Summary: Adenosine-deaminase (editase) domain
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Adenosine deaminase Edit Wikipedia article
Ribbon diagram of bovine adenosine deaminase. Zinc ion visible at center. From PDB 1VFL
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
crystal structure of plasmodium yoelii adenosine deaminase (py02076)
|Adenosine deaminase (editase) domain|
|Adenosine/AMP deaminase N-terminal|
Adenosine deaminase (also known as adenosine aminhydrolase, or ADA) is an enzyme (EC 188.8.131.52) involved in purine metabolism. It is needed for the breakdown of adenosine from food and for the turnover of nucleic acids in tissues.
Present in virtually all mammalian cells, its primary function in humans is the development and maintenance of the immune system. However, the full physiological role of ADA is not yet completely understood.
ADA exists in both small form (as a monomer) and large form (as a dimer-complex). In the monomer form, the enzyme is a polypeptide chain, folded into eight strands of parallel α/β barrels, which surround a central deep pocket that is the active site. In addition to the eight central β-barrels and eight peripheral α-helices, ADA also contains five additional helices: residues 19-76 fold into three helices, located between β1 and α1 folds; and two antiparallel carboxy-terminal helices are located across the amino-terminal of the β-barrel.
The ADA active site contains a zinc ion, which is located in the deepest recess of the active site and coordinated by five atoms from His15, His17, His214, Asp295, and the substrate. Zinc is the only cofactor necessary for activity.
The substrate, adenosine, is stabilized and bound to the active site by nine hydrogen bonds. The carboxyl group of Glu217, roughly coplanar with the substrate purine ring, is in position to form a hydrogen bond with N1 of the substrate. The carboxyl group of Asp296, also coplanar with the substrate purine ring, forms hydrogen bond with N7 of the substrate. The NH group of Gly184 is in position to form a hydrogen bond with N3 of the substrate. Asp296 forms bonds both with the Zn2+ ion as well as with 6-OH of the substrate. His238 also hydrogen bonds to substrate 6-OH. The 3'-OH of the substrate ribose forms a hydrogen bond with Asp19, while the 5'-OH forms a hydrogen bond with His17. Two further hydrogen bonds are formed to water molecules, at the opening of the active site, by the 2'-OH and 3'-OH of the substrate.
Due to the recessing of the active inside the enzyme, the substrate once bound is almost completely sequestered from solvent. The surface exposure of the substrate to solvent when bound is 0.5% the surface exposure of the substrate in the free state.
Two proposed mechanism exist for ADA-catalyzed deamination: 1) stereospecific addition-elimination via tetrahedral intermediate or 2) an SN2 reaction. By either mechanism, Zn2+ as a strong electrophile activates a water molecule, which is deprotonated by the basic Asp295 to form the attacking hydroxide. His238 orients the water molecule and stabilizes the charge of the attacking hydroxide. Glu217 is protonated to donate a proton to N1 of the substrate.
Competitive inhibition has been observed for ADA, where the product inosine acts at the competitive inhibitor to enzymatic activity.
ADA is considered one of the key enzymes of purine metabolism. The enzyme has been found in bacteria, plants, invertebrates, vertebrates, and mammals, with high conservation of amino acid sequence. The high degree of amino acid sequence conservation suggests the crucial nature of ADA in the purine salvage pathway.
Primarily, ADA in humans is involved in the development and maintenance of the immune system. However, ADA association has also been observed with epithelial cell differentiation, neurotransmission, and gestation maintenance. It has also been proposed that ADA, in addition to adenosine breakdown, stimulates release of excitatory amino acids and is necessary to the coupling of A1 adenosine receptors and heterotrimeric G proteins.
Some mutations in the gene for adenosine deaminase cause it not to be expressed. The resulting deficiency is one cause of (SCID). Deficient levels of ADA have also been associated with pulmonary inflammation, thymic cell death, and defective T-cell receptor signaling.
Conversely, mutations causing this enzyme to be overexpressed are one cause of .
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). ADA1 is involved mostly in intracellular activity, and exists both in small form (monomer) and large form (dimer). The interconversion of small to large forms is regulated by a 'conversion factor' in the lung.
- ADA2 was first identified in human spleen. 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. ADA2 is found predominantly in the human plasma and serum, and exists solely as a monomer.
- ADAT (ADAT1, ADAT2, ADAT3) is a tRNA-specific ADA, changing the tRNA to allow for a wobble base pairing.
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.
Total plasma ADA can be measured using high performance liquid chromatography or 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. It is the absence of ADA1 that causes SCID.
- Wilson, D. K.; Rudolph, F. B.; Quiocho, F. A. (1991). "Atomic structure of adenosine deaminase complexed with a transition-state analog: Understanding catalysis and immunodeficiency mutations". Science 252 (5010): 1278–1284. doi:10.1126/science.1925539. PMID 1925539.
- Cristalli, G.; Costanzi, S.; Lambertucci, C.; Lupidi, G.; Vittori, S.; Volpini, R.; Camaioni, E. (2001). "Adenosine deaminase: Functional implications and different classes of inhibitors". Medicinal Research Reviews 21 (2): 105–128. doi:10.1002/1098-1128(200103)21:2<105::AID-MED1002>3.0.CO;2-U. PMID 11223861.
- Daddona, P. E.; Kelley, W. N. (1977). "Human adenosine deaminase. Purification and subunit structure". The Journal of Biological Chemistry 252 (1): 110–115. PMID 13062.
- Glader, B. E.; Backer, K.; Diamond, L. K. (1983). "Elevated Erythrocyte Adenosine Deaminase Activity in Congenital Hypoplastic Anemia". New England Journal of Medicine 309 (24): 1486–1490. doi:10.1056/NEJM198312153092404. PMID 6646173.
