Adenosine deaminase

Adenosine deaminase (editase) domain
Identifiers
Symbol	A_deamin
Pfam	PF02137
InterPro	IPR002466
PROSITE	PDOC00419
SCOP	1add
SUPERFAMILY	1add
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

Adenosine/AMP deaminase
	crystal structure of plasmodium yoelii adenosine deaminase (py02076)
Identifiers
Symbol	A_deaminase
Pfam	PF00962
Pfam clan	CL0034
InterPro	IPR001365
PROSITE	PDOC00419
SCOP	1add
SUPERFAMILY	1add
Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

Adenosine deaminase
	; Ribbon diagram of bovine adenosine deaminase. Zinc ion visible at center. From PDB 1VFL
Available structures
PDB	1M7M, 3IAR , PDBe
Identifiers
Symbols	ADA;
External IDs	OMIM: 608958 MGI: 87916 HomoloGene: 37249 GeneCards: ADA Gene
EC number	3.5.4.4
Gene Ontology
Molecular function	• purine nucleoside binding; • adenosine deaminase activity; • adenosine deaminase activity; • adenosine deaminase activity; • protein binding; • zinc ion binding; • zinc ion binding; • hydrolase activity; • metal ion binding;
Cellular component	• extracellular space; • cytoplasm; • lysosome; • cytosol; • plasma membrane; • external side of plasma membrane; • cell surface; • membrane; • cell junction; • cytoplasmic vesicle; • dendrite cytoplasm; • neuronal cell body; • cytoplasmic membrane-bounded vesicle lumen;
Biological process	• response to hypoxia; • in utero embryonic development; • trophectodermal cell differentiation; • liver development; • placenta development; • germinal center B cell differentiation; • positive regulation of germinal center formation; • negative regulation of leukocyte migration; • negative regulation of mature B cell apoptosis; • purine base metabolic process; • adenosine catabolic process; • adenosine catabolic process; • deoxyadenosine catabolic process; • cell adhesion; • aging; • nucleotide metabolic process; • purine ribonucleoside monophosphate biosynthetic process; • positive regulation of heart rate; • positive regulation of B cell proliferation; • purine nucleotide salvage; • positive regulation of T cell differentiation in thymus; • regulation of cell-cell adhesion mediated by integrin; • T cell activation; • response to hydrogen peroxide; • negative regulation of apoptosis; • purine-containing compound salvage; • regulation of circadian sleep/wake cycle, sleep; • positive regulation of smooth muscle contraction; • dATP catabolic process; • hypoxanthine biosynthetic process; • inosine biosynthetic process; • inosine biosynthetic process; • xanthine biosynthetic process; • positive regulation of alpha-beta T cell differentiation; • lung alveolus development; • Peyer's patch development; • embryonic digestive tract development; • negative regulation of inflammatory response; • positive regulation of calcium-mediated signaling; • positive regulation of T cell receptor signaling pathway; • nucleobase, nucleoside and nucleotide metabolic process; • negative regulation of adenosine receptor signaling pathway; • negative regulation of penile erection; • negative regulation of thymocyte apoptosis; • negative regulation of mucus secretion;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs

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Adenosine/AMP deaminase N-terminal

Identifiers

Symbol

A_deaminase_N

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

Adenosine deaminase (also known as ADA) is an enzyme (EC 3.5.4.4) involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.

[edit] Reactions

ADA irreversibly deaminates adenosine, converting it to the related nucleoside inosine by the substitution of the amino group for a hydroxyl group.


Adenosine	Inosine

Inosine can then be deribosylated (removed from ribose) by another enzyme called purine nucleoside phosphorylase (PNP), converting it to hypoxanthine.

[edit] Pathology

Some mutations in the gene for adenosine deaminase cause it to be not expressed. The resulting deficiency is one cause of severe combined immunodeficiency (SCID).^[1]

Conversely, mutations causing this enzyme to be overexpressed are one cause of hemolytic anemia .^[2]

There is some evidence that a different allele (ADA2) may lead to autism.^[3]

[edit] Isoforms

There are 2 isoforms of ADA: ADA1 and ADA2.

ADA1 is found in most body cells, particularly lymphocytes and macrophages, where it is present not only in the cytosol and nucleus but also as the ecto- form on the cell membrane attached to dipeptidyl peptidase-4 (aka, CD26).

