P56658 (ADA_BOVIN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Adenosine deaminase
EC=3.5.4.4

Alternative name(s):
Adenosine aminohydrolase

Gene names

Name:

ADA

Organism

Bos taurus (Bovine)

Taxonomic identifier

9913 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Cetartiodactyla › Ruminantia › Pecora › Bovidae › Bovinae › Bos

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)

Function	Catalyzes the hydrolytic deamination of adenosine and 2-deoxyadenosine. Plays an important role in purine metabolism and in adenosine homeostasis. Modulates signaling by extracellular adenosine, and so contributes indirectly to cellular signaling events. Acts as a positive regulator of T-cell coactivation, by binding DPP4. Its interaction with DPP4 regulates lymphocyte-epithelial cell adhesion By similarity.
Catalytic activity	Adenosine + H2O = inosine + NH3.
Cofactor	Binds 1 zinc ion per subunit.
Subunit structure	Interacts with DPP4 (extracellular domain) By similarity. Ref.5
Subcellular location	Cell membrane; Peripheral membrane protein; Extracellular side By similarity. Cell junction By similarity. Cytoplasmic vesicle lumen By similarity. Cytoplasm By similarity. Note: Colocalized with DPP4 at the cell junction in lymphocyte-epithelial cell adhesion By similarity.
Pharmaceutical use	Available under the name Adagen (Enzon). This is a PEG-conjugated form (pegademase). Used to treat patients with severe combined immunodeficiency diseases (SCID).
Sequence similarities	Belongs to the adenosine and AMP deaminases family.
Mass spectrometry	Molecular mass is 40549±16 Da from positions 2 - 363. Determined by ESI. Ref.2

Ontologies

Keywords
Biological process	Cell adhesion Nucleotide metabolism
Cellular component	Cell junction Cell membrane Cytoplasm Cytoplasmic vesicle Membrane
Coding sequence diversity	Polymorphism
Ligand	Metal-binding Zinc
Molecular function	Hydrolase
PTM	Acetylation
Technical term	3D-structure Complete proteome Direct protein sequencing Pharmaceutical Reference proteome
Gene Ontology (GO)
Biological process	T cell activation Inferred from Biological aspect of Ancestor. Source: RefGenome adenosine catabolic process Inferred from sequence or structural similarity. Source: UniProtKB cell adhesion Inferred from electronic annotation. Source: UniProtKB-KW hypoxanthine salvage Inferred from Biological aspect of Ancestor. Source: RefGenome inosine biosynthetic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of adenosine receptor signaling pathway Inferred from Biological aspect of Ancestor. Source: RefGenome purine ribonucleoside monophosphate biosynthetic process Inferred from electronic annotation. Source: InterPro
Cellular component	cell junction Inferred from electronic annotation. Source: UniProtKB-SubCell cytoplasmic membrane-bounded vesicle lumen Inferred from electronic annotation. Source: UniProtKB-SubCell cytosol Inferred from Biological aspect of Ancestor. Source: RefGenome external side of plasma membrane Inferred from Biological aspect of Ancestor. Source: RefGenome
Molecular function	adenosine deaminase activity Inferred from sequence or structural similarity. Source: UniProtKB zinc ion binding Inferred from sequence or structural similarity. 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.2

Chain

2 – 363

362

Adenosine deaminase

PRO_0000194351

Sites

Active site

217

1

Proton donor Probable

Metal binding

15

1

Zinc; catalytic

Metal binding

17

1

Zinc; catalytic

Metal binding

214

1

Zinc; catalytic

Metal binding

295

1

Zinc; catalytic

Binding site

17

1

Substrate

Binding site

19

1

Substrate

Binding site

184

1

Substrate; via amide nitrogen and carbonyl oxygen

Binding site

296

1

Substrate

Site

238

1

Important for catalytic activity

Amino acid modifications

Modified residue

2

1

N-acetylalanine

Modified residue

54

1

N6-acetyllysine By similarity

Modified residue

232

1

N6-acetyllysine By similarity

Natural variations

Natural variant

199

1

K → Q.

Natural variant

246

1

A → T.

Natural variant

352

1

G → R.

Experimental info

Sequence conflict

8

1

N → D AA sequence Ref.2

Sequence conflict

32 – 33

2

RK → KR AA sequence Ref.2

Sequence conflict

57

1

S → T AA sequence Ref.2

Sequence conflict

60

1

E → D AA sequence Ref.2

Sequence conflict

77 – 79

3

EAV → DAI AA sequence Ref.2

Sequence conflict

261

1

V → I AA sequence Ref.2

Sequence conflict

279 – 281

3

PVV → AVI AA sequence Ref.2

Sequence conflict

313 – 314

2

NE → KD AA sequence Ref.2

Secondary structure

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363

Helix Strand Turn

Details...

