O94760 (DDAH1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
N(G),N(G)-dimethylarginine dimethylaminohydrolase 1
Short name=DDAH-1
Short name=Dimethylarginine dimethylaminohydrolase 1
EC=3.5.3.18

Alternative name(s):
DDAHI
Dimethylargininase-1

Gene names

Name:	DDAH1
Synonyms:	DDAH

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	285 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Hydrolyzes N(G),N(G)-dimethyl-L-arginine (ADMA) and N(G)-monomethyl-L-arginine (MMA) which act as inhibitors of NOS. Has therefore a role in the regulation of nitric oxide generation.
Catalytic activity	N(omega),N(omega)-dimethyl-L-arginine + H2O = dimethylamine + L-citrulline. Ref.8 Ref.11
Enzyme regulation	Inhibited by zinc ions By similarity. Enzyme purified in the absence of 1,10-phenanthroline contains on average 0.4 zinc atoms per subunit. Inhibited by 4-hydroxy-nonenal through the formation of a covalent adduct with His-173. Competitively inhibited by N(5)-iminopropyl-ornithine. Ref.8 Ref.11
Subunit structure	Monomer. Ref.11
Tissue specificity	Detected in brain, liver, kidney and pancreas, and at low levels in skeletal muscle. Ref.2
Sequence similarities	Belongs to the DDAH family.
Biophysicochemical properties	Kinetic parameters: KM=69 µM for asymmetric dimethylarginine (ADMA) Ref.8 Ref.11 KM=54 µM for monomethyl-L-arginine (MMA) KM=3.1 µM for S-methyl-L-thiocitrulline Vmax=356 nmol/min/mg enzyme with ADMA Vmax=154 nmol/min/mg enzyme with NMA pH dependence: Optimum pH is 8.5.

Ontologies

Keywords
Coding sequence diversity	Alternative splicing
Ligand	Metal-binding Zinc
Molecular function	Hydrolase
PTM	Acetylation
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	arginine catabolic process Traceable author statement Ref.1. Source: ProtInc citrulline metabolic process Inferred from direct assay Ref.11. Source: UniProtKB nitric oxide mediated signal transduction Traceable author statement Ref.1. Source: ProtInc positive regulation of angiogenesis Inferred from electronic annotation. Source: Compara positive regulation of nitric oxide biosynthetic process Inferred from sequence or structural similarity. Source: BHF-UCL regulation of systemic arterial blood pressure Inferred from sequence or structural similarity. Source: BHF-UCL
Cellular_component	mitochondrion Inferred from electronic annotation. Source: Compara
Molecular_function	amino acid binding Inferred from electronic annotation. Source: Compara dimethylargininase activity Inferred from direct assay Ref.11. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: O94760-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: O94760-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-103: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.1

Chain

2 – 285

284

N(G),N(G)-dimethylarginine dimethylaminohydrolase 1

PRO_0000171118

Regions

Region

78 – 79

2

Substrate binding

Sites

Active site

173

1

Proton donor Probable

Active site

274

1

Nucleophile Ref.11

Metal binding

274

1

Zinc By similarity

Binding site

30

1

Substrate; via carbonyl oxygen

Binding site

73

1

Substrate

Binding site

98

1

Substrate

Binding site

145

1

Substrate

Binding site

268

1

Substrate; via carbonyl oxygen

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.1

Natural variations

Alternative sequence

1 – 103

103

Missing in isoform 2.

VSP_043813

Experimental info

Mutagenesis

30

1

L → A: Reduces enzyme activity and affinity for asymmetric dimethylarginine about 12-fold. Ref.11

Mutagenesis

78

1

E → A: Reduces enzyme activity about 1000-fold, and affinity for asymmetric dimethylarginine about 100-fold. Ref.11

Mutagenesis

271

1

L → G: Reduces enzyme activity about 10-fold, and affinity for asymmetric dimethylarginine about 7-fold. Ref.11

Secondary structure

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285

Helix Strand Turn

Details...

