Adenosine deaminase (original) (raw)

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Mammalian protein found in Homo sapiens

ADA
Available structuresPDBOrtholog search: PDBe RCSB List of PDB id codes3IAR
Identifiers
Aliases ADA, entrez:100, Adenosine deaminase, ADA1
External IDs OMIM: 608958; MGI: 87916; HomoloGene: 37249; GeneCards: ADA; OMA:ADA - orthologs
Gene location (Human)Chromosome 20 (human)Chr.Chromosome 20 (human)[1]Chromosome 20 (human)Genomic location for ADAGenomic location for ADABand20q13.12Start44,584,896 bp[1]End44,652,252 bp[1]
Gene location (Mouse)Chromosome 2 (mouse)Chr.Chromosome 2 (mouse)[2]Chromosome 2 (mouse)Genomic location for ADAGenomic location for ADABand2 84.44 cM|2 H3Start163,568,504 bp[2]End163,592,159 bp[2]
RNA expression patternBgeeHuman Mouse (ortholog)Top expressed injejunal mucosaduodenumthymusgranulocytebody of stomachoocytesecondary oocyteright auricleapex of heartgastric mucosaTop expressed indeciduaduodenumesophagussuperior surface of tonguejejunumgastrulaintestinal villusthymuszygoteendothelial cell of lymphatic vesselMore reference expression dataBioGPSMore reference expression data
Gene ontologyMolecular function deaminase activity zinc ion binding metal ion binding hydrolase activity purine nucleoside binding protein binding adenosine deaminase activity Cellular component membrane cytoplasmic vesicle lumen cell surface cell junction soma dendrite cytoplasm cytoplasmic vesicle external side of plasma membrane extracellular space cytoplasm lysosome cytosol plasma membrane Biological process positive regulation of T cell differentiation histamine secretion negative regulation of circadian sleep/wake cycle, non-REM sleep purine nucleotide salvage positive regulation of T cell differentiation in thymus positive regulation of calcium-mediated signaling xanthine biosynthetic process response to hypoxia lung development placenta development deoxyadenosine catabolic process positive regulation of T cell receptor signaling pathway adenosine metabolic process purine-containing compound salvage dATP catabolic process ageing negative regulation of thymocyte apoptotic process negative regulation of apoptotic process in utero embryonic development negative regulation of mature B cell apoptotic process nucleotide metabolic process response to vitamin E positive regulation of heart rate negative regulation of adenosine receptor signaling pathway response to morphine regulation of cell-cell adhesion mediated by integrin T cell activation cell adhesion positive regulation of T cell activation positive regulation of B cell proliferation trophectodermal cell differentiation regulation of circadian sleep/wake cycle, sleep hypoxanthine biosynthetic process purine ribonucleoside monophosphate biosynthetic process germinal center B cell differentiation liver development lung alveolus development Peyer's patch development negative regulation of mucus secretion inosine biosynthetic process positive regulation of smooth muscle contraction negative regulation of inflammatory response negative regulation of leukocyte migration positive regulation of germinal center formation positive regulation of alpha-beta T cell differentiation embryonic digestive tract development negative regulation of penile erection regulation of T cell differentiation response to hydrogen peroxide adenosine catabolic process hypoxanthine salvage Sources:Amigo / QuickGO
OrthologsSpeciesHuman MouseEntrez10011486EnsemblENSG00000196839ENSMUSG00000017697UniProtP00813P03958RefSeq (mRNA)NM_000022NM_001322050NM_001322051NM_001272052NM_007398RefSeq (protein)NP_000013NP_001308979NP_001308980NP_001258981NP_031424Location (UCSC)Chr 20: 44.58 – 44.65 MbChr 2: 163.57 – 163.59 MbPubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Protein family

Adenosine/AMP deaminase
crystal structure of plasmodium yoelii adenosine deaminase (py02076)
Identifiers
Symbol A_deaminase
Pfam PF00962
Pfam clan CL0034
InterPro IPR001365
PROSITE PDOC00419
SCOP2 1add / SCOPe / SUPFAM
CDD cd01320
Available protein structures:Pfam structures / ECOD PDBRCSB PDB; PDBe; PDBjPDBsumstructure summary

Protein domain

Adenosine deaminase (editase) domain
Identifiers
Symbol A_deamin
Pfam PF02137
InterPro IPR002466
PROSITE PDOC00419
SCOP2 1add / SCOPe / SUPFAM
Available protein structures:Pfam structures / ECOD PDBRCSB PDB; PDBe; PDBjPDBsumstructure summary

Protein family

Adenosine/AMP deaminase N-terminal
Identifiers
Symbol A_deaminase_N
Pfam PF08451
InterPro IPR013659
Available protein structures:Pfam structures / ECOD PDBRCSB PDB; PDBe; PDBjPDBsumstructure summary

Adenosine deaminase (also known as adenosine aminohydrolase, or 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.

