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Information on EC 3.5.3.18 - dimethylargininase and Organism(s) Bos taurus and UniProt Accession P56965

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IUBMB Comments
Also acts on Nomega-methyl-L-arginine.
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Select one or more organisms in this record: ?
This record set is specific for:
Bos taurus
UNIPROT: P56965
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Word Map
The taxonomic range for the selected organisms is: Bos taurus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
ddah1, dimethylarginine dimethylaminohydrolase, ddah2, ddah-1, ddah-2, dimethylaminohydrolase, dimethylarginine dimethylaminohydrolase 1, dimethylargininase, human ddah-1, ddah-i, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimethylarginine dimethylaminohydrolase
-
Nomega,Nomega-dimethyl-L-arginine dimethylaminohydrolase-1
-
DDAH
-
-
-
-
DDAH-1
-
-
DDAH1
-
-
DDAHI
-
-
-
-
DDAHII
-
-
-
-
Dimethylargininase
-
-
-
-
dimethylarginine dimethylaminohydrolase
dimethylarginine dimethylaminohydrolase 1
-
-
G6a
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hydrolysis
-
hydrolysis of linear amidines
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
Nomega,Nomega'-dimethyl-L-arginine dimethylamidohydrolase
Also acts on Nomega-methyl-L-arginine.
CAS REGISTRY NUMBER
COMMENTARY hide
123644-75-7
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
-
-
-
?
N,N-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
NG-monomethyl-L-arginine + H2O
citrulline + methylamine
show the reaction diagram
-
-
-
-
?
Ngamma-monomethyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
-
-
-
?
S-methyl-L-thiocitrulline + H2O
L-citrulline + methanethiol
show the reaction diagram
-
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
enzyme is involved in regulation of the levels of the natural occuring free arginine derivatives L-Nomega,Nomega-dimethylarginine and L-Nomega-methylarginine, which are reversible inhibitors of nitric oxide synthase
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Zn2+
Zn2+ binding to DDAH-1 protects the enzyme from S-nitrosylation by free nitric oxide
Zn2+
-
contains one tightly bound zinc ion
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
L-citrulline
-
L-homocysteine
-
S-nitroso-L-cysteine
9-15% inhibition of the zinc-free enzyme at 0.5 mM, S-nitrosylation of the active site Cys273 in DDAH-1
S-nitroso-L-homocysteine
2-(N,N-dimethylamino)-diazenolate-2-oxide
-
S-nitrosylation of apo-enzyme, holo-enzyme resists, reaction with two of five Cys-residues
methylamine
-
10 mM, 80% of activity
N-nitro-L-arginine methylester
additional information
5 mM of L-cysteine, L-homocysteine, glutathione, dithiothreitol, or Tris(2-carboxyethyl)phosphine-HCl for 30 min at 37°C cannot restore inhibited activity, suggesting that the covalent product N-thiosulfoximide will remain stable under the reducing conditions present in the cytosol
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
D-histidine
-
activating ability in decreasing order: histamine, imidazole, L-histidine, D-histidine
histamine
-
activating ability in decreasing order: histamine, imidazole, L-histidine, D-histidine
imidazole
-
activating ability in decreasing order: histamine, imidazole, L-histidine, D-histidine
L-histidine
-
activating ability in decreasing order: histamine, imidazole, L-histidine, D-histidine
telmisartan
-
vitamin E
-
xanthone
-
additional information
-
type of buffer dramatically influences enzyme activity, activity in imidazole/HCl buffer is about 25% higher than in phosphate buffer
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.18
dimethyl-L-arginine
-
1.31
NG,NG-dimethyl-L-arginine
-
-
1.6
NG-monomethyl-L-arginine
-
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.27
NG,NG-dimethyl-L-arginine
-
-
0.34
NG-monomethyl-L-arginine
-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.69
S-nitroso-L-homocysteine
in the presence of 5 mM EDTA, at pH 7.3 and 37°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.075
S-nitroso-L-homocysteine
Bos taurus
in 50 mM HEPES/NaOH (pH 7.3), 150 mM KCl, and 5 mM EDTA for 30 min at 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.55
-
37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.8
-
imidazole/HCl buffer
additional information
-
