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Information on EC 3.5.3.18 - dimethylargininase and Organism(s) Mus musculus and UniProt Accession Q99LD8
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3.5.3.18 dimethylargininaseIUBMB Comments
Also acts on Nomega-methyl-L-arginine.
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Word Map
- 3.5.3.18
- endothelial
- cardiovascular
- artery
- hypertension
- angiotensin
- l-citrulline
- aortic
-
umbilical
-
vasodilation
- vein
-
endothelium-dependent
- dimethylamine
- atherosclerosis
- coronary
-
methylarginines
- ng,ng-dimethylarginine
- homocysteine
- medicine
- huvecs
-
endothelium-derived
- hyperhomocysteinemia
- nnos
-
l-nmma
-
ii-induced
- ng-monomethyl-l-arginine
-
monomethylarginine
-
ox-ldl
- analysis
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
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
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
DDAH
DDAH1
DDAHI
-
-
-
-
DDAHII
-
-
-
-
Dimethylargininase
-
-
-
-
dimethylarginine dimethylaminohydrolase
G6a
-
-
-
-
DDAH
-
-
-
-
dimethylarginine dimethylaminohydrolase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
123644-75-7
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Ngamma-monomethyl-L-arginine + H2O
L-citrulline + methylamine
-
-
-
?
S-methyl-L-thiocitrulline + H2O
L-citrulline + methanethiol
-
-
-
?
N,N-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
-
37°C, 2 h, pH 6.0
-
-
?
Ngamma-monomethyl-L-arginine + H2O
L-citrulline + methylamine
-
-
-
?
S-methyl-L-thiocitrulline + H2O
L-citrulline + methanethiol
-
-
-
?
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
-
enzyme plays an integral role in arginine handling
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
NG,NG-dimethyl-L-arginine + H2O
dimethylamine + L-citrulline
-
enzyme plays an integral role in arginine handling
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(N,N-dimethylamino)diazenolate-2-oxide
1 mM, 50% inhibition of DDAH-1
2-(N,N-dimethylamino)diazenolate-2-oxide
1 mM, 50% inhibition of DDAH-1
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
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
all-trans-retinoic acid
1.9fold increase in DDAH-2 mRNA and protein expression
all-trans-retinoic acid
1.9fold increase in DDAH-2 mRNA and protein expression
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
both DDAH1 and 2 are expressed in the developing limb buds in patterns overlapping areas with high nitric oxide synthase activity
-
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
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
global knockout of Ddah2 results in elevated blood pressure during periods of activity and changes in vascular responsiveness mediated by changes in methylarginine concentration, and systemic nitric oxide concentrations. In a model of severe polymicrobial sepsis, Ddah2 knockout affects outcome. Monocyte-specific deletion of Ddah2 results in a similar pattern of increased severity to that seen in globally deficient animals
malfunction
physiological function
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
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
in mice specifically lacking Ddah1 expression in endothelial cells, plasma asymmetrical dimethylarginine level is unchanged, and cultured aortas release amounts of asymmetrical dimethylarginine to similar to controls. Vasoreactivity ex vivo and hemodynamics in vivo are unaltered in endothelial DDAH1 mutant mice, while angiogenic responses both ex vivo and in vivo are significantly impaired
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). DDAH2_MOUSE
285
0
29646
Swiss-Prot
other Location (Reliability: 2)
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
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
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DDAH isoforms are expressed in a dynamic,overlapping pattern during embryonic development
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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
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
medicine
influence on atherosclerosis in experimental models by increased ADMA concentrations and reduced NO synthesis
medicine
global knockout of Ddah2 results in elevated blood pressure during periods of activity and changes in vascular responsiveness mediated by changes in methylarginine concentration, and systemic nitric oxide concentrations. In a model of severe polymicrobial sepsis, Ddah2 knockout affects outcome. Monocyte-specific deletion of Ddah2 results in a similar pattern of increased severity to that seen in globally deficient animals
medicine
influence on atherosclerosis in experimental models by increased ADMA concentrations and reduced NO synthesis
medicine
in a mouse model of severe malaria, Plasmodium berghei ANKA infection inactivates hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue asymmetric dimethylarginine, elevated asymmetric dimethylarginine/arginine ratio in plasma, and decreased whole blood nitrite concentration
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Santa Maria, J.; Vallance, P.; Charles, I.G.; Leiper, J.M.
Identification of microbial dimethylarginine dimethylaminohydrolase enzymes
Mol. Microbiol.
33
1278-1279
1999
Homo sapiens, Mycobacterium tuberculosis, Mus musculus, Pseudomonas aeruginosa, Rattus norvegicus, Streptomyces coelicolor
Dayal, S.; Rodionov, R.N.; Arning, E.; Bottiglieri, T.; Kimoto, M.; Murry, D.J.; Cooke, J.P.; Faraci, F.M.; Lentz, S.R.
