Information on EC 3.5.3.18 - dimethylargininase

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

EC NUMBER
COMMENTARY
3.5.3.18
-
RECOMMENDED NAME
GeneOntology No.
dimethylargininase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Nomega,Nomega'-dimethyl-L-arginine + H2O = dimethylamine + L-citrulline
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis
-
-
hydrolysis of linear amidines
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
Nomega,Nomega'-dimethyl-L-arginine dimethylamidohydrolase
Also acts on Nomega-methyl-L-arginine.
SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Adv-DDAH
-
-
DDAH
-
-
-
-
DDAH
-
-
DDAH
-
two seperate DDAH-proteins: Ddah1 and Ddah2
DDAH-1
-
isozyme
DDAH-1
O94760
-
DDAH-1
Q9CWS0
-
DDAH-1
O08557
-
DDAH-2
Q3SX44
-
DDAH-2
O95865
-
DDAH-2
Q6MG60
isozyme, mainly present in vascular tissues that co-express endothelial nitric oxide synthases
DDAH-2
-
-
DDAH-2
Q99LD8
-
DDAH-2
Q6MG60
-
DDAH-2
Q6MG60
isozyme
DDAH1
-
-
DDAH1
-
-
DDAH2
-
-
DDAHI
-
-
-
-
DDAHII
-
-
-
-
dimethlarginine dimethylaminohydrolase
-
-
Dimethylargininase
-
-
-
-
dimethylarginine dimethylamino-hydrolase
-
-
dimethylarginine dimethylaminohydrolase
-
-
-
-
dimethylarginine dimethylaminohydrolase
-
-
dimethylarginine dimethylaminohydrolase
Q3SX44
-
dimethylarginine dimethylaminohydrolase
-
-
dimethylarginine dimethylaminohydrolase
O94760, O95865
-
dimethylarginine dimethylaminohydrolase
Q6MG60
-
dimethylarginine dimethylaminohydrolase
-
-
dimethylarginine dimethylaminohydrolase
Q99LD8, Q9CWS0
-
dimethylarginine dimethylaminohydrolase
-
-
dimethylarginine dimethylaminohydrolase
-
-
dimethylarginine dimethylaminohydrolase
-
-
dimethylarginine dimethylaminohydrolase
-
-
dimethylarginine dimethylaminohydrolase
O08557
-
dimethylarginine dimethylaminohydrolase
Q6MG60
-
dimethylarginine dimethylaminohydrolase 1
-
-
dimethylarginine dimethylaminohydrolase 1
-
-
dimethylarginine dimethylaminohydrolase 1
-
-
dimethylarginine dimethylaminohydrolase 1
-
-
dimethylarginine dimethylaminohydrolase-2
-
-
dimethylarginine dimethylaminohydrolase-2
-
-
dimethylarginine-dimethylaminohydrolase
-
-
G6a
-
-
-
-
hDDAH-1
-
-
human DDAH-1
-
-
human dimethylarginine dimethylaminohydrolase-1
-
-
Nomega,Nomega-dimethyl-L-arginine dimethylaminohydrolase-1
-
-
CAS REGISTRY NUMBER
COMMENTARY
123644-75-7
-
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
isoform DDAH-1
UniProt
Manually annotated by BRENDA team
isoform DDAH-2
UniProt
Manually annotated by BRENDA team
adult mongrels
-
-
Manually annotated by BRENDA team
White leg-horn chick embryos
-
-
Manually annotated by BRENDA team
2 dimethylarginine dimethylaminohydrolases: DDAH I and II
UniProt
Manually annotated by BRENDA team
isoform DDAH-1
UniProt
Manually annotated by BRENDA team
transfected to rats with recombinant adenoviruses
-
-
Manually annotated by BRENDA team
transgenic mouse model with oxerexpressed human dimethylarginine dimethylaminohydrolase
-
-
Manually annotated by BRENDA team
C57BL/6J, after tretmend with an NOS inhibitor used as a model of chronic nitric oxide expression
-
-
Manually annotated by BRENDA team
heterozygous for cystathionine beta-synthase and wild-type
-
-
Manually annotated by BRENDA team
New Zealand white rabbits
-
-
Manually annotated by BRENDA team
male Sprague-Dawley rat
-
-
Manually annotated by BRENDA team
male sprague-dawley rats
-
-
Manually annotated by BRENDA team
Wistar rat embryos
-
-
Manually annotated by BRENDA team
Wister-Kyoto rat and spontaneously hyptertensive rat
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
DDAH1 knockout impairs endothelial sprouting from cultured aortic rings, and overexpression of constitutively active Akt or DDAH1 rescues endothelial sprouting in the aortic rings from these mice
malfunction
-
plasma and tissue asymmetrical dimethylarginine (ADMA) and N-monomethyl-L-arginine (L-NMMA) levels in DDAH1-/- mice are several folds higher than in wild-type mice, but growth and development of these knockout mice are similar to wild-type. Although the expression of DDAH2 is unaffected, DDAH activity is undetectable in all tissues tested. Results indicate that DDAH1 is the critical enzyme for ADMA and L-NMMA degradation
malfunction
-
using selective gene silencing of DDAH1 with small interfering RNA and overexpression of DDAH1 in HUVEC, it is shown that DDAH1 acts to promote endothelial cell proliferation, migration and tube formation both by Akt phosphorylation as well as through the traditional role of degrading ADMA. DDAH1 overexpression increases Ras activity
physiological function
-
heterozygous DDAH1 embryos express DDAH1 RNA and protein at approximately 50% of wild-type levels, while circulating plasma asymmetric dimethylarginine levels of heterozygotes are about 20% higher than those of wild-type mice. Homozygous DDAH1 null embryos are generated at low frequency, and do not progress through embryonic development. Mice carrying an inactivated DDAH2 locus have reduced DDAH2 expression at both the RNA and protein levels in all tissues studied. Breeding of these mice indicates that both heterozygous and homozygous inactivation of the DDAH2 locus does not impact on embryonic survival, with wild type, heterozygous and null mice produced in Mendelian ratios
physiological function
P56965, Q3SX44
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
P56965, Q3SX44
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
physiological function
-
results from this animal model of prolonged critical illness show that DDAH activities in several organs in concert determine plasma levels of ADMA, confirming that DDAH is an important player in the regulation of circulatory ADMA
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
Q3SX44
-
-
-
?
dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
-
-
-
-
?
dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
O08557
-
-
-
?
dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
Q99LD8, Q9CWS0
-
-
-
?
dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
O94760, O95865
-
-
-
?
dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
-
4 mM, pH 6.5, 37C, 2 h incubation time
-
-
?
N,N-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
-
-
-
?
N,N-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
-
-
?
N,N-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
37C, 2 h, pH 6.0
-
-
?
N-monomethyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
-
-
-
-
?
N5-(methoxycarbamimidoyl)-L-ornithine + H2O
L-citrulline + ?
show the reaction diagram
-
assay at 37C, 30 min, pH 7.4
-
-
?
N5-(methylcarbamimidoyl)-L-ornithine + H2O
L-citrulline + ?
show the reaction diagram
-
assay at 37C, 30 min, pH 7.4
-
-
?
N5-[2,5-dihydro-1H-pyrrol-1-yl(imino)methyl]-L-ornithine + H2O
L-citrulline + ?
show the reaction diagram
-
assay at 37C, 30 min, pH 7.4
-
-
?