type of buffer dramatically influences enzymatic activity
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
physiological function
overexpression of DDAH-1 increases endothelial nitric oxide by 24%. Small interfering RNA-mediated down-regulation of DDAH-1 reduces nitric oxide bioavailability by 27%. The reduction in nitric oxide production following DDAH-1 gene silencing is associated with a 48% reduction in L-Arg/asymmetric dimethylarginine and is partially restored with L-Arg supplementation
physiological function
overexpression of DDAH-2 increases endothelial nitric oxide by 18%. Small interfering RNA-mediated down-regulation of DDAH-2 reduces nitric oxide bioavailability by 57%. L-Arg and asymmetric dimethylarginine are unchanged in the DDAH-2-silenced cells, and L-Arg supplementation has no effect on nitric oxide
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
DDAH1_BOVIN
285
0
31289
Swiss-Prot
Mitochondrion (Reliability: 2)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
31200
electrospray ionization mass spectrometry
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
by sitting drop vapor diffusion, at 1.08-2.0 A resolution and at pH 6.3 and pH 9.0
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
50
-
2 h, holo-enzyme retains ca. 56% of the original activity, no residual activity of the apoenzyme. Thermal denaturation of both protein forms is irreversible
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
Zn2+ has a structure-stabilizing role
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
anion exchange chromatography and gel filtration chromatography
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
method for reversible preparation of metal-free and metal-containing enzyme
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
structure-based development of specific DDAH-1 inhibitors that might be useful in the therapeutic treatment of NOS dysfunction-related diseases
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Bogumil, R.; Knipp, M.; Fundel, S.M.; Vasak, M.
Characterization of dimethylargininase from bovine brain: evidence for a zinc binding site
Biochemistry
37
4791-4798
1998
Bos taurus
Manually annotated by BRENDA team
Knipp, M.; Charnock, J.M.; Garner, C.D.; Vasak, M.
Structural and functional characterization of the Zn(II) site in dimethylargininase-1 (DDAH-1) from bovine brain. Zn(II) release activates DDAH-1
J. Biol. Chem.
276
40449-40456
2001
Bos taurus
Manually annotated by BRENDA team
Knipp, M.; Braun, O.; Gehrig, P.M.; Sack, R.; Vasak, M.
Zn(II)-free dimethylargininase-1 (DDAH-1) is inhibited upon specific Cys-S-nitrosylation
J. Biol. Chem.
278
3410-3416
2003
Bos taurus
Manually annotated by BRENDA team
Hasegawa, K.; Wakino, S.; Tanaka, T.; Kimoto, M.; Tatematsu, S.; Kanda, T.; Yoshioka, K.; Homma, K.; Sugano, N.; Kurabayashi, M.; Saruta, T.; Hayashi, K.
Dimethylarginine dimethylaminohydrolase 2 increases vascular endothelial growth factor expression through Sp1 transcription factor in endothelial cells
Arterioscler. Thromb. Vasc. Biol.
26
1488-1494
2006
Bos taurus, Homo sapiens
Manually annotated by BRENDA team
Frey, D.; Braun, O.; Briand, C.; Vak, M.; Grtter, M.G.
Structure of the mammalian NOS regulator dimethylarginine dimethylaminohydrolase: a basis for the design of specific inhibitors
Structure
14
901-911
2006
Bos taurus (P56965), Bos taurus
Manually annotated by BRENDA team
Braun, O.; Knipp, M.; Chesnov, S.; Vasak, M.
Specific reactions of S-nitrosothiols with cysteine hydrolases: A comparative study between dimethylargininase-1 and CTP synthetase
Protein Sci.
16
1522-1534
2007
Bos taurus (P56965)
Manually annotated by BRENDA team
Wadham, C.; Mangoni, A.A.
Dimethylarginine dimethylaminohydrolase regulation: a novel therapeutic target in cardiovascular disease
Expert. Opin. Drug Metab. Toxicol.
5
303-319
2009
Bos taurus, Bos taurus (Q3SX44), Oryctolagus cuniculus, Rattus norvegicus (O08557), Rattus norvegicus (Q6MG60), Homo sapiens (O94760), Homo sapiens (O95865), Mus musculus (Q99LD8), Mus musculus (Q9CWS0)
Manually annotated by BRENDA team
Pope, A.J.; Karrupiah, K.; Kearns, P.N.; Xia, Y.; Cardounel, A.J.
Role of dimethylarginine dimethylaminohydrolases in the regulation of endothelial nitric oxide production
J. Biol. Chem.
284
35338-35347
2009
Bos taurus (P56965), Bos taurus (Q3SX44)
Manually annotated by BRENDA team