team
-
normal and from patients with citrullinemia
Manually annotated by BRENDA team
-
parental cell line MGL8B2 and canavanine-resistant cell line MGL8D1
Manually annotated by BRENDA team
-
extraradical myecelium
Manually annotated by BRENDA team
-
increased co-expression of AS and TNF-a mRNA is observed in non-small cell lung and stomach cancer, compared with normal corresponding tissues
Manually annotated by BRENDA team
-
AS mRNA increases 2- to 3fold by 24 h in both the IGROV-1 cell line, and a second ovarian cancer cell line OVCAR-3, following treatment with TNF-alpha. In contrast, although the ovarian cancer cell lines, PEO1 and SKOV-3, express AS in abundance, this is not TNF-a-inducible; TNF-alpha induces prolonged expression of AS mRNA and protein in ovarian tumour cells, contrasting with short-lived expression of AS mRNA in the normal ovarian epithelial cells. AS mRNA is higher expressed in ovarian tumor tissue compared to normal ovarian tissue. Moreover, AS protein colocalises with TNF-alpha in ovarian cancer cells, with significantly higher levels of AS in malignant compared with normal ovarian tissue.
Manually annotated by BRENDA team
-
pancreatic cancer cell line, very low ASS expression level
Manually annotated by BRENDA team
-
pancreatic cancer cell line, low ASS expression level
Manually annotated by BRENDA team
-
a human epithelium cell line
Manually annotated by BRENDA team
-
argininosuccinate synthase accumulates in circulation within 1 h after treatment with both lipopolysaccharide alone and hepatotoxic combination of lipopolysaccharide and D-Galactosamine
Manually annotated by BRENDA team
-, Q2Z0F6
Northern analyses of ass during fruiting body formation and post-harvest development reveals that expression is significantly up-regulated from developmental stage 3 on for all the tissues studied (gills, stip and cap). The expression reaches a maximum at the later stages of fruiting body growth, stages 6 and 7
Manually annotated by BRENDA team
-
increased co-expression of AS and TNF-a mRNA is observed in non-small cell lung and stomach cancer, compared with normal corresponding tissues
Manually annotated by BRENDA team
-
pancreatic cancer cell line, very low ASS expression level
Manually annotated by BRENDA team
additional information
-
treatment of BAEC cells with tumor necrosis factor-alpha supresses argininosuccinate synthase expression. reporter gene analysis demonstrates that TNF-alpha suppresses the AS proximal promoter and electrophoretic mobility shift assay shows reduced binding to three essential Sp1 elements
Manually annotated by BRENDA team
additional information
-, Q2Z0F6
ASS is up-regulated within 3 h after harvest showing that the induction mechanism is very sensitive to the harvest event and emphasizes the importance of the arginine biosynthetic pathway/ornithine cycle in post-harvest physiology
Manually annotated by BRENDA team
additional information
-
87% of human tumors and 5 of 7 cancer cell lines lack ASS expression, overview
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the enzyme is mainly mitochondrial in fetal and new-born liver, and cytoplasmic in adult liver
Manually annotated by BRENDA team
-
outer membrane; the enzyme is mainly mitochondrial in fetal and new-born liver, and cytoplasmic in adult liver
Manually annotated by BRENDA team
additional information
-
at the activity level, the colocation of argininosuccinate synthetase is changing during fetal and neonatal developement and is under the control of corticosteroid and pancreatic hormones
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
Campylobacter jejuni subsp. jejuni serotype O:2 (strain NCTC 11168)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
45000
-
-
SDS-PAGE
46000
-
P16460
SDS-PAGE
47270
-
-, Q2Z0F6
deduced from cDNA
48500
-
Q0KKQ0
deduced from cDNA
80000
-
-
gel filtration
158000
-
-
gel filtration
175000
-
-
gel filtration
180000
-
-
gel filtration
183000
-
-
gel filtration
185000
-
-
gel filtration
185000
-
-
sucrose density gradient centrifugation
185000
-
-
gel filtration
185000
-
-
gel filtration
207000
-
-
sedimentation equilibrium centrifugation
228000
-
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 48000, SDS-PAGE
?
-
x * 46000, immunoblot analysis
?
