Reviewed, UniProtKB/Swiss-Prot P00813 (ADA_HUMAN)

Names and origin

Protein names

Recommended name:
    Adenosine deaminase
    EC=3.5.4.4
Alternative name(s):
    Adenosine aminohydrolase

Gene names

Name:

ADA

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	363 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)

Catalytic activity	Adenosine + H2O = inosine + NH3.
Tissue specificity	Found in all tissues, occurs in large amounts in T-lymphocytes and, at the time of weaning, in gastrointestinal tissues.
Polymorphism	There is a common allele, ADA*2, also known as the ADA 2 allozyme. It is associated with the reduced metabolism of adenosine to inosine. It specifically enhances deep sleep and slow-wave activity (SWA) during sleep.
Involvement in disease	Defects in ADA are the cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-negative due to adenosine deaminase deficiency (ADASCID) [MIM:102700]. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. ADA-SCID is an autosomal recessive form accounting for about 50% of non-X-linked SCIDs. ADA deficiency has been diagnosed in chronically ill teenagers and adults (late or adult onset). Population and newborn screening programs have also identified several healthy individuals with normal immunity who have partial ADA deficiency. Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 In hereditary hemolytic anemia, the level of this enzyme in erythrocytes increases 50-70 times.
Sequence similarities	Belongs to the adenosine and AMP deaminases family.

Ontologies

Keywords
Biological process	Nucleotide metabolism
Coding sequence diversity	Polymorphism
Disease	Disease mutation Hereditary hemolytic anemia SCID
Molecular function	Hydrolase
PTM	Acetylation
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	T cell activation Inferred from direct assay. Source: UniProtKB adenosine catabolic process Inferred from direct assay. Source: UniProtKB inosine biosynthetic process Inferred from direct assay. Source: MGI negative regulation of adenosine receptor signaling pathway Inferred from direct assay. Source: UniProtKB purine nucleotide salvage Inferred from mutant phenotype. Source: UniProtKB purine ribonucleoside monophosphate biosynthetic process Inferred from electronic annotation. Source: InterPro regulation of cell-cell adhesion mediated by integrin Inferred from direct assay. Source: UniProtKB response to hypoxia Inferred from direct assay. Source: UniProtKB
Cellular component	cytosol Ref.14 Inferred from Experiment. Source: Reactome external side of plasma membrane Inferred from direct assay. Source: UniProtKB lysosome Inferred from direct assay. Source: UniProtKB
Molecular function	adenosine deaminase activity Ref.14 Inferred from direct assay. Source: UniProtKB protein binding Inferred from physical interaction. Source: UniProtKB zinc ion binding Ref.20 Inferred from mutant phenotype. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.8

Chain

2 – 363

362

Adenosine deaminase

PRO_0000194352

Sites

Active site

214

1

Potential

Active site

262

1

Potential

Active site

295

1

Potential

Active site

296

1

Potential

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.8

Natural variations

Natural variant

8

1

D → N in allele ADA*2; in about 10% of the population; 20% to 30% decrease in activity; affects duration and intensity of deep sleep. Ref.11 Ref.23

VAR_002209

Natural variant

15

1

H → D in ADASCID; loss of activity. Ref.20

VAR_002210

Natural variant

20

1

G → R in ADASCID; loss of activity. Ref.18

VAR_002211

Natural variant

74

1

G → C in ADASCID; delayed-onset. Ref.22

VAR_002212

Natural variant

76

1

R → W in ADASCID.

VAR_002213

Natural variant

80

1

K → R Ref.19 Ref.23

VAR_002214

Natural variant

83

1

A → D in ADASCID; loss of activity. Ref.20

VAR_002215

Natural variant

101

1

R → L in ADASCID. Ref.13 Ref.14 Ref.17

VAR_002216

Natural variant

101

1

R → Q in ADASCID; loss of activity. Ref.13 Ref.14 Ref.17

VAR_002218

Natural variant

101

1

R → W in ADASCID. Ref.13 Ref.14 Ref.17

VAR_002217

Natural variant

107

1

L → P in ADASCID.