Beta strand

14 – 19

6

Helix

25 – 28

4

Helix

40 – 55

16

Turn

56 – 58

3

Beta strand

61 – 65

5

Turn

72 – 75

4

Helix

77 – 80

4

Beta strand

81 – 84

4

Beta strand

87 – 90

4

Helix

96 – 101

6

Helix

102 – 110

9

Turn

111 – 113

3

Beta strand

115 – 118

4

Helix

128 – 130

3

Beta strand

131 – 133

3

Beta strand

138 – 145

8

Helix

148 – 157

10

Turn

158 – 160

3

Beta strand

163 – 167

5

Helix

174 – 176

3

Beta strand

177 – 182

6

Beta strand

185 – 189

5

Helix

192 – 203

12

Beta strand

205 – 207

3

Beta strand

210 – 216

7

Helix

217 – 220

4

Beta strand

223 – 227

5

Turn

228 – 230

3

Beta strand

231 – 237

7

Turn

239 – 241

3

Helix

243 – 251

9

Beta strand

255 – 260

6

Helix

263 – 266

4

Turn

267 – 269

3

Helix

273 – 275

3

Beta strand

277 – 279

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: CD8875DF267EF39B	FASTA	285	31,122
	10 20 30 40 50 60 MAGLGHPAAF GRATHAVVRA LPESLGQHAL RSAKGEEVDV ARAERQHQLY VGVLGSKLGL 70 80 90 100 110 120 QVVELPADES LPDCVFVEDV AVVCEETALI TRPGAPSRRK EVDMMKEALE KLQLNIVEMK 130 140 150 160 170 180 DENATLDGGD VLFTGREFFV GLSKRTNQRG AEILADTFKD YAVSTVPVAD GLHLKSFCSM 190 200 210 220 230 240 AGPNLIAIGS SESAQKALKI MQQMSDHRYD KLTVPDDIAA NCIYLNIPNK GHVLLHRTPE 250 260 270 280 EYPESAKVYE KLKDHMLIPV SMSELEKVDG LLTCCSVLIN KKVDS
	Isoform 2 [UniParc]. Checksum: 0612A4D0E824A1EE	FASTA	182	20,189
	10 20 30 40 50 60 MMKEALEKLQ LNIVEMKDEN ATLDGGDVLF TGREFFVGLS KRTNQRGAEI LADTFKDYAV 70 80 90 100 110 120 STVPVADGLH LKSFCSMAGP NLIAIGSSES AQKALKIMQQ MSDHRYDKLT VPDDIAANCI 130 140 150 160 170 180 YLNIPNKGHV LLHRTPEEYP ESAKVYEKLK DHMLIPVSMS ELEKVDGLLT CCSVLINKKV DS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Purification, cDNA cloning and expression of human NG,NG-dimethylarginine dimethylaminohydrolase." Kimoto M., Miyatake S., Sasagawa T., Yamashita H., Okita M., Oka T., Ogawa T., Tsuji H. Eur. J. Biochem. 258:863-868(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 2-12 AND 35-50, ABSENCE OF BOUND ZINC, ACETYLATION AT ALA-2. Tissue: Kidney and Liver.
[2]	"Identification of two human dimethylarginine dimethylaminohydrolases with distinct tissue distributions and homology with microbial arginine deiminases." Leiper J.M., Santa Maria J., Chubb A., MacAllister R.J., Charles I.G., Whitley G.S., Vallance P. Biochem. J. 343:209-214(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY.
[3]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Endometrial cancer.
[4]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Colon, Kidney, Stomach and Testis.
[7]	Lubec G., Vishwanath V., Chen W.-Q., Sun Y. Submitted (DEC-2008) to UniProtKB Cited for: PROTEIN SEQUENCE OF 20-31; 46-57; 112-136; 150-196; 212-230 AND 268-281, MASS SPECTROMETRY. Tissue: Brain, Cajal-Retzius cell and Fetal brain cortex.
[8]	"Mechanism of 4-HNE mediated inhibition of hDDAH-1: implications in NO regulation." Forbes S.P., Druhan L.J., Guzman J.E., Parinandi N., Zhang L., Green-Church K.B., Cardounel A.J. Biochemistry 47:1819-1826(2008) [PubMed] [Europe PMC] [Abstract] Cited for: CATALYTIC ACTIVITY, ENZYME REGULATION, MASS SPECTROMETRY, BIOPHYSICOCHEMICAL PROPERTIES.
[9]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]	"Disruption of methylarginine metabolism impairs vascular homeostasis." Leiper J., Nandi M., Torondel B., Murray-Rust J., Malaki M., O'Hara B., Rossiter S., Anthony S., Madhani M., Selwood D., Smith C., Wojciak-Stothard B., Rudiger A., Stidwill R., McDonald N.Q., Vallance P. Nat. Med. 13:198-203(2007) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 2-284 IN COMPLEXES WITH CITRULLINE AND INHIBITOR L-257.
[11]	"Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide." Wang Y., Monzingo A.F., Hu S., Schaller T.H., Robertus J.D., Fast W. Biochemistry 48:8624-8635(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) IN COMPLEX WITH N-1-IMINOPROPYL-L-ORNITHINE, CATALYTIC ACTIVITY, ZINC-BINDING, ENZYME REGULATION, SUBUNIT, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVE SITE, MUTAGENESIS OF LEU-30; GLU-78 AND LEU-271, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AB001915 mRNA. Translation: BAA37117.1.
BX648145 mRNA. Translation: CAI45988.1.
AC092807 Genomic DNA. No translation available.
AL078459 Genomic DNA. No translation available.
AL360219 Genomic DNA. No translation available.
CH471097 Genomic DNA. Translation: EAW73199.1.
BC033680 mRNA. Translation: AAH33680.1.
BC043235 mRNA. Translation: AAH43235.2.