-
x * 47000, calculated for His-tagged recombinant protein
dimer
-
2 * 45000, SDS-PAGE under reducing and nonreducing conditions
homotetramer
-
4 * 50000, SDS-PAGE
homotetramer
-
each monomer of tetrameric EAS consits of a nucleotide binding domain and a novel catalytic/multimerization domain, subunit/domain structure, subunit interactions
homotetramer
-
4 * 45400, Western blot analysis, calculation from the amino acid sequence
tetramer
-
2 * 90000, SDS-PAGE in absence of reducing agent; 4 * 45000, two pairs of monomers crosslinked by disulfide bonds, SDS-PAGE in presence of reducing agent
tetramer
-
4 * 48000, SDS-PAGE, PAGE with 6 M urea
tetramer
-
, 4 * 49000, SDS-PAGE in presence of 2-mercaptoethanol
tetramer
-
4 * 43000, SDS-PAGE
tetramer
-
4 * 46500, SDS-PAGE in presence of 2-mercaptoethanol
tetramer
-
4 * 45000, SDS-PAGE
tetramer
-
-
tetramer
-
4 * 46000, SDS-PAGE
tetramer
-
4 * 44815, recombinant tAsS, subunit/domain structure, amino acid sequence
tetramer
P00966
two dimers, dimeric and tetrameric interface structures, overview
tetramer
Saccharomyces cerevisiae 1278b
-
, 4 * 49000, SDS-PAGE in presence of 2-mercaptoethanol
-
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
nitrosylation
-
exposure of ASS to IL-1beta in Caco-2 cells induces the nitrosylation of the ASS protein
phosphoprotein
-
regulation of argininosuccinate synthase by dynamic phosphorylation through protein kinase A, the enzyme lacks a consensus Akt phosphorylation motif R-X-R-X-X-S/T
additional information
-
it is shown that IL-1beta inhibits the ASS activity through a post-translational mechanism since increase in both specific mRNA-level and protein amount can be detected after long-time exposure of Caco-2 cells to IL-1beta. The inhibiting effect of IL-1beta is linked to the production of nitric oxide (NO) induced by IL-1beta
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
crystal strucures in complex with intact ATP and with ATP and citrulline, hanging drop vapour-diffusion technique, X-ray analysis
-
recombinant EAS, hanging drop vapour-diffusion technique, X-ray analysis
-
purified recombinant ASS1 by hanging-drop method, 0.001 ml of protein solution containing 17 mg/ml protein in 500 mM NaCl, 2 mM TCEP, 30 mM HEPES, pH 7.5, 10 mM aspartate, and 10 mM citrulline, is mixed with 0.001 ml of reservoir solution containing 16% w/v PEG 3350, 0.15 M dl-malic acid pH 7.0, X-ray diffraction structure determination and analysis at 2.4-2.5 A resolution
P00966
3-dimensional structure of free enzyme and of complexes with intact ATP, adenylyl imidodiphosphate, arginine or succinate, hanging drop method
-
structures of enzyme complexed with intact ATP and substrates citrulline and aspartate, complexed with AMP and argininosuccinate, and complexed with AMP-PNP, arginine, aspartate and Mg2+, vapor diffusion method, X-ray analysis
P59846, -
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
45
-
-
enzyme forms ASSI and II are stable, enzyme form ASSIII is very unstable
50
-
-
7 min, enzyme from normal liver and from patients with citrullinemia, in presence of 10 mM argininosuccinate, about 10% loss of activity; 7 min, enzyme from normal liver, in absence of argininosuccinate, about 65% loss of activity; 7 min, enzyme from patients with citrullinemia, in absence of argininosuccinate, 95% loss of activity
additional information
-
-
argininosuccinate stabilizes against heat treatment
GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
unstable during purification
-
argininosuccinate stabilizes against heat treatment
-
in presence of 5 mM argininosuccinate, the activities of the three forms of the enzyme are resistant to chymotrypsin
-
STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
-70C, stable for 3 months
-
quite stable frozen or as ammonium sulfate precipitate
-
-20C, 0.05 M citrulline, 0.05 M Asp, or 0.01 M argininosuccinate, stable for more than 1 year
-
-20C, stable for months
-
0-4C, without (NH4)2SO4, stable for about 2 weeks
-
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
recombinant His-tagged enzyme from Escherichia coli by nickel affinty chromatography
-
recombinant EAS
-
affinity chromatography
-
recombinant
-
recombinant ASS1 by His affinity chromatography and gel filtration
P00966
affinity chromatography