VAR_002219

Natural variant

129

1

V → M in ADASCID; delayed-onset. Ref.22

VAR_002220

Natural variant

140

1

G → E in ADASCID. Ref.22

VAR_002221

Natural variant

142

1

R → Q in ADASCID; 20% of activity; ADA deficiency of late onset. Ref.19

VAR_002222

Natural variant

149

1

R → Q in ADASCID. Ref.22

VAR_002223

Natural variant

149

1

R → W in ADASCID. Ref.22

VAR_002224

Natural variant

152

1

L → M in ADASCID; 1,5% of activity, partial ADA deficiency. Ref.21

VAR_002225

Natural variant

156

1

R → C in ADASCID. Ref.16 Ref.17

VAR_002226

Natural variant

156

1

R → H in ADASCID. Ref.16 Ref.17

VAR_002227

Natural variant

177

1

V → M in ADASCID; loss of activity. Ref.17

VAR_002228

Natural variant

179

1

A → D in ADASCID; loss of activity. Ref.20

VAR_002229

Natural variant

199

1

Q → P in ADASCID; delayed-onset. Ref.22

VAR_002230

Natural variant

211

1

R → C in ADASCID; late onset. Ref.14

VAR_002231

Natural variant

211

1

R → H in ADASCID. Ref.14

VAR_002232

Natural variant

215

1

A → T in ADASCID.

VAR_002233

Natural variant

216

1

G → R in ADASCID; severe.

VAR_002234

Natural variant

233

1

T → I in ADASCID; 20% of activity, partial ADA deficiency. Ref.21

VAR_002235

Natural variant

274

1

P → L in ADASCID.

VAR_002236

Natural variant

291

1

S → L in ADASCID. Ref.16

VAR_002237

Natural variant

297

1

P → Q in ADASCID. Ref.15

VAR_002238

Natural variant

304

1

L → R in ADASCID; loss of activity.

VAR_002239

Natural variant

329

1

A → V in ADASCID. Ref.14

VAR_002240

Natural variant

337

1

Missing in ADASCID.

VAR_002241

Experimental info

Sequence conflict

340

1

K → R in BAD97117. Ref.5

Secondary structure

1

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363

Helix Strand Turn

Details...