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
O95865
-
-
-
?
NG,NG-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,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
-
-
ir
NG,NG-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,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
Q6MG60
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
Q6MG60
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
the key role of dimethylarginine dimethylaminohydrolase may be to ensure that under normal conditions the levels of methylarginines are kept low throughout the whole cell
-
-
-
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
enzyme plays an integral role in arginine handling
-
-
-
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
-
-
-
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
enzyme plays a role in metabolism of NG,NG-dimethyl-L-arginine
-
-
-
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
the enzyme plays a functional role in the regulation of nitric oxide synthase
-
-
-
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
the enzyme might play a role as a regulator of nitric oxide generation in human tissues
-
-
-
NG,NG-dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
-
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
-
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
-
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
?
show the reaction diagram
-
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
?
show the reaction diagram
-
-
-
-
?
NG,NG-dimethyl-L-homoarginine + H2O
?
show the reaction diagram
-
at 2.8% of the activity with NG,NG-dimethyl-L-arginine
-
-
?
NG-amino-L-arginine + H2O
?
show the reaction diagram
-
-
-
-
?
NG-hydroxy-L-arginine + H2O
?
show the reaction diagram
-
-
-
-
?
NG-methyl arginine + H2O
L-citrulline + methylamine
show the reaction diagram
-
-
-
-
?
NG-methyl-L-arginine + H2O
?
show the reaction diagram
-
-
-
-
?
NG-methyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
-
-
-
-
?
NG-methyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
-
-
-
-
?
NG-monomethyl-L-arginine + H2O
citrulline + methylamine
show the reaction diagram
O95865
-
-
-
?
NG-monomethyl-L-arginine + H2O
citrulline + methylamine
show the reaction diagram
-
-
-
-
?
NG-monomethyl-L-arginine + H2O
citrulline + methylamine
show the reaction diagram
-
-
-
-
?
NG-monomethyl-L-arginine + H2O
citrulline + methylamine
show the reaction diagram
-
at 61% of the activity with NG,NG-dimethyl-L-arginine
-
-
?
Ngamma-monomethyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
Q3SX44
-
-
-
?
Ngamma-monomethyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
-
-
-
-
?
Ngamma-monomethyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
O08557
-
-
-
?
Ngamma-monomethyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
Q99LD8, Q9CWS0
-
-
-
?
Ngamma-monomethyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
O94760, O95865
-
-
-
?
Nomega,Nomega-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
O94760
-
-
-
?
Nomega-monomethyl-L-arginine + H2O
L-citrulline + methylamine
show the reaction diagram
Q9I4E3
-
-
-
?
S-methyl-L-thiocitrulline + H2O
?
show the reaction diagram
-
-
-
-
?
S-methyl-L-thiocitrulline + H2O
methanethiol + L-citrulline
show the reaction diagram
-
-
-
-
?
S-methyl-L-thiocitrulline + H2O
methanethiol + L-citrulline
show the reaction diagram
-
-
-
-
?
S-methyl-L-thiocitrulline + H2O
L-citrulline + methanethiol
show the reaction diagram
Q3SX44
-
-
-
?
S-methyl-L-thiocitrulline + H2O
L-citrulline + methanethiol
show the reaction diagram
-
-
-
-
?
S-methyl-L-thiocitrulline + H2O
L-citrulline + methanethiol
show the reaction diagram
O08557
-
-
-
?
S-methyl-L-thiocitrulline + H2O
L-citrulline + methanethiol
show the reaction diagram
Q99LD8, Q9CWS0
-
-
-
?
S-methyl-L-thiocitrulline + H2O
L-citrulline + methanethiol
show the reaction diagram
O94760, O95865
-
-
-
?
S-methyl-L-thiocitrulline + H2O
L-citrulline + methanethiol
show the reaction diagram
O94760
-
-
-
?
L-arginine + H2O
?
show the reaction diagram
-
-
-
-
?
additional information
?
-
O95865
no hydrolysis of NG,NG-dimethyl-L-arginine
-
-
-
additional information
?
-
-
bad substrates are creatine, creatinine, argininosuccinate, guanidinoacetate, L-homoarginine, L-canvanine
-
-
-
additional information
?
-
-
incapable of hydrolyzing peptide incorporated methylarginines
-
-
-
additional information
?
-
-
L-arginine is no substrate
-
-
-
additional information
?
-
O94760
no substrate: S-ethyl-2-thiopseudourea, S-ethyl-N-phenylisothiourea and phenylene-1,3-bis(ethane-2-isothiourea)
-
-
-
additional information
?
-
-
DDAH1 forms a protein complex with Ras
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
the key role of dimethylarginine dimethylaminohydrolase may be to ensure that under normal conditions the levels of methylarginines are kept low throughout the whole cell
-
-
-
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
enzyme plays an integral role in arginine handling
-
-
-
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
-
-
-
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
enzyme plays a role in metabolism of NG,NG-dimethyl-L-arginine
-
-
-
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
the enzyme plays a functional role in the regulation of nitric oxide synthase
-
-
-
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
show the reaction diagram
-
the enzyme might play a role as a regulator of nitric oxide generation in human tissues
-
-
-
NG,NG-dimethyl-L-arginine + H2O
L-citrulline + dimethylamine
show the reaction diagram
-
-
-
-
?
additional information
?