Tissue-specific downregulation of dimethylarginine dimethylaminohydrolase in hyperhomocysteinemia
Am. J. Physiol. Heart Circ. Physiol.
295
H816-H825
2008
Mus musculus
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)
Sakurada, M.; Shichiri, M.; Imamura, M.; Azuma, H.; Hirata, Y.
Nitric oxide upregulates dimethylarginine dimethylaminohydrolase-2 via cyclic GMP induction in endothelial cells
Hypertension
52
903-909
2008
Homo sapiens, Mus musculus, Rattus norvegicus
Lee, W.J.; Kim, S.H.; Kim, G.H.; Han, S.M.; Won, J.C.; Jung, C.H.; Park, H.S.; Choi, d.o..S.; Lee, K.U.; Park, J.Y.
Alpha-lipoic acid activates dimethylarginine dimethylaminohydrolase in cultured endothelial cells
Biochem. Biophys. Res. Commun.
398
653-658
2010
Mus musculus
Breckenridge, R.A.; Kelly, P.; Nandi, M.; Vallance, P.J.; Ohun, T.J.; Leiper, J.
A role for dimethylarginine dimethylaminohydrolase 1 (DDAH1) in mammalian development
Int. J. Dev. Biol.
54
215-220
2010
Mus musculus
Li, J.; Wilson, A.; Gao, X.; Kuruba, R.; Liu, Y.; Poloyac, S.; Pitt, B.; Xie, W.; Li, S.
Coordinated regulation of dimethylarginine dimethylaminohydrolase-1 and cationic amino acid transporter-1 by farnesoid X receptor in mouse liver and kidney and its implication in the control of blood levels of asymmetric dimethylarginine
J. Pharmacol. Exp. Ther.
331
234-243
2009
Mus musculus
Hu, X.; Atzler, D.; Xu, X.; Zhang, P.; Guo, H.; Lu, Z.; Fassett, J.; Schwedhelm, E.; Boeger, R.H.; Bache, R.J.; Chen, Y.
Dimethylarginine dimethylaminohydrolase-1 is the critical enzyme for degrading the cardiovascular risk factor asymmetrical dimethylarginine
Arterioscler. Thromb. Vasc. Biol.
31
1540-1546
2011
Mus musculus
Zhang, P.; Hu, X.; Xu, X.; Chen, Y.; Bache, R.J.
Dimethylarginine dimethylaminohydrolase 1 modulates endothelial cell growth through nitric oxide and Akt
Arterioscler. Thromb. Vasc. Biol.
31
890-897
2011
Homo sapiens, Mus musculus
Lambden, S.; Kelly, P.; Ahmetaj-Shala, B.; Wang, Z.; Lee, B.; Nandi, M.; Torondel, B.; Delahaye, M.; Dowsett, L.; Piper, S.; Tomlinson, J.; Caplin, B.; Colman, L.; Boruc, O.; Slaviero, A.; Zhao, L.; Oliver, E.; Khadayate, S.; Singer, M.; Arrigoni, F.; Leiper, J.
Dimethylarginine dimethylaminohydrolase 2 regulates nitric oxide synthesis and hemodynamics and determines outcome in polymicrobial sepsis
Arterioscler. Thromb. Vasc. Biol.
35
1382-1392
2015
Mus musculus (Q99LD8)
Dowsett, L.; Piper, S.; Slaviero, A.; Dufton, N.; Wang, Z.; Boruc, O.; Delahaye, M.; Colman, L.; Kalk, E.; Tomlinson, J.; Birdsey, G.; Randi, A.M.; Leiper, J.
Endothelial dimethylarginine dimethylaminohydrolase 1 is an important regulator of angiogenesis but does not regulate vascular reactivity or hemodynamic homeostasis
Circulation
131
2217-2225
2015
Mus musculus (Q9CWS0), Mus musculus
Chertow, J.H.; Alkaitis, M.S.; Nardone, G.; Ikeda, A.K.; Cunnington, A.J.; Okebe, J.; Ebonyi, A.O.; Njie, M.; Correa, S.; Jayasooriya, S.; Casals-Pascual, C.; Billker, O.; Conway, D.J.; Walther, M.; Ackerman, H.
Plasmodium infection is associated with impaired hepatic dimethylarginine dimethylaminohydrolase activity and disruption of nitric oxide synthase inhibitor/substrate homeostasis
PLoS Pathog.
11
e1005119
2015
Homo sapiens (O94760), Homo sapiens, Mus musculus (Q9CWS0), Mus musculus
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