Beta strand

11 – 13

3

Helix

18 – 20

3

Helix

24 – 33

10

Turn

43 – 45

3

Helix

46 – 49

4

Helix

58 – 72

15

Helix

76 – 92

17

Beta strand

95 – 102

8

Helix

104 – 107

4

Beta strand

109 – 111

3

Helix

126 – 144

19

Beta strand

147 – 155

9

Helix

159 – 161

3

Helix

162 – 171

10

Turn

174 – 176

3

Beta strand

177 – 184

8

Helix

191 – 193

3

Helix

195 – 206

12

Beta strand

210 – 219

10

Helix

221 – 229

9

Beta strand

234 – 238

5

Helix

240 – 244

5

Helix

246 – 255

10

Beta strand

258 – 261

4

Helix

263 – 268

6

Beta strand

270 – 272

3

Helix

279 – 285

7

Beta strand

290 – 292

3

Helix

297 – 300

4

Helix

304 – 312

9

Turn

313 – 315

3

Helix

319 – 331

13

Helix

337 – 350

14

Sequences

	Sequence		Length	Mass (Da)
	P56658 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: 69F6D25ACFF2A3E5	FASTA	363	40,919
	10 20 30 40 50 60 MAQTPAFNKP KVELHVHLDG AIKPETILYY GRKRGIALPA DTPEELQNII GMDKPLSLPE 70 80 90 100 110 120 FLAKFDYYMP AIAGCREAVK RIAYEFVEMK AKDGVVYVEV RYSPHLLANS KVEPIPWNQA 130 140 150 160 170 180 EGDLTPDEVV SLVNQGLQEG ERDFGVKVRS ILCCMRHQPS WSSEVVELCK KYREQTVVAI 190 200 210 220 230 240 DLAGDETIEG SSLFPGHVKA YAEAVKSGVH RTVHAGEVGS ANVVKEAVDT LKTERLGHGY 250 260 270 280 290 300 HTLEDATLYN RLRQENMHFE VCPWSSYLTG AWKPDTEHPV VRFKNDQVNY SLNTDDPLIF 310 320 330 340 350 360 KSTLDTDYQM TKNEMGFTEE EFKRLNINAA KSSFLPEDEK KELLDLLYKA YGMPSPASAE QCL