-
-
DDAH1 forms a protein complex with Ras
-
-
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zn2+
-
contains one tightly bound zinc ion
Zn2+
-
Zn2+ binding to DDAH-1 protects the enzyme from S-nitrosylation by free nitric oxide
Zn2+
-
Zn2+-containing enzyme
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S)-2-amino-5-(ethanimidoylamino)pentanoic acid
-
-
(2S)-2-amino-5-(N'-butylcarbamimidamido)pentanoic acid
-
-
(2S)-2-amino-5-(pent-4-enimidoylamino)pentanoic acid
-
-
(2S)-2-amino-5-(pentanimidoylamino)pentanoic acid
-
-
(2S)-2-amino-5-(propanimidoylamino)pentanoic acid
-
-
(2S)-2-amino-5-[(4E)-hex-4-enimidoylamino]pentanoic acid
-
-
(2S)-2-amino-5-[N'-(3,3,3-trifluoropropyl)carbamimidamido]pentanoic acid
-
-
(2S)-2-amino-5-[N'-(3-methoxypropyl)carbamimidamido]pentanoic acid
-
-
(2S)-2-amino-5-[N'-(4-amino-4-oxobutyl)carbamimidamido]pentanoic acid
-
-
(2S)-2-amino-5-[N'-(but-3-en-1-yl)carbamimidamido]pentanoic acid
-
-
(2S)-2-amino-5-[N'-(but-3-yn-1-yl)carbamimidamido]pentanoic acid
-
-
(2S)-2-amino-5-[N'-(nitromethyl)carbamimidamido]pentanoic acid
-
-
(2S)-2-amino-5-[N'-(pent-4-en-1-yl)carbamimidamido]pentanoic acid
-
-
2,3-dimethoxy-1,4-naphthoquinone
-
1 mM
2-(N,N-diethylamino)-diazenolate-2-oxide
-
1 mM
2-(N,N-dimethylamino)-diazenolate-2-oxide
-
S-nitrosylation of apo-enzyme, holo-enzyme resists, reaction with two of five Cys-residues
2-(N,N-dimethylamino)-diazenolate-2-oxide
-
i.e. DEANONOate, inhibition by S-nitrosylation, reversed by dithiothreitol
2-(N,N-dimethylamino)diazenolate-2-oxide
O94760, O95865
1 mM, 50% inhibition of DDAH-1
2-(N,N-dimethylamino)diazenolate-2-oxide
Q99LD8, Q9CWS0
1 mM, 50% inhibition of DDAH-1; 1 mM, 50% inhibition of DDAH-1
2-(N,N-dimethylamino)diazenolate-2-oxide
O08557
1 mM, 50% inhibition of DDAH-1
2-amino-4-(NG-methyl-guanidino)butanoic acid
-
incubation of lysed red blood cells, dose dependent inhibition of NG,NG-dimethyl-L-arginine degradation with the highest dose (1 mM) reversing the pattern to a net increase in NG,NG-dimethyl-L-arginine concentration for the 1- and 3h time points
2-amino-4-(NG-methyl-guanidino)butanoic acid
-
a series of analogues designed, reversible DDAH inhibitors
2-chloroacetamidine
-
irreversible inhibition in a time- and concentration-dependent manner
2-hydroxymethyl-4-chloropyridine
-
solution studies support an inactivation mechanismin in which the active site Asp66 residue stabilizes the pyridinium form of the inactivator, which has enhanced reactivity toward the active site Cys, resulting in covalent bond formation, loss of the halide, and irreversible inactivation
-
4-hydroxy-2-nonenal
O94760, O95865
50 microM, 50% relative activity
4-hydroxy-nonenal
-
dose-dependently inhibits DDAH activity with 15% inhibition at 0.01 mM and complete inhibition at 0.5 mM
angiotensin II
O94760, O95865
1 microM, about 55% relative activity; 1 microM, about 55% relative activity
aprotinin inhibitor
-
NG,NG-dimethyl-L-arginine release from freeze-thaw whole blood 34% inhibited
-
CoCl2
-
-
cytokine induced nitric-oxide synthesis
O94760, O95865
-
-
D-Arginine
-
0.1 mM D-arginine reduces DDAH activity to 24.7%
darbepoetin alpha
-
inhibits DDAH in a dose dependent manner, inhibition of DDAH is abolished by incubation with EPO antibody or with antioxidant pyrrolidine dithiocarbamate
-
epoetin beta
-
inhibits DDAH in a dose dependent manner, inhibition of DDAH is abolished by incubation with EPO antibody or with antioxidant pyrrolidine dithiocarbamate
-
erythropoetin
O94760, O95865
200 units/ml, about 75% relative activity; 200 units/ml, about 75% relative activity
-
glucose
O94760, O95865
;
glucose
Q99LD8, Q9CWS0
25.5 mmol/l; 25.5 mmol/l
glucose
O08557
25.5 mmol/l; 25.5 mmol/l
glycosylated bovine serum albumin
O08557
;
-
H2O2
-
43% inhibition at 1 mM
homocysteine
O94760, O95865
;
homocysteine
-
inhibition of the expression of DDAH-2 reduces the NO production induced by IL-1beta
hydrogen peroxide
O94760, O95865
100 microM, 50% relative activity
hyperglycemia
-
-
-
iodoacetamide
-
pH dependent DDAH inactivation, addition of 2.5 mM NG-methyl-L-arginine at pH 8.5 can prevent inactivation by idoacetamide, inactivation may be due to modification at the active site of DDAH, inactivation increases at higher pH values
L-arginine
-
0.1 mM L-arginine competitively inhibits DDAH enzyme activity to 5.6%
L-arginine
O94760
-
L-citrulline
-
competitive
L-citrulline
-
-
L-citrulline
O94760
-
L-homocysteine
-
-
L-homocysteine
-
-
L-lysine
-
competitive inhibitor; potential competitive inhibitor
Leupeptin
-
NG,NG-dimethyl-L-arginine release from freeze-thaw whole blood 55% inhibited
lipopolysaccharide
O94760, O95865
1 microg/ml, 24 h, about 55% relative activity; 1 microg/ml, about 55% relative activity
low-density-lipoprotein
O94760, O95865
; 100 microg/ml
-
lysophosphatidylcholine
-
-
lysophosphatidylcholine
-
activity is significantly decreased in cells treated with lysophosphatidylcholine (0.005 mg/ml) for 48 h, 0.001-0.005 mM probucol or 0.001 mM pyrrolidindithiocarbamate significantly attenuate inhibition of DDAH activity by lysophosphatidylcholine
lysophosphatidylcholine
O94760, O95865
; 10 microg/ml, about 35% relative activity
Mercuric chloride
O08557
;
methylamine
-
10 mM, 80% of activity
N(G)-nitro-L-arginine methyl ester
-
reduced DDAH-2 mRNA level
N-(2-methoxyethyl)-L-arginine
O08557
complete inhibition at 100 microM; complete inhibition at 100 microM
N-(2-methoxyethyl)arginine
Q99LD8, Q9CWS0
;
N-(2-methoxyethyl)arginine methyl esther
Q99LD8, Q9CWS0
;
N-(but-3-yn-1-yl)-2-chloroethanimidamide
-
click chemistry mediated in vivo activity probe that labels the active fraction of DDAH-1 in intact mammalian cells and that can be blocked by the presence of competitive reversible and irreversible inhibitors
N-nitro-L-arginine methylester
Q3SX44
1mM, 1 h, 47.1% relative activity; 1 mM, 1 h, 47.1% relative activity
N-nitro-L-arginine methylester
O94760, O95865
; 1mM, 1 h, 47.1% relative activity
N-nitro-L-arginine methylester
Q99LD8, Q9CWS0
;
N-nitro-L-arginine methylester
-
1 mM, 1 h, 47.1% relative activity
N-nitro-L-arginine methylester
O08557
;
N5-(1-iminoethyl)-L-ornithine
O94760
-
N5-(1-iminohexyl)-L-ornithine
O94760
-
N5-(1-iminopentyl)-L-ornithine
O94760
-
N5-(1-iminopropyl)-L-ornithine
O94760
crystallization data. Reversible competitive inhibition, consistent with a reversible covalent mode of DDAH inhibition by alkylamidine inhibitors
N5-(but-3-en-1-ylcarbamimidoyl)-L-ornithine
-
1 mM, 71% inhibition
N5-(nitrocarbamimidoyl)-L-ornithine
-
1 mM, 6% inhibition
N5-(prop-2-en-1-ylcarbamimidoyl)-L-ornithine
-
1 mM, 70% inhibition
N5-(prop-2-yn-1-ylcarbamimidoyl)-L-ornithine
-
1 mM, 83% inhibition
N5-(propylcarbamimidoyl)-L-ornithine
-
1 mM, 60% inhibition