ADA2 was first identified in human spleen.^[4] It was subsequently found in other tissues including the macrophage where it co-exists with ADA1. The two isoforms regulate the ratio of adenosine to deoxyadenosine potentiating the killing of parasites.

ADAR is an RNA-specific ADA.^[5]

ADAT (ADAT1, ADAT2, ADAT3) is a tRNA-specific ADA, changing the tRNA to allow for a wobble base pairing.

[edit] Clinical significance

ADA2 is the predominant form present in human blood plasma and is increased in many diseases, particularly those associated with the immune system: for example rheumatoid arthritis, psoriasis and sarcoidosis. The plasma ADA2 isoform is also increased in most cancers. ADA2 is not ubiquitous but co-exists with ADA1 only in monocytes-macrophages.^{[citation needed]}

Total plasma ADA can be measured using high performance liquid chromatography, enzymatic or colorimetric techniques. Perhaps the simplest system is the measurement of the ammonia released from adenosine when broken down to inosine. After incubation of plasma with a buffered solution of adenosine the ammonia is reacted with a Berthelot reagent to form a blue colour which is proportionate to the amount of enzyme activity. To measure ADA2, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) is added prior to incubation so as to inhibit the enzymatic activity of ADA1[4]. It is the absence of ADA1 that causes SCID.

ADA can also be used in the workup of lymphocytic pleural effusions, in that such specimens with low ADA levels essentially excludes tuberculosis from consideration. ^[6] .

Tuberculosis pleural effusions can now be diagnosed accurately by increased levels of pleural fluid adenosine deaminase, above 40 U per liter.^[7]

[edit] See also

Adenosine deaminase deficiency

[edit] References

^ Sanchez JJ, Monaghan G, Børsting C, Norbury G, Morling N, Gaspar HB (2007). "Carrier frequency of a nonsense mutation in the adenosine deaminase (ADA) gene implies a high incidence of ADA-deficient severe combined immunodeficiency (SCID) in Somalia and a single, common haplotype indicates common ancestry". Ann. Hum. Genet. 71 (Pt 3): 336–47. doi:10.1111/j.1469-1809.2006.00338.x. PMID 17181544.
^ Chottiner EG, Cloft HJ, Tartaglia AP, Mitchell BS (1987). "Elevated adenosine deaminase activity and hereditary hemolytic anemia. Evidence for abnormal translational control of protein synthesis". J. Clin. Invest. 79 (3): 1001–5. doi:10.1172/JCI112866. PMC 424261. PMID 3029177. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=424261.
^ Persico AM, Militerni R, Bravaccio C, et al. (2000). "Adenosine deaminase alleles and autistic disorder: case-control and family-based association studies". Am. J. Med. Genet. 96 (6): 784–90. doi:10.1002/1096-8628(20001204)96:6<784::AID-AJMG18>3.0.CO;2-7. PMID 11121182.
^ Schrader WP, Pollara B, Meuwissen HJ (January 1978). "Characterization of the residual adenosine deaminating activity in the spleen of a patient with combined immunodeficiency disease and adenosine deaminase deficiency". Proc. Natl. Acad. Sci. U.S.A. 75 (1): 446–50. doi:10.1073/pnas.75.1.446. PMC 411266. PMID 24216. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=411266.
^ Keegan LP, Leroy A, Sproul D, O'Connell MA (2004). "Adenosine deaminases acting on RNA (ADARs): RNA-editing enzymes". Genome Biol. 5 (2): 209. doi:10.1186/gb-2004-5-2-209. PMC 395743. PMID 14759252. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=395743.
^ http://erj.ersjournals.com/cgi/content/abstract/21/2/220
^ Schwartz's principles of surgery, 8th edition, self assessment and board review, chapter 18 question 16