Beta strand

10 – 17

8

Helix

23 – 33

11

Helix

42 – 49

8

Helix

57 – 61

5

Helix

64 – 71

8

Helix

75 – 92

18

Beta strand

94 – 101

8

Helix

103 – 106

4

Helix

125 – 143

19

Beta strand

146 – 154

9

Helix

161 – 170

10

Turn

173 – 175

3

Beta strand

176 – 183

8

Helix

190 – 192

3

Helix

194 – 206

13

Beta strand

209 – 218

10

Helix

220 – 228

9

Beta strand

233 – 237

5

Helix

239 – 243

5

Helix

245 – 254

10

Beta strand

257 – 260

4

Helix

262 – 268

7

Beta strand

269 – 271

3

Helix

278 – 285

8

Beta strand

288 – 291

4

Helix

296 – 299

4

Helix

303 – 312

10

Turn

313 – 315

3

Helix

318 – 330

13

Beta strand

332 – 334

3

Helix

336 – 350

15

Sequences

	Sequence		Length	Mass (Da)
	P00813-1 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 786BC5085CA9AFCB	FASTA	363	40,764
	10 20 30 40 50 60 MAQTPAFDKP KVELHVHLDG SIKPETILYY GRRRGIALPA NTAEGLLNVI GMDKPLTLPD 70 80 90 100 110 120 FLAKFDYYMP AIAGCREAIK RIAYEFVEMK AKEGVVYVEV RYSPHLLANS KVEPIPWNQA 130 140 150 160 170 180 EGDLTPDEVV ALVGQGLQEG ERDFGVKARS ILCCMRHQPN WSPKVVELCK KYQQQTVVAI 190 200 210 220 230 240 DLAGDETIPG SSLLPGHVQA YQEAVKSGIH RTVHAGEVGS AEVVKEAVDI LKTERLGHGY 250 260 270 280 290 300 HTLEDQALYN RLRQENMHFE ICPWSSYLTG AWKPDTEHAV IRLKNDQANY SLNTDDPLIF 310 320 330 340 350 360 KSTLDTDYQM TKRDMGFTEE EFKRLNINAA KSSFLPEDEK RELLDLLYKA YGMPPSASAG QNL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human adenosine deaminase. cDNA and complete primary amino acid sequence." Daddona P.E., Shewach D.S., Kelley W.N., Argos P., Markham A.F., Orkin S.H. J. Biol. Chem. 259:12101-12106(1984) [PubMed: 6090454] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Sequence of human adenosine deaminase cDNA including the coding region and a small intron." Wiginton D.A., Adrian G.S., Hutton J.J. Nucleic Acids Res. 12:2439-2446(1984) [PubMed: 6546794] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Adenosine deaminase: characterization and expression of a gene with a remarkable promoter." Valerio D., Duyvesteyn M.G.C., Dekker B.M.M., Weeda G., Berkvens T.M., van der Voorn L., van Ormondt H., van der Eb A.J. EMBO J. 4:437-443(1985) [PubMed: 3839456] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Complete sequence and structure of the gene for human adenosine deaminase." Wiginton D.A., Kaplan D.J., States J.C., Akeson A.L., Perme C.M., Bilyk I.J., Vaughn A.J., Lattier D.L., Hutton J.J. Biochemistry 25:8234-8244(1986) [PubMed: 3028473] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Thymus.
[6]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain and Placenta.
[8]	Bienvenut W.V. Submitted (AUG-2004) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-11, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: B-cell lymphoma.
[9]	"Molecular cloning of human adenosine deaminase gene sequences." Orkin S.H., Daddona P.E., Shewach D.S., Markham A.F., Bruns G.A., Goff S.C., Kelley W.N. J. Biol. Chem. 258:12753-12756(1983) [PubMed: 6688808] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 141-363.
[10]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[11]	"An Asp8Asn substitution results in the adenosine deaminase (ADA) genetic polymorphism (ADA 2 allozyme): occurrence on different chromosomal backgrounds and apparent intragenic crossover." Hirschhorn R., Yang D.R., Israni A. Ann. Hum. Genet. 58:1-9(1994) [PubMed: 8031011] [Abstract] Cited for: VARIANT ADA*2 ASN-8.
[12]	"Structure of adenosine deaminase mRNAs from normal and adenosine deaminase-deficient human cell lines." Adrian G.S., Wiginton D.A., Hutton J. Mol. Cell. Biol. 4:1712-1717(1984) [PubMed: 6208479] [Abstract] Cited for: VARIANTS ADASCID.
[13]	"Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency." Bonthron D.T., Markham A.F., Ginsburg D., Orkin S.H. J. Clin. Invest. 76:894-897(1985) [PubMed: 3839802] [Abstract] Cited for: VARIANT ADASCID GLN-101.
[14]	"Mutant human adenosine deaminase alleles and their expression by transfection into fibroblasts." Akeson A.L., Wiginton D.A., Dusing M.R., States J.C., Hutton J.J. J. Biol. Chem. 263:16291-16296(1988) [PubMed: 3182793] [Abstract] Cited for: VARIANTS ADASCID TRP-101; HIS-211 AND VAL-329.
[15]	"Identification of a point mutation resulting in a heat-labile adenosine deaminase (ADA) in two unrelated children with partial ADA deficiency." Hirschhorn R., Tzall S., Ellenbogen A., Orkin S.H. J. Clin. Invest. 83:497-501(1989) [PubMed: 2783588] [Abstract] Cited for: VARIANT ADASCID GLN-297.
[16]	"Identification of two new missense mutations (R156C and S291L) in two ADA-SCID patients unusual for response to therapy with partial exchange transfusions." Hirschhorn R. Hum. Mutat. 1:166-168(1992) [PubMed: 1284479] [Abstract] Cited for: VARIANTS ADASCID CYS-156 AND LEU-291.
[17]	"Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype." Santisteban I., Arredondo-Vega F.X., Kelly S., Mary A., Fischer A., Hummell D.S., Lawton A., Sorensen R.U., Stiehm E.R., Uribe L., Weinberg K., Hershfield M.S. J. Clin. Invest. 92:2291-2302(1993) [PubMed: 8227344] [Abstract] Cited for: VARIANTS ADASCID LEU-101; HIS-156 AND MET-177.
[18]	"Homozygosity for a missense mutation (G20R) associated with neonatal onset adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID)." Yang D.R., Huie M.L., Hirschhorn R. Clin. Immunol. Immunopathol. 70:171-175(1994) [PubMed: 8299233] [Abstract] Cited for: VARIANT ADASCID ARG-20.
[19]	"Three new adenosine deaminase mutations that define a splicing enhancer and cause severe and partial phenotypes: implications for evolution of a CpG hotspot and expression of a transduced ADA cDNA." Santisteban I., Arredondo-Vega F.X., Kelly S., Loubser M., Meydan N., Roifman C., Howell P.L., Bowen T., Weinberg K.I., Schroeder M.L., Hershfield M.S. Hum. Mol. Genet. 4:2081-2087(1995) [PubMed: 8589684] [Abstract] Cited for: VARIANT ADASCID GLN-142, VARIANT ARG-80.
[20]	"Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5' splice site." Santisteban I., Arredondo-Vega F.X., Kelly S., Debre M., Fisher A., Perignon J.L., Hilman B., Eldahr J., Dreyfus D.H., Gelfand E.W., Howell P.L., Hershfield M.S. Hum. Mutat. 5:243-250(1995) [PubMed: 7599635] [Abstract] Cited for: VARIANTS ADASCID ASP-15; ASP-83 AND ASP-179.
[21]	"Two newly identified mutations (Thr233Ile and Leu152Met) in partially adenosine deaminase-deficient (ADA-) individuals that result in differing biochemical and metabolic phenotypes." Hirschhorn R., Borkowsky W., Jiang C.-K., Yang D.R., Jenkins T. Hum. Genet. 100:22-29(1997) [PubMed: 9225964] [Abstract] Cited for: VARIANTS ADASCID MET-152 AND ILE-233.
[22]	"Seven novel mutations in the adenosine deaminase (ADA)gene in patients with severe and delayed onset combined immunodeficiency: G74C, V129M, G140E, R149W, Q199P, 462delG, and E337del." Arredondo-Vega F.X., Santisteban I., Notarangelo L.D., el Dahr J., Buckley R., Roifman C., Conley M.E., Hershfield M.S. Hum. Mutat. 11:482-482(1998) Cited for: VARIANTS ADASCID CYS-74; MET-129; GLU-140; TRP-149 AND PRO-199.
[23]	"A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans." Retey J.V., Adam M., Honegger E., Khatami R., Luhmann U.F.O., Jung H.H., Berger W., Landolt H.-P. Proc. Natl. Acad. Sci. U.S.A. 102:15676-15681(2005) [PubMed: 16221767] [Abstract] Cited for: EFFECT OF VARIANT ADA*2 ASN-8 ON SLEEP.
+	Additional computationally mapped references.