N5-but-3-enimidoyl-L-ornithine
-
1 mM, 97% inhibition
N5-butanimidoyl-L-ornithine
-
1 mM, 78% inhibition
N5-ethanimidoyl-L-ornithine
-
1 mM, 24% inhibition
N5-propanimidoyl-L-ornithine
-
1 mM, 65% inhibition
N5-[(2,2,2-trifluoroethyl)carbamimidoyl]-L-ornithine
-
1 mM, 41% inhibition
N5-[(2-methoxyethyl)carbamimidoyl]-L-ornithine
-
1 mM, 89% inhibition
N5-[(3-amino-3-oxopropyl)carbamimidoyl]-L-ornithine
-
1 mM, 43% inhibition
N5-[(3E)-pent-3-enimidoyl]-L-ornithine
-
1 mM, 73% inhibition
N5-[imino(morpholin-4-yl)methyl]-L-ornithine
-
1 mM, 23% inhibition
Nicotine
O94760, O95865
50% decrease in DDAH-2 mRNA
nitric oxide
Q6MG60
-
nitric oxide
O94760, O95865
increased NO production nitrosates DDAH
nitrite
-
1 mM
nitroglycerine
O94760, O95865
10 microM, 16 h, about 55% relative activity; 10 microM, about 55% relative activity
OH radical
-
47% inhibition at 1 mM
oxidized-low density lipoprotein
-
-
-
oxidized-low density lipoprotein
-
activity is significantly decreased in cells treated with oxidized-low density lipoprotein (0.1 mg/ml) for 48 h, 0.001-0.005 mM probucol or 0.001 mM pyrrolidindithiocarbamat significantly attenuate inhibition of DDAH activity by oxidized-low density lipoprotein
-
pentafluorophenyl sulfonates
-
between 30-76% DDAH inhibition depending on molecular structure of the pentafluoropenyl sulfonate
-
peroxynitrite
-
inhibition of 15% after exposure to peroxynitrite at concentrations ranging from 0.01-0.1 mM, 25% inhibition at 1 mM
peroxynitrite
O94760, O95865
-
PMSF
-
NG,NG-dimethyl-L-arginine release from freeze-thaw whole blood 57% inhibited
protease inhibitor
-
NG,NG-dimethyl-L-arginine release from freeze-thaw whole blood 25-85% inhibited
-
S-2-amino-4(3-methylguanidino)butanoic acid
-
-
S-2-amino-4-[N-(2-methoxyethyl)guanidino]butanoic acid benzyl ester
O08557
;
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
-
-
S-nitroso-L-homocysteine
-
96% inhibition of the zinc-free enzyme at 0.5 mM, leads to the unique formation of an N-thiosulfoximide
S-nitroso-L-homocysteine
-
-
sulfurosalicylic acid
-
inactivates DDAH
TNF-alpha
O94760, O95865
; 250 U/ml, 63% relative activity
-
Zinc acetate
-
-
Zn2+
-
besides the tightly bound zinc, additional Zn2+ inhibit competitively
Zn2+
-
endogenous inhibitor, regulatory role
Zn2+
-
one mol per mol of enzyme, apo-enzyme is active, holoenzyme is activated by removal of Zn2+
Zn2+
-
incubation of lysed red blood cells, diminished hydrolyis of NG,NG-dimethyl-L-arginine by addition of physiologically relevant concentrations (0.02 mM)
Zn2+
-
-
Zn2+
-
-
Zn2+
Q3SX44
20 microM, 40% relative activity; 20 microM, 40% relative activity
monocrotaline
-
DDAH activity and DDAH1, but not DDAH2, protein expression are significantly reduced after 60mg/kg monocrotaline treatment
additional information
-
not inhibited by 2-chloroacetamide
-
additional information
-
incubation of lysed red blood cells with EDTA or glucose failed to attenuate the degradation of NG,NG-dimethyl-L-arginine, incubation of whole blood cells with arginine methyltransferase inhibitors does not reduce NG,NG-dimethyl-L-arginine release
-
additional information
-
probucol or pyrrolidindithiocarbamate itself have no effect on the activity of DDAH
-
additional information
-
5 mM of L-cysteine, L-homocysteine, glutathione, dithiothreitol, or Tris(2-carboxyethyl)phosphine-HCl for 30 min at 37C cannot restore inhibited activity, suggesting that the covalent product N-thiosulfoximide will remain stable under the reducing conditions present in the cytosol
-
additional information
-
exposure to pathophysiological levels of reactive oxygen has little to no effect on the activity of the enzyme
-
additional information
-
insensitive to hydrogen peroxide
-
additional information
-
tissue-specific decrease of levels of Ddah1 and Ddah2 RNA after feeding a high-methionine/low-folate diet for 5 to 11 month
-
additional information
-
decrease of DDAH-2 mRNA level induced by 10% serum, ionomycin or endothelial growth factors
-
additional information
O94760
S-ethyl-2-thiopseudourea, S-ethyl-N-phenylisothiourea and phenylene-1,3-bis(ethane-2-isothiourea) do not inhibit DDAH-1 at concentrations below 1 mM
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
adiponectin
O94760, O95865
;
-
all-trans retinoic acid
-
inhibits cobalt chloride induced inhibition of DDAH
all-trans-retinoic acid
Q99LD8, Q9CWS0
1.9fold increase in DDAH-2 mRNA and protein expression; 1.9fold increase in DDAH-2 mRNA and protein expression
Aminoguanidine
O08557
;
aspirin
O08557
;
D-histidine
-
activating ability in decreasing order: histamine, imidazole, L-histidine, D-histidine
EDTA
O08557
;
epigallocatechin gallate
O94760, O95865
;
fenofibrate
O94760, O95865
;
histamine
-
activating ability in decreasing order: histamine, imidazole, L-histidine, D-histidine
imidazole
-
activating ability in decreasing order: histamine, imidazole, L-histidine, D-histidine
Insulin
O94760, O95865
;
-
Interleukin-1beta
O08557
2fold increase in DDAH-1 protein expression
-
L-histidine
-
activating ability in decreasing order: histamine, imidazole, L-histidine, D-histidine
nebivolol
O94760, O95865
2fold increase in DDAH-2 mRNA and protein expression
-
oestradiol
O94760, O95865
60-70% increase in DDAH-2 mRNA and protein expression
pioglitazone
O08557
2-3fold increase of DDAH-2 mRNA and protein levels
pravastatin
O08557
;
probucol
O94760, O95865
;
-
SNAP
-
increase of DDAH-2 mRNA and protein level, time and concentration dependent
-
taurin
Q3SX44
;
taurin
O94760, O95865
;
taurin
O08557
;
taurine
Q99LD8, Q9CWS0
;
telmisartan
Q3SX44
;
telmisartan
O94760, O95865
;
telmisartan
Q99LD8, Q9CWS0
;
telmisartan
-
-
telmisartan
O08557
;
visfatin
-
mRNA and protein expression of DDAH2 upregulated after 24 h stimulation of visfatin
-
vitamin E
Q3SX44
;
vitamin E
O94760, O95865
;
vitamin E
Q99LD8, Q9CWS0
;
vitamin E
O08557
;
xanthone
Q3SX44
;
-
xanthone
O94760, O95865
;
-
xanthone
Q99LD8, Q9CWS0
;
-
xanthone
-
-
-
xanthone
O08557
;
-
losartan
O94760, O95865
;
additional information
-
type of buffer dramatically influences enzyme activity, activity in imidazole/HCl buffer is about 25% higher than in phosphate buffer
-
additional information
-
probucol and the intracellular antioxidant pyrrolidine dithiocarbamate significantly attenuate inhibition of endothelial DDAH activity by oxidized-low density lipoprotein or lysophosphatidylcholine, but probucol or PDTC itself had no effect on the activity of DDAH
-
additional information
-
mRNA expression levels of DDAH-I are not changed in pioglitazone-treated rats
-
additional information
-
increase of DDAH-2 mRNA and protein level induced by SNAP, NOR, 8-bromo-cGMP or CNP
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.18