[edit] Further reading

da Cunha JG (1992). "[Adenosine deaminase. A pluridisciplinary enzyme]". Acta médica portuguesa 4 (6): 315–23. PMID 1807098.
Franco R, Casadó V, Ciruela F, et al. (1997). "Cell surface adenosine deaminase: much more than an ectoenzyme". Prog. Neurobiol. 52 (4): 283–94. doi:10.1016/S0301-0082(97)00013-0. PMID 9247966.
Valenzuela A, Blanco J, Callebaut C, et al. (1997). "HIV-1 envelope gp120 and viral particles block adenosine deaminase binding to human CD26". Adv. Exp. Med. Biol. 421: 185–92. PMID 9330696.
Moriwaki Y, Yamamoto T, Higashino K (1999). "Enzymes involved in purine metabolism--a review of histochemical localization and functional implications". Histol. Histopathol. 14 (4): 1321–40. PMID 10506947.
Hirschhorn R (1993). "Identification of two new missense mutations (R156C and S291L) in two ADA- SCID patients unusual for response to therapy with partial exchange transfusions". Hum. Mutat. 1 (2): 166–8. doi:10.1002/humu.1380010214. PMID 1284479.
Berkvens TM, van Ormondt H, Gerritsen EJ, et al. (1990). "Identical 3250-bp deletion between two AluI repeats in the ADA genes of unrelated ADA-SCID patients". Genomics 7 (4): 486–90. doi:10.1016/0888-7543(90)90190-6. PMID 1696926.
Aran JM, Colomer D, Matutes E, et al. (1991). "Presence of adenosine deaminase on the surface of mononuclear blood cells: immunochemical localization using light and electron microscopy". J. Histochem. Cytochem. 39 (8): 1001–8. PMID 1856451.
Bielat K, Tritsch GL (1989). "Ecto-enzyme activity of human erythrocyte adenosine deaminase". Mol. Cell. Biochem. 86 (2): 135–42. doi:10.1007/BF00222613. PMID 2770711.
Hirschhorn R, Tzall S, Ellenbogen A, Orkin SH (1989). "Identification of a point mutation resulting in a heat-labile adenosine deaminase (ADA) in two unrelated children with partial ADA deficiency". J. Clin. Invest. 83 (2): 497–501. doi:10.1172/JCI113909. PMC 303706. PMID 2783588. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=303706.
Murray JL, Perez-Soler R, Bywaters D, Hersh EM (1986). "Decreased adenosine deaminase (ADA) and 5'nucleotidase (5NT) activity in peripheral blood T cells in Hodgkin disease". Am. J. Hematol. 21 (1): 57–66. doi:10.1002/ajh.2830210108. PMID 3010705.
Wiginton DA, Kaplan DJ, States JC, et al. (1987). "Complete sequence and structure of the gene for human adenosine deaminase". Biochemistry 25 (25): 8234–44. doi:10.1021/bi00373a017. PMID 3028473.
Akeson AL, Wiginton DA, Dusing MR, et al. (1988). "Mutant human adenosine deaminase alleles and their expression by transfection into fibroblasts". J. Biol. Chem. 263 (31): 16291–6. PMID 3182793.
Glader BE, Backer K (1988). "Elevated red cell adenosine deaminase activity: a marker of disordered erythropoiesis in Diamond-Blackfan anaemia and other haematologic diseases". Br. J. Haematol. 68 (2): 165–8. doi:10.1111/j.1365-2141.1988.tb06184.x. PMID 3348976.
Petersen MB, Tranebjaerg L, Tommerup N, et al. (1987). "New assignment of the adenosine deaminase gene locus to chromosome 20q13 X 11 by study of a patient with interstitial deletion 20q". J. Med. Genet. 24 (2): 93–6. doi:10.1136/jmg.24.2.93. PMC 1049896. PMID 3560174. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1049896.
Orkin SH, Goff SC, Kelley WN, Daddona PE (1985). "Transient expression of human adenosine deaminase cDNAs: identification of a nonfunctional clone resulting from a single amino acid substitution". Mol. Cell. Biol. 5 (4): 762–7. PMC 366780. PMID 3838797. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=366780.
Valerio D, Duyvesteyn MG, Dekker BM, et al. (1985). "Adenosine deaminase: characterization and expression of a gene with a remarkable promoter". EMBO J. 4 (2): 437–43. PMC 554205. PMID 3839456. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=554205.
Bonthron DT, Markham AF, Ginsburg D, Orkin SH (1985). "Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency". J. Clin. Invest. 76 (2): 894–7. doi:10.1172/JCI112050. PMC 423929. PMID 3839802. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=423929.
Daddona PE, Shewach DS, Kelley WN, et al. (1984). "Human adenosine deaminase. cDNA and complete primary amino acid sequence". J. Biol. Chem. 259 (19): 12101–6. PMID 6090454.
Valerio D, Duyvesteyn MG, Meera Khan P, et al. (1984). "Isolation of cDNA clones for human adenosine deaminase". Gene 25 (2-3): 231–40. doi:10.1016/0378-1119(83)90227-5. PMID 6198240.