References

[1]	"The binding site of human adenosine deaminase for CD26/dipeptidyl peptidase IV: the Arg142Gln mutation impairs binding to CD26 but does not cause immune deficiency." Richard E., Arredondo-Vega F.X., Santisteban I., Kelly S.J., Patel D.D., Hershfield M.S. J. Exp. Med. 192:1223-1236(2000) [PubMed: 11067872] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Primary structure of bovine adenosine deaminase." Kelly M.A., Vestling M.M., Murphy C.M., Hua S., Sumpter T., Fenselau C. J. Pharm. Biomed. Anal. 14:1513-1519(1996) [PubMed: 8877857] [Abstract] Cited for: PROTEIN SEQUENCE OF 2-357, MASS SPECTROMETRY.
[3]	"Structure of bovine adenosine deaminase complexed with 6-hydroxy-1,6-dihydropurine riboside." Kinoshita T., Nishio N., Nakanishi I., Sato A., Fujii T. Acta Crystallogr. D 59:299-303(2003) [PubMed: 12554940] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 2-356 IN COMPLEX WITH ZINC IONS AND TRANSITION STATE ANALOG 6-HYDROXY-1,6-DIHYDROPURINE RIBOSIDE.
[4]	"A highly potent non-nucleoside adenosine deaminase inhibitor: efficient drug discovery by intentional lead hybridization." Terasaka T., Kinoshita T., Kuno M., Nakanishi I. J. Am. Chem. Soc. 126:34-35(2004) [PubMed: 14709046] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 2-356 IN COMPLEX WITH INHIBITOR AND ZINC IONS.
[5]	"Crystal structure of CD26/dipeptidyl-peptidase IV in complex with adenosine deaminase reveals a highly amphiphilic interface." Weihofen W.A., Liu J., Reutter W., Saenger W., Fan H. J. Biol. Chem. 279:43330-43335(2004) [PubMed: 15213224] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.03 ANGSTROMS) OF 1-357 IN COMPLEX WITH ZINC IONS AND DPP4, SUBUNIT.
[6]	"Structure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors." Terasaka T., Okumura H., Tsuji K., Kato T., Nakanishi I., Kinoshita T., Kato Y., Kuno M., Seki N., Naoe Y., Inoue T., Tanaka K., Nakamura K. J. Med. Chem. 47:2728-2731(2004) [PubMed: 15139750] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 2-356 IN COMPLEX WITH INHIBITOR.
[7]	"Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors." Terasaka T., Kinoshita T., Kuno M., Seki N., Tanaka K., Nakanishi I. J. Med. Chem. 47:3730-3743(2004) [PubMed: 15239652] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 2-356 IN COMPLEX WITH INHIBITOR.
[8]	"Structural basis of compound recognition by adenosine deaminase." Kinoshita T., Nakanishi I., Terasaka T., Kuno M., Seki N., Warizaya M., Matsumura H., Inoue T., Takano K., Adachi H., Mori Y., Fujii T. Biochemistry 44:10562-10569(2005) [PubMed: 16060665] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 2-356 IN COMPLEX WITH INHIBITOR.
[9]	"Crystal structures of HIV-1 Tat-derived nonapeptides Tat-(1-9) and Trp2-Tat-(1-9) bound to the active site of dipeptidyl-peptidase IV (CD26)." Weihofen W.A., Liu J., Reutter W., Saenger W., Fan H. J. Biol. Chem. 280:14911-14917(2005) [PubMed: 15695814] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (3.15 ANGSTROMS) OF 2-362 IN COMPLEX WITH DPP4 AND A HIV-1 TAT PEPTIDE.
[10]	"Rational design of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors: predicting enzyme conformational change and metabolism." Terasaka T., Tsuji K., Kato T., Nakanishi I., Kinoshita T., Kato Y., Kuno M., Inoue T., Tanaka K., Nakamura K. J. Med. Chem. 48:4750-4753(2005) [PubMed: 16033254] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 2-356 IN COMPLEX WITH INHIBITOR AND ZINC IONS.
[11]	"Conformational change of adenosine deaminase during ligand-exchange in a crystal." Kinoshita T., Tada T., Nakanishi I. Biochem. Biophys. Res. Commun. 373:53-57(2008) [PubMed: 18549808] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.52 ANGSTROMS) OF 2-357 IN COMPLEX WITH EHNA.
+	Additional computationally mapped references.

Web resources

Worthington enzyme manual

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF280603 mRNA. Translation: AAF91430.1.

IPI

IPI00704185.

RefSeq

NP_776312.1. NM_173887.2.

UniGene

Bt.4303.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1KRM	X-ray	2.50	A	2-356	[»]
1NDV	X-ray	2.30	A	2-356	[»]
1NDW	X-ray	2.00	A	2-356	[»]
1NDY	X-ray	2.00	A	2-356	[»]
1NDZ	X-ray	2.00	A	2-356	[»]
1O5R	X-ray	2.35	A	2-356	[»]
1QXL	X-ray	2.25	A	2-356	[»]
1UML	X-ray	2.50	A	2-356	[»]
1V79	X-ray	2.50	A	2-356	[»]
1V7A	X-ray	2.50	A	2-356	[»]
1VFL	X-ray	1.80	A	2-356	[»]
1W1I	X-ray	3.03	E/F/G/H	1-357	[»]
1WXY	X-ray	2.50	A	2-356	[»]
1WXZ	X-ray	2.80	A	2-356	[»]
2BGN	X-ray	3.15	E/F/G/H	2-362	[»]
2E1W	X-ray	2.50	A	2-356	[»]
2Z7G	X-ray	2.52	A	2-357	[»]

ProteinModelPortal

P56658.

SMR

P56658. Positions 4-351.

ModBase

Search...

Protein-protein interaction databases

STRING

P56658.

Proteomic databases

PRIDE

P56658.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

GeneID

280712.

KEGG

bta:280712.

Organism-specific databases

CTD

100.

Phylogenomic databases

eggNOG

maNOG09219.

GeneTree

ENSGT00510000047600.

HOVERGEN

HBG001718.

InParanoid

P56658.

OrthoDB

EOG40K808.

PhylomeDB

P56658.

Family and domain databases

InterPro

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

KO

K01488.

PANTHER

PTHR11409:SF21. PTHR11409:SF21. 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

DrugBank

DB00061. Pegademase bovine.

Entry information

Entry name

ADA_BOVIN

Accession

Primary (citable) accession number: P56658
Secondary accession number(s): Q9MYY1

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	January 23, 2007
Last modified:	December 14, 2011
This is version 89 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program