dimethyl-L-arginine
Q3SX44
;
0.18
dimethyl-L-arginine
O94760, O95865
;
0.18
dimethyl-L-arginine
Q99LD8, Q9CWS0
;
0.18
dimethyl-L-arginine
-
-
0.18
dimethyl-L-arginine
O08557
;
0.133
N,N-dimethyl-L-arginine
-
pH 7.4, 37C
-
0.13
N5-(methoxycarbamimidoyl)-L-ornithine
-
37C, 30 min, pH 7.4
0.106
N5-(methylcarbamimidoyl)-L-ornithine
-
37C, 30 min, pH 7.4
0.161
N5-[2,5-dihydro-1H-pyrrol-1-yl(imino)methyl]-L-ornithine
-
37C, 30 min, pH 7.4
0.039
NG,NG-dimethyl-L-arginine
-
at pH 8.0
0.18
NG,NG-dimethyl-L-arginine
-
-
0.31
NG,NG-dimethyl-L-arginine
-
-
0.687
NG,NG-dimethyl-L-arginine
-
at 37C
1.31
NG,NG-dimethyl-L-arginine
-
-
9.24
NG,NG-dimethyl-L-arginine
-
-
33
NG,NG-Dimethyl-L-homoarginine
-
-
1.11
NG-Amino-L-arginine
-
-
2.3
NG-Hydroxy-L-arginine
-
-
0.044
NG-methyl-L-arginine
-
at pH 8.0
0.536
NG-methyl-L-arginine
-
at 37C
0.67
NG-methyl-L-arginine
-
-
0.36
NG-monomethyl-L-arginine
-
-
0.51
NG-monomethyl-L-arginine
O95865
DDAH I
1.6
NG-monomethyl-L-arginine
-
-
0.11
Nomega,Nomega-dimethyl-L-arginine
O94760
wild-type, pH 7.3, temperature not specified in the publication
0.75
Nomega,Nomega-dimethyl-L-arginine
O94760
mutant L271G, pH 7.3, temperature not specified in the publication
1.4
Nomega,Nomega-dimethyl-L-arginine
O94760
mutant L30A, pH 7.3, temperature not specified in the publication
13.7
Nomega,Nomega-dimethyl-L-arginine
O94760
mutant E78A, pH 7.3, temperature not specified in the publication
0.0014
S-methyl-L-thiocitrulline
O94760
mutant L271G, pH 7.3, temperature not specified in the publication
0.0031
S-methyl-L-thiocitrulline
O94760
wild-type, pH 7.3, temperature not specified in the publication
0.0036
S-methyl-L-thiocitrulline
O94760
mutant L30A, pH 7.3, temperature not specified in the publication
0.019
S-methyl-L-thiocitrulline
O94760
mutant E78AA, pH 7.3, temperature not specified in the publication
0.026
S-methyl-L-thiocitrulline
-
at pH 8.0
0.143
S-methyl-L-thiocitrulline
-
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.27
NG,NG-dimethyl-L-arginine
-
-
0.56
NG,NG-dimethyl-L-arginine
-
-
1.27
NG,NG-dimethyl-L-arginine
-
at pH 8.0
0.009
NG,NG-Dimethyl-L-homoarginine
-
-
0.12
NG-Amino-L-arginine
-
-
0.33
NG-Hydroxy-L-arginine
-
-
0.31
NG-methyl-L-arginine
-
-
0.59
NG-methyl-L-arginine
-
at pH 8.0
0.094
NG-monomethyl-L-arginine
-
-
0.34
NG-monomethyl-L-arginine
-
-
0.0015
Nomega,Nomega-dimethyl-L-arginine
O94760
mutant E78A, pH 7.3, temperature not specified in the publication
0.0087
Nomega,Nomega-dimethyl-L-arginine
O94760
mutant L271G, pH 7.3, temperature not specified in the publication
0.014
Nomega,Nomega-dimethyl-L-arginine
O94760
wild-type, pH 7.3, temperature not specified in the publication
0.0163
Nomega,Nomega-dimethyl-L-arginine
O94760
mutant L30A, pH 7.3, temperature not specified in the publication
0.0097
S-methyl-L-thiocitrulline
O94760
mutant L271G, pH 7.3, temperature not specified in the publication
0.03
S-methyl-L-thiocitrulline
O94760
mutant E78AA, pH 7.3, temperature not specified in the publication
0.042
S-methyl-L-thiocitrulline
O94760
mutant L30A, pH 7.3, temperature not specified in the publication; wild-type, pH 7.3, temperature not specified in the publication
0.84
S-methyl-L-thiocitrulline
-
-
1.3
S-methyl-L-thiocitrulline
-
at pH 8.0
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00012
Nomega,Nomega-dimethyl-L-arginine
O94760
mutant E78A, pH 7.3, temperature not specified in the publication
7914
0.0115
Nomega,Nomega-dimethyl-L-arginine
O94760
mutant L271G, pH 7.3, temperature not specified in the publication
7914
0.0116
Nomega,Nomega-dimethyl-L-arginine
O94760
mutant L30A, pH 7.3, temperature not specified in the publication
7914
0.127
Nomega,Nomega-dimethyl-L-arginine
O94760
wild-type, pH 7.3, temperature not specified in the publication
7914
1.58
S-methyl-L-thiocitrulline
O94760
mutant E78AA, pH 7.3, temperature not specified in the publication
4690
6.83
S-methyl-L-thiocitrulline
O94760
mutant L271G, pH 7.3, temperature not specified in the publication
4690
11.7
S-methyl-L-thiocitrulline
O94760
mutant L30A, pH 7.3, temperature not specified in the publication
4690
13.55
S-methyl-L-thiocitrulline
O94760
wild-type, pH 7.3, temperature not specified in the publication
4690
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1.155
(2S)-2-amino-5-(ethanimidoylamino)pentanoic acid
-
pH 7.4, 37C
0.09
(2S)-2-amino-5-(N'-butylcarbamimidamido)pentanoic acid
-
pH 7.4, 37C
0.002
(2S)-2-amino-5-(pent-4-enimidoylamino)pentanoic acid
-
pH 7.4, 37C
0.032
(2S)-2-amino-5-(pentanimidoylamino)pentanoic acid
-
pH 7.4, 37C
0.145
(2S)-2-amino-5-(propanimidoylamino)pentanoic acid
-
pH 7.4, 37C
0.036
(2S)-2-amino-5-[(4E)-hex-4-enimidoylamino]pentanoic acid
-
pH 7.4, 37C
0.606
(2S)-2-amino-5-[N'-(3,3,3-trifluoropropyl)carbamimidamido]pentanoic acid
-
pH 7.4, 37C
0.013
(2S)-2-amino-5-[N'-(3-methoxypropyl)carbamimidamido]pentanoic acid
-
pH 7.4, 37C, inhibitor is selective over NOS and over arginase
0.764
(2S)-2-amino-5-[N'-(4-amino-4-oxobutyl)carbamimidamido]pentanoic acid
-
pH 7.4, 37C
0.058
(2S)-2-amino-5-[N'-(but-3-en-1-yl)carbamimidamido]pentanoic acid
-
pH 7.4, 37C
0.017
(2S)-2-amino-5-[N'-(but-3-yn-1-yl)carbamimidamido]pentanoic acid
-
pH 7.4, 37C
1.968
(2S)-2-amino-5-[N'-(nitromethyl)carbamimidamido]pentanoic acid
-
pH 7.4, 37C
0.057
(2S)-2-amino-5-[N'-(pent-4-en-1-yl)carbamimidamido]pentanoic acid
-
pH 7.4, 37C
3.1
2-chloroacetamidine
-
-
0.4
L-lysine
-
at pH 7.3
4
L-lysine
-
at pH 7.3
0.057
N5-(but-3-en-1-ylcarbamimidoyl)-L-ornithine
-
-
0.058
N5-(prop-2-en-1-ylcarbamimidoyl)-L-ornithine
-
-
0.017
N5-(prop-2-yn-1-ylcarbamimidoyl)-L-ornithine
-
-
0.09
N5-(propylcarbamimidoyl)-L-ornithine
-
-
0.002
N5-but-3-enimidoyl-L-ornithine
-
-
0.032
N5-butanimidoyl-L-ornithine
-
-
0.145
N5-propanimidoyl-L-ornithine
-
-
0.013
N5-[(2-methoxyethyl)carbamimidoyl]-L-ornithine
-
-
0.036
N5-[(3E)-pent-3-enimidoyl]-L-ornithine
-
-
0.69
S-nitroso-L-homocysteine
-
in the presence of 5 mM EDTA, at pH 7.3 and 37C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.05
4-hydroxy-nonenal
-
at 37C
0.131
L-arginine
O94760
pH 7.3, temperature not specified in the publication
3.7
L-citrulline
O94760
pH 7.3, temperature not specified in the publication
0.35
N-(but-3-yn-1-yl)-2-chloroethanimidamide
-
pH not specified in the publication, temperature not specified in the publication
0.99
N5-(1-iminoethyl)-L-ornithine
O94760
pH 7.3, temperature not specified in the publication
0.11
N5-(1-iminohexyl)-L-ornithine
O94760
pH 7.3, temperature not specified in the publication
0.0075
N5-(1-iminopentyl)-L-ornithine
O94760
pH 7.3, temperature not specified in the publication
0.052
N5-(1-iminopropyl)-L-ornithine
O94760
pH 7.3, temperature not specified in the publication
0.189
N5-(but-3-en-1-ylcarbamimidoyl)-L-ornithine
