Adenosine deaminase

"Adenosine deaminase" (also known as ADA) is an enzyme (EC number|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.

Reactions

ADA irreversibly deaminates adenosine, converting it to the related nucleoside inosine by the removal of an amino group.

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

Pathology

Mutations in the gene for adenosine deaminase causing it to not be expressed are one cause of severe combined immunodeficiency (SCID).cite journal |author=Sanchez JJ, Monaghan G, Børsting C, Norbury G, Morling N, Gaspar HB |title=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 |journal=Ann. Hum. Genet. |volume=71 |issue=Pt 3 |pages=336–47 |year=2007 |pmid=17181544 |doi=10.1111/j.1469-1809.2006.00338.x]

Mutations causing it to be overexpressed are one cause of hemolytic anemia.cite journal |author=Chottiner EG, Cloft HJ, Tartaglia AP, Mitchell BS |title=Elevated adenosine deaminase activity and hereditary hemolytic anemia. Evidence for abnormal translational control of protein synthesis |journal=J. Clin. Invest. |volume=79 |issue=3 |pages=1001–5 |year=1987 |pmid=3029177 |doi=10.1172/JCI112866]

There is some evidence that a different allelle (ADA2) may lead to autism.cite journal |author=Persico AM, Militerni R, Bravaccio C, "et al" |title=Adenosine deaminase alleles and autistic disorder: case-control and family-based association studies |journal=Am. J. Med. Genet. |volume=96 |issue=6 |pages=784–90 |year=2000 |pmid=11121182 |doi=10.1002/1096-8628(20001204)96:6<784::AID-AJMG18>3.0.CO;2-7]

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.cite journal | author = Schrader WP, Pollara B, Meuwissen HJ | title = Characterization of the residual adenosine deaminating activity in the spleen of a patient with combined immunodeficiency disease and adenosine deaminase deficiency | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 75 | issue = 1 | pages = 446–50 | year = 1978 | month = January | pmid = 24216 | pmc = 411266 | doi = | url = | issn = ] 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.

* is an RNA-specific ADA. [cite journal |author=Keegan LP, Leroy A, Sproul D, O'Connell MA |title=Adenosine deaminases acting on RNA (ADARs): RNA-editing enzymes |journal=Genome Biol. |volume=5 |issue=2 |pages=209 |year=2004 |pmid=14759252 |doi=10.1186/gb-2004-5-2-209 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=395743]

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

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 AD2 isoform is also increased in most cancers.

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 acivity of ADA1 [4] . It is the absence of ADA1 that causes SCID.

ee also

* Adenosine deaminase deficiency
* ADAR, a human gene encoding a RNA-specific adenosine deaminase

References

Further reading

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

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