IPI

IPI00220342.

RefSeq

NP_001127917.1. NM_001134445.1.
NP_036269.1. NM_012137.3.

UniGene

Hs.713411.
Hs.731520.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2JAI	X-ray	2.30	A/B	2-284	[»]
2JAJ	X-ray	2.00	A/B	2-284	[»]
3I2E	X-ray	2.03	A/B	1-285	[»]
3I4A	X-ray	1.90	A/B	1-285	[»]
3P8E	X-ray	2.49	A/B	1-285	[»]
3P8P	X-ray	2.50	A/B	1-285	[»]

ProteinModelPortal

O94760.

ModBase

Search...

Protein-protein interaction databases

IntAct

O94760. 2 interactions.

STRING

9606.ENSP00000284031.

PTM databases

PhosphoSite

O94760.

2D gel databases

REPRODUCTION-2DPAGE

IPI00220342.

Proteomic databases

PaxDb

O94760.

PeptideAtlas

O94760.

PRIDE

O94760.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000284031; ENSP00000284031; ENSG00000153904.
ENST00000535924; ENSP00000439045; ENSG00000153904.
ENST00000539042; ENSP00000438604; ENSG00000153904.

GeneID

23576.

KEGG

hsa:23576.

UCSC

uc001dlb.3. human.

Organism-specific databases

CTD

23576.

GeneCards

GC01M085785.

HGNC

HGNC:2715. DDAH1.

HPA

HPA006308.

MIM

604743. gene.

neXtProt

NX_O94760.

PharmGKB

PA27185.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1834.

HOGENOM

HOG000161035.

HOVERGEN

HBG055937.

InParanoid

O94760.

KO

K01482.

OMA

LNIVEMT.

OrthoDB

EOG4320ZN.

PhylomeDB

O94760.

Gene expression databases

ArrayExpress

O94760.

Bgee

O94760.

CleanEx

HS_DDAH1.

Genevestigator

O94760.

GermOnline

ENSG00000153904. Homo sapiens.

Family and domain databases

InterPro

IPR003198. Amidino_trans.
[Graphical view]

Pfam

PF02274. Amidinotransf. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

O94760.

ChEMBL

CHEMBL6036.

ChiTaRS

DDAH1. human.

DrugBank

DB00155. L-Citrulline.

EvolutionaryTrace

O94760.

GenomeRNAi

23576.

NextBio

46178.

SOURCE

Search...

Entry information

Entry name

DDAH1_HUMAN

Accession

Primary (citable) accession number: O94760
Secondary accession number(s): Q5HYC8, Q86XK5

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 30, 2000
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 120 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.