-
-
0.207
N5-(prop-2-en-1-ylcarbamimidoyl)-L-ornithine
-
-
0.055
N5-(prop-2-yn-1-ylcarbamimidoyl)-L-ornithine
-
-
0.283
N5-(propylcarbamimidoyl)-L-ornithine
-
-
0.013
N5-but-3-enimidoyl-L-ornithine
-
-
0.07
N5-butanimidoyl-L-ornithine
-
-
0.3
N5-propanimidoyl-L-ornithine
-
-
0.029
N5-[(2-methoxyethyl)carbamimidoyl]-L-ornithine
-
-
0.079
N5-[(3E)-pent-3-enimidoyl]-L-ornithine
-
-
0.075
S-nitroso-L-homocysteine
-
in 50 mM HEPES/NaOH (pH 7.3), 150 mM KCl, and 5 mM EDTA for 30 min at 37C
0.0088
Zinc acetate
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.55
-
37C
0.9
-
mice fed the high-methionine/low folate diet, heterozygous cystathionine beta-synthase
1.1
-
mice fed the high-methionine/low folate diet, homozygous cystathionine beta-synthase
1.6
-
mice fed the control diet
additional information
-
-
additional information
-
different values in different tissues: value between 10 and 12 micromol/min/mg in myocardium, value between 1.9 and 2.3 micromol/min/mg in skeletal muscle, value between 25 and 40 micromol/min/mg in kidney, value between 4.5 and 9.5 in liver
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6.2
-
hydrolysis of NG,NG-dimethyl-L-arginine
6.2
-
phosphate buffer
6.5
-
hydrolysis of NG,NG-dimethyl-L-arginine
6.5
-
assay at
6.7
-
hydrolysis of NG-monomethyl-L-arginine
6.8
-
imidazole/HCl buffer
6.9
-
assay at
7.4
-
assay at
additional information
-
type of buffer dramatically influences enzymatic activity
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.5 - 9.5
-
-
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
-
assay at
37
-
assay at
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
DDAH-2 is strongly expressed in blood vessels
Manually annotated by BRENDA team
-
DDAHII immunoreactivity is localized to infiltrating inflammatory cells and blood vessels in the healing infarct
Manually annotated by BRENDA team
O95865
DDAH I is highly expressed
Manually annotated by BRENDA team
-
entire ventricular zone and tegmentum, ciliarly ganglion, inferior olive, interpeduncular nucleus, red nucleus, dorsal tegmental nucleus and nuclues of the lateral lemniscus
Manually annotated by BRENDA team
-
both DDAHI and DDAHII proteins are detected in peri-infarct cardiomyocytes, while DDAHII immunoreactivity is additionally localized to infiltrating inflammatory cells and blood vessels in the healing infarct. Both plasma and left ventricular concentrations of the DDAH substrate, ADMA, are increased post-myocardial infarction
Manually annotated by BRENDA team
-
DDAH-2 protein expression is higher in osteoarthritic cartilage than in normal cartilage
Manually annotated by BRENDA team
-
7th cranial nerve
Manually annotated by BRENDA team
-
in healthy hearts, DDAHI is absent, and DDAHII is localized to endothelium and endocardium with a similar distribution to that of eNOS
Manually annotated by BRENDA team
-
human microvascular and ubilical vein endothelial cells
Manually annotated by BRENDA team
-
aortic endothelial cell
Manually annotated by BRENDA team
-
coronary microvessels, arteries and veins, strong staining
Manually annotated by BRENDA team
-
in healthy hearts, DDAHI is absent, and DDAHII is localized to endothelium and endocardium with a similar distribution to that of eNOS
Manually annotated by BRENDA team
-
mainly in the smooth muscle and in the mucosa
Manually annotated by BRENDA team
O94760, O95865
-
Manually annotated by BRENDA team
O95865
DDAH II is highly expressed
Manually annotated by BRENDA team
-
DDAH1 RNA is expressed in the left ventricle, cardiac outflow tract and developing vasculature. DDAH2 expression is seen in the developing left ventricle and cardiac outflow tract, and additionally in the peripheral nervous system
Manually annotated by BRENDA team
-
in healthy hearts, DDAHI is absent, and DDAHII is localized to endothelium and endocardium with a similar distribution to that of eNOS
Manually annotated by BRENDA team
-
DDAHII immunoreactivity is localized to infiltrating inflammatory cells and blood vessels in the healing infarct
Manually annotated by BRENDA team
-
in the serosa of and in the boundary between the smooth muscle and submucosa
Manually annotated by BRENDA team
-
highest activity
Manually annotated by BRENDA team
O95865
DDAH I and DDAH II are highly expressed
Manually annotated by BRENDA team
-
in the tubules
Manually annotated by BRENDA team
-
normal human chondrocytes are isolated from knee cartilage obtained
Manually annotated by BRENDA team
-
both DDAH1 and 2 are expressed in the developing limb buds in patterns overlapping areas with high nitric oxide synthase activity
Manually annotated by BRENDA team
O95865
DDAH I is highly expressed, low level expression of DDAH II
Manually annotated by BRENDA team
-
expression of mRNA for DDAH-1 is 7fold higher in the liver compared to DDAH-2
Manually annotated by BRENDA team
O95865
low level expression of DDAH II
Manually annotated by BRENDA team
-
lowest activity in skeletal muscle
Manually annotated by BRENDA team
O95865
DDAH I is highly expressed, low level expression of DDAH II
Manually annotated by BRENDA team
-
undifferentiated pheochromocytoma
Manually annotated by BRENDA team
Q99LD8, Q9CWS0
-
Manually annotated by BRENDA team
O95865
DDAH II is highly expressed
Manually annotated by BRENDA team
-
expression of mRNA for DDAH-1 is 2fold higher in the renal cortex compared to DDAH-2
Manually annotated by BRENDA team
-
in the nuclear layer and pigment layer
Manually annotated by BRENDA team
-
endothelial cells
Manually annotated by BRENDA team
O95865
DDAH I and II is expressed at a low level
Manually annotated by BRENDA team
-
DDAH-1 mRNA expression is especially strong in the ventral horn and dorsal root ganglion, and also localized in cervical, thoracic and lumbar spinal cord and sympathetic ganglion
Manually annotated by BRENDA team
-
in the gray matter, especially in the ventral portion and sympathetic ganglion
Manually annotated by BRENDA team
-
in the serosa, mucosa and smooth muscle
Manually annotated by BRENDA team
-
overexpression in the immortalized cell line
Manually annotated by BRENDA team
additional information
O95865
DDAH I predominates in tissues that express neuronal nitric oxide synthase, DDAH II predominates in tissues expressing endothelial nitric oxide synthase
Manually annotated by BRENDA team
additional information
-
digestive tract
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
no specific association with organelles or with plasma membrane
Manually annotated by BRENDA team
-
conventional immunofluorescence and confocal microscopy reveal the presence of DDAH-2 in the mitochondria of IL-1beta-stimulated chondrocytes. Blocking the translocation to mitochondria reduces the NO production induced by IL-1beta
Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
29000
-
monomer, hydrodynamic measurement
652942
30420
-
mass spectrometry, mutant H162G
667726
30500
-
calculated from the protein sequence of wild-type DDAH, after removal of the N-terminal methionine residue; deconvoluted mass spectrum of a control reaction mixture that included wild-type DDAH but no inactivator
664074
30500
-
by ESI-MS; by sequence analysis
667675
30500
-
electrospray ionization mass spectrometry; mass spectrometry, wilde type DDAH
667726
30560
-
fully inactivated wild-type DDAH by 2-chloroacetamidine
664074
31200
-
electrospray ionization mass spectrometry
677028
32000
-
gel filtration
288971
33440
-
electrospray ionization mass spectrometry
687644
34000
-
DDAH1, SDS-PAGE
684357
37000
-
DDAH-1, SDS-PAGE
685205
58000
-
dimer, hydrodynamic measurement
652942
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
-
x * 40000, SDS-PAGE, His-tagged protein
?
-
x * 40000, SDS-PAGE, Myc-tagged protein
dimer
-
2 * 29000, dynamic equilibrium between monomer and homodimer, hydrodynamic measurements
homodimer
-
PaDDAH exists in dynamic equilibrium between symmetric homodimer and monomer states
monomer
-
1 * 34000, SDS-PAGE
monomer
-
1 * 29000, dynamic equilibrium between monomer and homodimer, hydrodynamic measurements, PaDDAH exists in dynamic equilibrium between monomer and symmetric homodimer states
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
-
N5-(1-iminopropyl)-L-ornithine:DDAH-1 complex, to 1.9 A resolution, covalent bond formation between the inhibitors amidino carbon and the active-site Cys274, and solution studies show reversible competitive inhibition, consistent with a reversible covalent mode of DDAH inhibition by alkylamidine inhibitors
O94760
A 2.18 A resolution X-ray crystal structure of the inactivated complex elucidates the orientation of the inactivator and its covalent attachment to the active site Cys
-
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5 - 8.5
-
stable between
288971
10
-
activity decreases at pH values above 10
687644
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
45
-
stable
288971
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
288969
additional information
-
-
288971
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
Zn2+ has a structure-stabilizing role
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-30C, 0.1 M sodium phosphate buffer, pH 7.0, 10% glycerol, 1 mM 2-mercaptoethanol
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
anion exchange chromatography and gel filtration chromatography
-
HisTrap column chromatography and HiTrap Q Sepharose column chromatography
-
Ni-NTA affinity resin chromatography and phenyl-Sepharose column chromatography
-
recombinant enzyme, partial
-
using Ni-NTA-agarose
-
by immobilized nickel-affinity chromatography and gel filtration
-
recombinant enzyme, partial
-
to more than 95% homogeneity
-
wild type to more than 98% homogeneity, by Ni-NTA affinity chromatography, mutant required additional purification step, ion-exchange chromatography followed by affinity chromatography, mutant purified to more than 95% homogeneity
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21 (DE3) cells
-
expressed in Escherichia coli BL21star cells
-
expression in Escherichia coli BL21
-
expression in sEnd.1 cells
-
human DDAH-1 is expressed in Escherichia coli BL21
-
isoform DDAH-1 bearing an N-terminal Myc-tag, expression in HEK 293T cells
-
cloned into a pET-28a expression vector, N-terminal His6-tagged protein overexpressed in Escherichia coli BL21 (DE3)
-
expression in Escherichia coli
-
expression in Escherichia coli BL21 (DE3)
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
DDAH-2 protein expression is higher in osteoarthritic cartilage than in normal cartilage
-
in chondrocyte mitochondria extracts, DDAH-2 expression is significantly increased after exposure to IL-1beta
-
DDAH isoforms are expressed in a dynamic,overlapping pattern during embryonic development
-
alpha-lipoic acid increases the gene expression and activity of DDAH, and signal transducer and activator of transcription STAT3 phosphorylation. Transfection of STAT3 increases DDAH II promoter activity, and alpha-lipoic acid amplifies it. alpha-Lipoic acid-induced increase in DDAH II promoter activity is attenuated in the promoter that has a mutation in the putative STAT3-binding site
-
treatment of mice with farnesoid X receptor agonist 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole, i.e. GW4064, leads to increased expression of DDAH-1 and cationic amino acid transporter CAT-1 in both liver and kidney
-
following myocardial infarction, left ventricular DDAH activity is increased to 210% of control
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C274A
-
no detectable activity
C274A
-
inactive and is not labeled by inhbitor N-(but-3-yn-1-yl)-2-chloroethanimidamide
C275A
-
retains a kcat value about half of wild type protein
H173A
-
no detectable activity
C249S
-
catalytically inactive
C249S
-
C249 is predominant target for S-nitrosylation
C249S
-
active-site Cys249 residue
C249S
-
Cys249 as the catalytic nucleophile required for intermediate formation
C249S
-
the C249S mutant and D66N mutant are both incapable of forming a covalent adduct when incubated with 2-hydroxymethyl-4-chloropyridine
D244N
-
wild type and D244N DDAH variants both form covalent adducts upon incubation with 2-hydroxymethyl-4-chloropyridine, showing mass additions that are consistent with covalent attachment of one equivalent of hydroxymethylpyridine to each enzyme. These results also indicate that Asp244 is not essential for covalent modification to occur
D66N
-
the C249S mutant and D66N mutant are both incapable of forming a covalent adduct when incubated with 2-hydroxymethyl-4-chloropyridine
E33H
-
weakening of the homodimer interaction observed for wild type protein, expressed in Escherichia coli at levels similar to the wild type
E33Q
-
weakening of the homodimer interaction observed for wild type protein, expressed in Escherichia coli at levels similar to the wild type
H162G
-
catalytically inactive
H162G
-
active-site His162 residue
H162G
-
mutation of the active-site histidine residue
N36D
-
expressed in Escherichia coli at levels similar to the wild type
N36H
-
weakening of the homodimer interaction observed for wild type protein, expressed in Escherichia coli at levels similar to the wild type
N36W
-
more stable homodimer than the wild type protein, expressed in Escherichia coli at levels similar to the wild type
Q43H
-
weakening of the homodimer interaction observed for wild type protein, expressed in Escherichia coli at levels similar to the wild type