Web resources

ADAbase

ADA mutation db

GeneReviews

Wikipedia

Adenosine deaminase entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

X02994 mRNA. Translation: CAA26734.1.
X02189 , X02190, X02191, X02192, X02193, X02194, X02195, X02196, X02197, X02198, X02199 Genomic DNA. Translation: CAA26130.1. Sequence problems.
M13792 Genomic DNA. Translation: AAA78791.1.
AL139352, Z97053 Genomic DNA. Translation: CAH73885.1.
Z97053, AL139352 Genomic DNA. Translation: CAB09782.2.
AK223397 mRNA. Translation: BAD97117.1.
BC007678 mRNA. Translation: AAH07678.1.
BC040226 mRNA. Translation: AAH40226.1.

IPI

IPI00296441.

PIR

DUHUA. A91032.

RefSeq

NP_000013.2.

UniGene

Hs.654536

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1M7M	model	-	A	1-363	[»]

SMR

P00813. Positions 3-350, 4-351.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:371N.

PTM databases

PhosphoSite

P00813.

2-D gel databases

Aarhus/Ghent-2DPAGE

5305. IEF.

Proteomic databases

PeptideAtlas

P00813.

PRIDE

P00813.

Genome annotation databases

Ensembl

ENSG00000196839. Homo sapiens. [Contig view]

GeneID

100.

KEGG

hsa:100.

UCSC

uc002xmj.1. human.

Organism-specific databases

GeneCards

GC20M042681.

H-InvDB

HIX0015842.

HGNC

HGNC:186. ADA.

HPA

CAB004307.
HPA001399.

MIM

102700. phenotype.
608958. gene.

Orphanet

277. Severe combined immunodeficiency due to adenosine deaminase deficiency.

PharmGKB

PA24503.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P00813.

HOVERGEN

P00813.

Enzyme and pathway databases

BRENDA

3.5.4.4. 247.

Reactome

REACT_1698. Metablism of nucleotides.

Gene expression databases

ArrayExpress

P00813.

Bgee

P00813.

CleanEx

HS_ADA.

GermOnline

ENSG00000196839. Homo sapiens.

Family and domain databases

InterPro

IPR006650. A/AMP_deam_AS.
IPR001365. A/AMP_deaminase.
IPR006330. A_deaminase.
[Graphical view]

PANTHER

PTHR11409. A/AMP_deaminase. 1 hit.

Pfam

PF00962. A_deaminase. 1 hit.
[Graphical view]

TIGRFAMs

TIGR01430. aden_deam. 1 hit.

PROSITE

PS00485. A_DEAMINASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

BindingDB

P00813.

DrugBank

DB00640. Adenosine.
DB00242. Cladribine.
DB00975. Dipyridamole.
DB00199. Erythromycin.
DB01073. Fludarabine.
DB00249. Idoxuridine.
DB01280. Nelarabine.
DB00552. Pentostatin.
DB00277. Theophylline.
DB00194. Vidarabine.

NextBio

377.

SOURCE

Search...

Entry information

Entry name

ADA_HUMAN

Accession

Primary (citable) accession number: P00813
Secondary accession number(s): Q53F92, Q6LA59

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	January 23, 2007
Last modified:	July 7, 2009
This is version 123 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)