Its primary function in humans is the development and maintenance of the immune system.[5] However, the full physiological role of ADA is not yet completely understood.[6]

ADA exists in both small form (as a monomer) and large form (as a dimer-complex).[6] In the monomer form, the enzyme is a polypeptide chain,[7] folded into eight strands of parallel α/β barrels, which surround a central deep pocket that is the active site.[5] 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.[5] Zinc is the only cofactor necessary for activity.

The substrate, adenosine, is stabilized and bound to the active site by nine hydrogen bonds.[5] 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 site inside the enzyme, the substrate, once bound, is almost completely sequestered from solvent.[5] The surface exposure of the substrate to solvent when bound is 0.5% the surface exposure of the substrate in the free state.

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

Adenosine

Inosine

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

Mechanism of catalysis

[edit]

The proposed mechanism for ADA-catalyzed deamination is stereospecific addition-elimination via tetrahedral intermediate.[8] By either mechanism, Zn2+ as a strong electrophile activates a water molecule, which is deprotonated by the basic Asp295 to form the attacking hydroxide.[5] 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.

The reaction is stereospecific due to the location of the zinc, Asp295, and His238 residues, which all face the B-side of the purine ring of the substrate.[5]

Competitive inhibition has been observed for ADA, where the product inosine acts at the competitive inhibitor to enzymatic activity.[9]

ADA is considered one of the key enzymes of purine metabolism.[8] The enzyme has been found in bacteria, plants, invertebrates, vertebrates, and mammals, with high conservation of amino acid sequence.[6] 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.[10] 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.[6] Adenosine deaminase deficiency leads to pulmonary fibrosis,[11] suggesting that chronic exposure to high levels of adenosine can exacerbate inflammation responses rather than suppressing them. It has also been recognized that AMP deaminase protein and activity is upregulated in mouse hearts that overexpress HIF-1α,[12] which in part explains the attenuated levels of adenosine in HIF-1α expressing hearts during ischemic stress.[13]

In meiotic and post-meiotic male germ cells ADA2 regulates heterochromatin via translation of the MDC1 gene.[14]

Some mutations in the gene for adenosine deaminase cause it not to be expressed. The resulting deficiency is one cause of severe combined immunodeficiency (SCID), particularly of autosomal recessive inheritance.[15] Deficient levels of ADA have also been associated with pulmonary inflammation, thymic cell death, and defective T-cell receptor signaling.[16][17]

Conversely, mutations causing this enzyme to be overexpressed are one cause of hemolytic anemia.[18]

There is some evidence that a different allele (ADA2) may lead to autism.[19]

Elevated levels of ADA has also been associated with AIDS.[16][20]

There are 2 isoforms of ADA: ADA1 and ADA2.

Clinical significance

[edit]

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

ADA can also be used in the workup of lymphocytic pleural effusions or peritoneal ascites, in that such specimens with low ADA levels essentially excludes tuberculosis from consideration.[24]

Tuberculosis pleural effusions can now be diagnosed accurately by increased levels of pleural fluid adenosine deaminase, above 40 U per liter.[25]

Cladribine and Pentostatin are anti-neoplastic agents used in the treatment of hairy cell leukemia; their mechanism of action is inhibition of adenosine deaminase.