- Saboury, A. A.; Divsalar, A.; Jafari, G. A.; Moosavi-Movahedi, A. A.; Housaindokht, M. R.; Hakimelahi, G. H. (2002). "A product inhibition study on adenosine deaminase by spectroscopy and calorimetry". Journal of biochemistry and molecular biology 35 (3): 302–305. doi:10.5483/BMBRep.2002.35.3.302. PMID 12297022.
- Moriwaki, Y.; Yamamoto, T.; Higashino, K. (1999). "Enzymes involved in purine metabolism--a review of histochemical localization and functional implications". Histology and histopathology 14 (4): 1321–1340. PMID 10506947.
- 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.
- Blackburn, M. R.; Kellems, R. E. (2005). Adenosine Deaminase Deficiency: Metabolic Basis of Immune Deficiency and Pulmonary Inflammation. "Advances in Immunology Volume 86". Advances in immunology. Advances in Immunology 86: 1–41. doi:10.1016/S0065-2776(04)86001-2. ISBN 9780120044863. PMID 15705418.
- Apasov, S. G.; Blackburn, M. R.; Kellems, R. E.; Smith, P. T.; Sitkovsky, M. V. (2001). "Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling". Journal of Clinical Investigation 108 (1): 131–141. doi:10.1172/JCI10360. PMC 209335. PMID 11435465.
- 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.
- 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.
- Cowan, M. J.; Brady, R. O.; Widder, K. J. (1986). "Elevated erythrocyte adenosine deaminase activity in patients with acquired immunodeficiency syndrome". Proceedings of the National Academy of Sciences of the United States of America 83 (4): 1089–1091. doi:10.1073/pnas.83.4.1089. PMC 323016. PMID 3006027.
- Schrader, W. P.; Stacy, A. R. (1977). "Purification and subunit structure of adenosine deaminase from human kidney". The Journal of Biological Chemistry 252 (18): 6409–6415. PMID 893413.
- 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.
- 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.
- Schwartz's principles of surgery, 8th edition, self assessment and board review, chapter 18 question 16
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- ADA human gene location in the UCSC Genome Browser.
- ADA human gene details in the UCSC Genome Browser.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Adenosine-deaminase (editase) domain Provide feedback
Adenosine deaminases acting on RNA (ADARs) can deaminate adenosine to form inosine. In long double-stranded RNA, this process is non-specific; it occurs site-specifically in RNA transcripts. The former is important in defence against viruses, whereas the latter may affect splicing or untranslated regions. They are primarily nuclear proteins, but a longer isoform of ADAR1 is found predominantly in the cytoplasm. ADARs are derived from the Tad1-like tRNA deaminases that are present across eukaryotes. These in turn belong to the nucleotide/nucleic acid deaminase superfamily and are characterized by a distinct insert between the two conserved cysteines that are involved in binding zinc .
Iyer LM, Zhang D, Rogozin IB, Aravind L;, Nucleic Acids Res. 2011; [Epub ahead of print]: Evolution of the deaminase fold and multiple origins of eukaryotic editing and mutagenic nucleic acid deaminases from bacterial toxin systems. PUBMED:21890906 EPMC:21890906
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002466Editase (EC) are enzymes that alter mRNA by catalyzing the site-selective deamination of adenosine residue into inosine residue. The editase domain contains the active site and binds three Zn atoms [PUBMED:9159072]. Several editases share a common global arrangement of domains, from N to C terminus: two 'double-stranded RNA-specific adenosine deaminase' (DRADA) repeat domains (INTERPRO), followed by three 'double-stranded RNA binding' (DsRBD) domains (INTERPRO), followed by the editase domain. Other editases have a simplified domains structure with no DRADA_REP and possibly fewer DSRBD domains. Editase that deaminate cytidine are not detected by this signature.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||RNA binding (GO:0003723)|
|adenosine deaminase activity (GO:0004000)|
|Biological process||RNA processing (GO:0006396)|
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This clan contains both free nucleotide and nucleic acid deaminases that act on adenosine, cytosine, guanine and cytidine, and are collectively known as the deaminase superfamily. The conserved fold consists of a three-layered alpha/beta/alpha structure with 3 helices and 4 strands in the 2134 order [1,2].This superfamily is further divided into two major divisions based on the presence of a helix (helix-4) that renders the terminal strands (strands 4 and 5) either parallel to each other in its presence, or anti-parallel in its absence . Structurally, the deaminase-like fold is present in four other superfamilies including the JAB-like metalloproteins, the C-terminal AICAR transformylase-catalyzing domains of PurH, Tm1506 and the formate dehydrogenase accessory subunit FdhD. The active site of the deaminases is composed of three residues that coordinate a zinc ion between conserved helices 2 and 3. The residues are typically found as [HCD]xE and CxxC motifs at the beginning of helices 2 and 3. The zinc ion activates a water molecule, which forms a tetrahderal intermediate with the carbon atom that is linked to the amine group. This is followed by deamination of the base.
The clan contains the following 16 members:A_deamin AICARFT_IMPCHas APOBEC_C APOBEC_N Bd3614-deam dCMP_cyt_deam_1 dCMP_cyt_deam_2 DYW_deaminase LmjF365940-deam MafB19-deam OTT_1508_deam Pput2613-deam SCP1201-deam Toxin-deaminase XOO_2897-deam YwqJ-deaminase
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Curation and family details
|Author:||Mian N, Bateman A, Iyer LM, Zhang D, Aravind L|
|Number in seed:||59|
|Number in full:||781|
|Average length of the domain:||308.00 aa|
|Average identity of full alignment:||27 %|
|Average coverage of the sequence by the domain:||55.17 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null --hand HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||13|
|Download:||download the raw HMM for this family|
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the A_deamin domain has been found. There are 2 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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