Q43R
-
weakening of the homodimer interaction observed for wild type protein, expressed in Escherichia coli at levels similar to the wild type
R40E
-
weakening of the homodimer interaction observed for wild type protein, expressed in Escherichia coli at levels similar to the wild type
R40E-R98H
-
exclusively monomeric, expressed in Escherichia coli at levels similar to the wild type
R40E/R98H
-
about 95% of wild type activity, stable monomer
R40W
-
not expressed in Escherichia coli at levels similar to the wild type
R98H
-
weakening of the homodimer interaction observed for wild type protein, expressed in Escherichia coli at levels similar to the wild type
R98N
-
not expressed in Escherichia coli at levels similar to the wild type
S248N
-
mutant is still capable of substrate turnover and is still inactivated by 2-hydroxymethyl-4-chloropyridine with a second order inactivation rate constant that is approximately 2fold less than wild type DDAH
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
method for reversible preparation of metal-free and metal-containing enzyme
-
inhibition by 2-(N,N-dimethylamino)-diazenolate-2-oxide is reversed by dithiothreitol
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
expression and secretion of the vascular endothelial growth factor is not increased in DDAH1-transfected cells
medicine
-
structure-based development of specific DDAH-1 inhibitors that might be useful in the therapeutic treatment of NOS dysfunction-related diseases
medicine
-
influence on atherosclerosis in experimental models by increased ADMA concentrations and reduced NO synthesis
analysis
-
use of inhibitor N-(but-3-yn-1-yl)-2-chloroethanimidamide as a broad-specificity probe for labeling endogenous DDAH isoforms and enzymes with similar pharmacophores. Inhibitor labels the active fraction of DDAH-1 in intact mammalian cells and can be blocked by the presence of competitive reversible and irreversible inhibitors. Incorporation of the alkyne tag allows to derivatize with a variety of reagents after in vivo tagging
medicine
-
decreased DDAH-1 expression may cause accumulation of endogenous inhibitors of enothelial NO synthase, thereby contributing to endothelial dysfunction in the failing heart
medicine
-
epoetin beta and darbepoetin alpha posttranslationally impair DDAH activity via increased oxidative stress, causing NG,NG-dimethyl-L-arginine as an important cardiovascular risk factor to accumulate and inhibit NO-synthesis
medicine
-
expression and secretion of the vascular endothelial growth factor is not increased in DDAH1-transfected cells
medicine
-
protective effect of probucol on endothelium related to enhancement of DDAH activity
medicine
-
placental dysfunction of dimethylarginine dimethylaminohydrolase has been suggested as one of the initiating events in the development of preeclampsia
medicine
-
DDAH influences insulin sensitivity by regulating the endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine
medicine
-
influence on atherosclerosis in experimental models by increased ADMA concentrations and reduced NO synthesis
medicine
-
novel therapeutic strategy for the treatment of chronic kidney disease
medicine
-
hyperhomocysteinemia is induced in human DDAH1 transgenic mice and wild-type littermates using a high methionine/low folate diet. Plasma total homocysteine is elevated approximately 3fold in both wild-type and DDAH1 transgenic mice fed the high methionine/low folate diet compared with the control diet. Plasma asymmetrical dimethylarginine is approximately 40% lower in DDAH1 transgenic mice compared with wild-type mice irrespective of diet. Responses to 10 microM papaverine, a direct smooth muscle dilator, are impaired with the high methionine/low folate diet in wild-type mice but not DDAH1 transgenic mice. DDAH1 transgenic mice also are protected from hypertrophy of cerebral arterioles but not from accelerated carotid artery thrombosis induced by the high methionine/low folate diet
medicine
-
influence on atherosclerosis in experimental models by increased ADMA concentrations and reduced NO synthesis
medicine
-
influence on atherosclerosis in experimental models by increased ADMA concentrations and reduced NO synthesis
medicine
-
DDAH activity and elevated endogenous asymmetric dimethylarginine is implicated in endothelial dysfunction exposed to glycosylated bovine serum albumin, aminoguanidine can protect endothelium against injury induced by glycosylated bovine serum albumin both in vitro and in vivo
medicine
-
endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (hydrolyzed by DDAH) is elevated in many patients and may contribute to the initiation and progression of their disease
medicine
-
in vivo administration of DDAH inhibitors (2-amino-4-(NG-methyl-guanidino)butanoic acid and its analogues) increases plasma NG,NG-dimethyl-L-arginine levels, giving proof of concept that these can be used to probe the physiological effects of DDAH inhibition, with potential for pharmaceutical use of DDAH inhibitors in diseases where excess NO production is implicated
medicine
-
influence on atherosclerosis in experimental models by increased ADMA concentrations and reduced NO synthesis
medicine
-
decreased DDAH-1 expression may cause accumulation of endogenous inhibitors of enothelial NO synthase, thereby contributing to endothelial dysfunction in the failing heart
additional information
-
DDAH1 plays an important role in development
medicine
-
2-chloroacetamidine may potentially find wide applicability as a general pharmacophore, useful in delineating characteristics of the amidinotransferase superfamily
additional information
-
dimerization is not critical for the maintenance of the biological function of the protein
medicine
-
seven days after coronary artery ligation, L-Arg and methylated arginine content, as well as DDAH activity are determined in homogenates of left ventricular infarct and border. In healthy hearts, DDAHI is absent, and DDAHII is localized to endothelium and endocardium with a similar distribution to that of eNOS. Following myocardial infarction, left ventricular DDAH activity is increased to 210% of control. Both DDAHI and DDAHII proteins are detected in peri-infarct cardiomyocytes, while DDAHII immunoreactivity is additionally localized to infiltrating inflammatory cells and blood vessels in the healing infarct. Both plasma and left ventricular concentrations of the DDAH substrate, ADMA, are increased post-myocardial infarction, although the ratio of Arg:ADMA is retained in the left ventricular post-myocardial infarction relative to sham operated controls
additional information
-
DDAH1 plays an important role in development