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000196839 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000017697 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d e f g Wilson DK, Rudolph FB, Quiocho FA (May 1991). "Atomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations". Science. 252 (5010): 1278–84. Bibcode:1991Sci...252.1278W. doi:10.1126/science.1925539. PMID 1925539.
  6. ^ a b c d e Cristalli G, Costanzi S, Lambertucci C, Lupidi G, Vittori S, Volpini R, et al. (Mar 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. S2CID 24003578.
  7. ^ Daddona PE, Kelley WN (Jan 1977). "Human adenosine deaminase. Purification and subunit structure". The Journal of Biological Chemistry. 252 (1): 110–5. doi:10.1016/S0021-9258(17)32805-3. PMID 13062.
  8. ^ a b Losey HC, Ruthenburg AJ, Verdine GL (Jan 2006). "Crystal structure of Staphylococcus aureus tRNA adenosine deaminase TadA in complex with RNA". Nature Structural & Molecular Biology. 13 (2): 153–9. doi:10.1038/nsmb1047. PMID 16415880. S2CID 34848284.
  9. ^ Saboury AA, Divsalar A, Jafari GA, Moosavi-Movahedi AA, Housaindokht MR, Hakimelahi GH (May 2002). "A product inhibition study on adenosine deaminase by spectroscopy and calorimetry". Journal of Biochemistry and Molecular Biology. 35 (3): 302–5. doi:10.5483/BMBRep.2002.35.3.302. PMID 12297022.
  10. ^ Moriwaki Y, Yamamoto T, Higashino K (Oct 1999). "Enzymes involved in purine metabolism--a review of histochemical localization and functional implications". Histology and Histopathology. 14 (4): 1321–40. PMID 10506947.
  11. ^ Blackburn MR (2003). "Too much of a good thing: adenosine overload in adenosine-deaminase-deficient mice". Trends in Pharmacological Sciences. 24 (2): 66–70. doi:10.1016/S0165-6147(02)00045-7. PMID 12559769.
  12. ^ Wu J (2014). "4. HIF-1α in the Heart: Remodeling of nucleotide metabolism leading to attenuation of adenosine accumulation during ischemic stress". HIF-1α in the Heart: Provision of Ischemic Cardioprotection and Remodeling of Nucleotide Metabolism (PDF) (PhD). Electronic Theses and Dissertations. East Tennessee State University. pp. 63–81. 2450.
  13. ^ Wu J, Bond C, Chen P, Chen M, Li Y, Shohet RV, et al. (2015). "HIF-1α in the heart: remodeling nucleotide metabolism". Journal of Molecular and Cellular Cardiology. 82: 194–200. doi:10.1016/j.yjmcc.2015.01.014. PMC 4405794. PMID 25681585.
  14. ^ Chukrallah LG, Badrinath A, Vittor GG, Snyder EM (February 2022). "ADAD2 regulates heterochromatin in meiotic and post-meiotic male germ cells via translation of MDC1". J Cell Sci. 135 (4): jcs259196. doi:10.1242/jcs.259196. PMC 8919335. PMID 35191498. (This paper currently has an expression of concern, see doi:10.1242/jcs.260435, PMID 35946499. If this is an intentional citation to a such a paper, please replace {{[expression of concern](/wiki/Template:Expression%5Fof%5Fconcern "Template:Expression of concern")|...}} with {{[expression of concern](/wiki/Template:Expression%5Fof%5Fconcern "Template:Expression of concern")|...|intentional=yes}}.)
  15. ^ Sanchez JJ, Monaghan G, Børsting C, Norbury G, Morling N, Gaspar HB (May 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". Annals of Human Genetics. 71 (Pt 3): 336–47. doi:10.1111/j.1469-1809.2006.00338.x. PMID 17181544. S2CID 34850391.
  16. ^ a b Blackburn MR, Kellems RE (2005). Adenosine Deaminase Deficiency: Metabolic Basis of Immune Deficiency and Pulmonary Inflammation. Advances in Immunology. Vol. 86. pp. 1–41. doi:10.1016/S0065-2776(04)86001-2. ISBN 978-0-12-004486-3. PMID 15705418.
  17. ^ Apasov SG, Blackburn MR, Kellems RE, Smith PT, Sitkovsky MV (Jul 2001). "Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling". The Journal of Clinical Investigation. 108 (1): 131–141. doi:10.1172/JCI10360. PMC 209335. PMID 11435465.
  18. ^ Chottiner EG, Cloft HJ, Tartaglia AP, Mitchell BS (Mar 1987). "Elevated adenosine deaminase activity and hereditary hemolytic anemia. Evidence for abnormal translational control of protein synthesis". The Journal of Clinical Investigation. 79 (3): 1001–5. doi:10.1172/JCI112866. PMC 424261. PMID 3029177.
  19. ^ Persico AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S, et al. (Dec 2000). "Adenosine deaminase alleles and autistic disorder: case-control and family-based association studies". American Journal of Medical Genetics. 96 (6): 784–90. doi:10.1002/1096-8628(20001204)96:6<784::AID-AJMG18>3.0.CO;2-7. PMID 11121182.
  20. ^ Cowan MJ, Brady RO, Widder KJ (Feb 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): 1089–91. Bibcode:1986PNAS...83.1089C. doi:10.1073/pnas.83.4.1089. PMC 323016. PMID 3006027.
  21. ^ Schrader WP, Stacy AR (Sep 1977). "Purification and subunit structure of adenosine deaminase from human kidney". The Journal of Biological Chemistry. 252 (18): 6409–15. doi:10.1016/S0021-9258(17)39973-8. PMID 893413.
  22. ^ a b Schrader WP, Pollara B, Meuwissen HJ (Jan 1978). "Characterization of the residual adenosine deaminating activity in the spleen of a patient with combined immunodeficiency disease and adenosine deaminase deficiency". Proceedings of the National Academy of Sciences of the United States of America. 75 (1): 446–50. Bibcode:1978PNAS...75..446S. doi:10.1073/pnas.75.1.446. PMC 411266. PMID 24216.
  23. ^ Zavialov AV, Engström A (Oct 2005). "Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity". The Biochemical Journal. 391 (Pt 1): 51–57. doi:10.1042/BJ20050683. PMC 1237138. PMID 15926889.
  24. ^ Jiménez Castro D, Díaz Nuevo G, Pérez-Rodríguez E, Light RW (2003). "Diagnostic value of adenosine deaminase in nontuberculous lymphocytic pleural effusions" (PDF). Eur. Respir. J. 21 (2): 220–4. doi:10.1183/09031936.03.00051603. PMID 12608433. S2CID 10703687.
  25. ^ Brunicardi F, Andersen D, Billiar T, Dunn D, Hunter J, Pollock RE (2005). "Chapter 18, question 16". Schwartz's principles of surgery (8th ed.). McGraw-Hill Professional. ISBN 978-0-07-141090-8.