P16460
analysis by native gel electrophoresis shows that argininosuccinate synthetase can bind bacterial lipopolysaccharide and lipid A; argininosuccinate synthetase is purified from mouse liver. Livers are excised from 20 male mice (C3H/He strain, age 7-8 weeks) and homogenized in 100 mM Tris-HCl (pH 7.5) containing 1 mM citrulline and 1 mM aspartic acid. Homogenate is centrifuged. After salting-out with (NH4)2SO4. The sample is subjected to anion-exchange chromatography on DE-52. Concentrated samples are loaded on a column of Sephacryl S-300 HR. The collected first peak fractions are dialyzed and subjected to anion-exchange chromatography on UNO S-1
-
3 enzyme forms ASSI, ASSII, and ASSIII
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
cloned in Escherichia coli
-, Q2Z0F6
expression analysis, the AS gene promoter contains a a near consensus PPARgamma response element, PPRE, overview
-
expression of the His-tagged enzyme in Escherichia coli
-
expression in Escherichia coli BB101
-
expressed as a C-terminal fusion protein with maltose-binding protein in Escherichia coli
-
expression alone or together with FLAG-tagged HSCARG or with HSCARG siRNA in HeLa and HEK-293 cells, expression analysis, overview
-
expression in Escherichia coli
-
expression of ASS1
P00966
expression in Escherichia coli
-
the gene encoding argininosuccinate synthetase of Porphyra yezoensis is obtained by PCR using an expressed sequence tag clone as a template, and subcloned into the yeast expression vector pYES2. The gene is expressed when the vector harboring PyARG1 is introduced into an ARG1-deficient strain of Saccharomyces cerevisiae, which results in complementation of the mutant phenotype. The transformed cells survive on a selective medium lacking arginine, and transcripts of PyARG1 are detected by RT-PCR. A quantitative comparison shows that the rescued mutant cells grow in the selective liquid medium with a minor reduction in growth rate relative to wild-type cells
Q0KKQ0
expression in Escherichia coli as fusion protein with maltose binding protein
-
expression in Escherichia coli BL21(DE3)pLysE
P59846, -
overexpression in Escherichia coli
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
tumoural enzyme downregulation by hepatocellular carcinoma, malignant melanoma, malignant pleural mesothelioma, prostate and renal cancer
-
downregulation of enzyme expression is associated with the development of platinum resistance to platinum-based drugs
-
hepatic argininosuccinate synthase expression is hormonally regulated, expression of endothelial and inflammatory cell argininosuccinate synthase is under control of cytokines
-
overexpression of argininosuccinate synthase in primary ovarian, stomach and colorectal cancer cells results in platinum sensitive tumours
-
increased expression in drug resistant mutant
A4I066, -
threefold repression of enzyme formation by arginine
-
threefold repression of enzyme formation by arginine
Sulfolobus solfataricus P1
-
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
A192V
-
mutant G280R has no ASS activity, mutants A192V, R272C, and R304W have low ASS activity and abnormal kinetics. A higher Km for citrulline than in wild-type enzyme is obtained with mutants A192V, R272C, and R304W
D296G
-
mutation of the argininosuccinate synthetase gene, found in patients
E191Q
-
mutation of the argininosuccinate synthetase gene, found in patients
G1168A
-
mutation results in citrullinemia type I
G156del
-
mutation of the argininosuccinate synthetase gene, found in patients
G280R
-
mutant G280R has no ASS activity, mutants A192V, R272C, and R304W have low ASS activity and abnormal kinetics. A higher Km for citrulline than in wild-type enzyme is obtained with mutants A192V, R272C, and R304W
G324V
-
mutation of the argininosuccinate synthetase gene, found in patients
G347R
-
mutation of the argininosuccinate synthetase gene, found in patients
K277T
-
mutation of the argininosuccinate synthetase gene, found in patients
L160P
-
mutation of the argininosuccinate synthetase gene, found in patients
N158del
-
mutation of the argininosuccinate synthetase gene, found in patients
P96H
-
mutation of the argininosuccinate synthetase gene, found in patients
Q311del
-
mutation of the argininosuccinate synthetase gene, found in patients
Q401del
-
mutation of the argininosuccinate synthetase gene, found in patients
R127Q
-
mutation of the argininosuccinate synthetase gene, found in patients
R127W
-
mutation of the argininosuccinate synthetase gene, found in patients
R265C
-
mutation of the argininosuccinate synthetase gene, found in patients
R272C
-
mutant G280R has no ASS activity, mutants A192V, R272C, and R304W have low ASS activity and abnormal kinetics. A higher Km for citrulline than in wild-type enzyme is obtained with mutants A192V, R272C, and R304W
R304W
-
mutant G280R has no ASS activity, mutants A192V, R272C, and R304W have low ASS activity and abnormal kinetics. A higher Km for citrulline than in wild-type enzyme is obtained with mutants A192V, R272C, and R304W
R344del
-
mutation of the argininosuccinate synthetase gene, found in patients
S341F
-
mutation of the argininosuccinate synthetase gene, found in patients
S79P
-
mutation of the argininosuccinate synthetase gene, found in patients
T284I
-
mutation of the argininosuccinate synthetase gene, found in patients
Y291S
-
mutation of the argininosuccinate synthetase gene, found in patients
Y359D
-
mutation of the argininosuccinate synthetase gene, found in patients
additional information
-, Q2Z0F6
an alignment with ASS proteins from other organisms reveals high similarity with fungal (6163%) and mammalian (5155%) ASS proteins
L206P
-
mutation of the argininosuccinate synthetase gene, found in patients
additional information
P00966
clinical mutations, phenotypes, overview
additional information
-
enzyme overexpression induces a relocalization of HSCARG
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
-
the downregulation of tumor necrosis factor-alpha is an added insult to endothelial function because of its important role in NO production and in endothelial viability
drug development
-
high levels of AS expression, which may be required for several arginine-dependent processes in cancer, including the production of nitric oxide, proline, pyrimidines and polyamines, is regulated by TNF-alpha and may provide an important molecular pathway linking inflammation and metabolism to ovarian tumorigenesis
medicine
-
neuronal and glial ASS expression is increased in brains of patients with Alzheimer disease
medicine
-
a case of late-onset CTLN1 (citrullinemia) in a patient is described by biochemical analyses and ASS gene mutation confirmation. This is the first report of a Korean patient with late-onset CTLN1 confirmed by ASS gene mutation identification
medicine
-
potential novel therapeutic strategies for ovarian cancer
medicine
-
potential target in platinum sensitive tumours
medicine
-
novel target for the therapy of hypertension-related disorders
medicine
-
AS and GTP cyclohydrolase I are intimately associated with inflammatory arthritis, they may be important modulators of arthritis and may represent novel targets for modulation of disease activity
medicine
-
citrulline-arginine recycling enzyme, intervention in the supply of arginine may represent a new therapeutic approach to the treatment of NO-mediated neurodegenerative damage in the brain
medicine
-
argininosuccinate synthetase is inhibited by endotoxin, implying that bacterial products might potentially regulate the arginine metabolism in the host and perturb NO synthesis
medicine
P16460
novel target for the therapy of hypertension-related disorders
molecular biology
Q0KKQ0
report in which the function of a Porphyra yezoensis gene has been directly demonstrated by the rescue of a Saccharomyces cerevisiae mutant. This technique may provide new opportunities for further investigations into the functions of various genes in Porphyra yezoensis and other macroalgal species
medicine
-
transient ischemia induces changes in nitric oxide synthase, argininosuccinate synthetase and argininsuccinate lyase co-expression in the rat striatal neurons. At 24 h after reperfusion in the animals with a longer survival and better motor-sensory performances there is an increase in these neuronal populations. It is hypothesized that the elevated expression of argininosuccinate synthetase and argininsuccinate lyase protects ischemic striatal neurons from tissue damages by maintaining a correct NO production