Adenosine deaminase: Difference between revisions

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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details.
{{Infobox gene}}
-->{{PBB_Controls
{{Infobox protein family
| update_page = yes
| Symbol = A_deaminase
| require_manual_inspection = no
| Name = Adenosine/AMP deaminase
| update_protein_box = yes
| image = PDB 2amx EBI.jpg
| update_summary = no
| width =
| update_citations = yes
| caption = crystal structure of plasmodium yoelii adenosine deaminase (py02076)
| Pfam = PF00962
| Pfam_clan = CL0034
| InterPro = IPR001365
| SMART =
| PROSITE = PDOC00419
| MEROPS =
| SCOP = 1add
| TCDB =  
| OPM family =  
| OPM protein =  
| CAZy =  
| CDD =  
}}
}}
<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{Infobox protein family
{{GNF_Protein_box
| Symbol = A_deamin
| image = Adenosine deaminase 1VFL.png
| Name = Adenosine deaminase (editase) domain
| image_source = Ribbon diagram of [[cattle|bovine]] adenosine deaminase. [[Zinc]] ion visible at center. From {{PDB|1VFL}}
| image =  
| PDB = {{PDB2|1krm}}, {{PDB2|1ndv}}, {{PDB2|1ndw}}, {{PDB2|1ndy}}, {{PDB2|1ndz}}, {{PDB2|1o5r}}, {{PDB2|1qxl}}, {{PDB2|1uml}}, {{PDB2|1v79}}, {{PDB2|1v7a}}, {{PDB2|1vfl}}, {{PDB2|1w1i}}, {{PDB2|1wxy}}, {{PDB2|1wxz}}, {{PDB2|2bgn}}, {{PDB2|2e1w}}
| width =  
| Name = Adenosine deaminase
| caption = crystal structure of the catalytic domain of an adenosine deaminase that acts on rna (hadar2) bound to inositol hexakisphosphate (ihp)
| HGNCid = 186
| Pfam = PF02137
| Symbol = ADA
| Pfam_clan =   
| AltSymbols =;
| InterPro = IPR002466
| OMIM = 608958
| SMART =  
| ECnumber = 
| PROSITE = PDOC00419
| Homologene = 37249
| MEROPS =  
| MGIid = 87916
| SCOP = 1add
| GeneAtlas_image1 = PBB_GE_ADA_204639_at_tn.png
| TCDB =  
| GeneAtlas_image2 = PBB_GE_ADA_216705_s_at_tn.png
| OPM family =  
| Function = {{GNF_GO|id=GO:0004000 |text = adenosine deaminase activity}} {{GNF_GO|id=GO:0016787 |text = hydrolase activity}}
| OPM protein =  
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| CAZy =  
| Process = {{GNF_GO|id=GO:0006163 |text = purine nucleotide metabolic process}} {{GNF_GO|id=GO:0006955 |text = immune response}} {{GNF_GO|id=GO:0009168 |text = purine ribonucleoside monophosphate biosynthetic process}} {{GNF_GO|id=GO:0019735 |text = antimicrobial humoral response}}
| CDD =  
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 100
    | Hs_Ensembl = ENSG00000196839
    | Hs_RefseqProtein = NP_000013
    | Hs_RefseqmRNA = NM_000022
    | Hs_GenLoc_db =   
    | Hs_GenLoc_chr = 20
    | Hs_GenLoc_start = 42681577
    | Hs_GenLoc_end = 42713797
    | Hs_Uniprot = P00813
    | Mm_EntrezGene = 11486
    | Mm_Ensembl = ENSMUSG00000017697
    | Mm_RefseqmRNA = NM_007398
    | Mm_RefseqProtein = NP_031424
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 163418025
    | Mm_GenLoc_end = 163441618
    | Mm_Uniprot = Q4FJZ7
  }}
}}
}}
{{Infobox protein family
| Symbol = A_deaminase_N
| Name = Adenosine/AMP deaminase N-terminal
| image =
| width =
| caption = crystal structure of human adenosine deaminase growth factor, adenosine deaminase type 2 (ada2) complexed with transition state analogue, coformycin
| Pfam = PF08451
| Pfam_clan = 
| InterPro = IPR013659
| SMART =
| PROSITE =
| MEROPS =
| SCOP =
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}
'''''Adenosine deaminase''''' (also known as adenosine aminohydrolase, or '''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 acid]]s in tissues.
Its primary  function in humans is the development and maintenance of the immune system.<ref name="four">{{cite journal | vauthors = Wilson DK, Rudolph FB, Quiocho FA | title = Atomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations | journal = Science | volume = 252 | issue = 5010 | pages = 1278–1284 | date = May 1991 | pmid = 1925539 | doi = 10.1126/science.1925539 }}</ref> However, the full physiological role of ADA is not yet completely understood.<ref name="eight">{{cite journal | vauthors = Cristalli G, Costanzi S, Lambertucci C, Lupidi G, Vittori S, Volpini R, Camaioni E | title = Adenosine deaminase: functional implications and different classes of inhibitors | journal = Medicinal Research Reviews | volume = 21 | issue = 2 | pages = 105–128 | date = Mar 2001 | pmid = 11223861 | pmc =  | doi = 10.1002/1098-1128(200103)21:2<105::AID-MED1002>3.0.CO;2-U }}</ref>
== Structure ==


'''''Adenosine deaminase''''' (also known as '''ADA''') is an [[enzyme]] ({{EC number|3.5.4.4}}) involved in [[Purine#Metabolism|purine metabolism]]. It is needed for the breakdown of [[adenosine]] from food and for the turnover of [[nucleic acid]]s in tissues.
ADA exists in both small form (as a monomer) and large form (as a dimer-complex).<ref name="eight" /> In the monomer form, the enzyme is a polypeptide chain,<ref name="two">{{cite journal | vauthors = Daddona PE, Kelley WN | title = Human adenosine deaminase. Purification and subunit structure | journal = The Journal of Biological Chemistry | volume = 252 | issue = 1 | pages = 110–115 | date = Jan 1977 | pmid = 13062 }}</ref> folded into eight strands of parallel α/β barrels, which surround a central deep pocket that is the active site.<ref name="four" /> In addition to the eight central [[beta barrel|β-barrels]] and eight peripheral [[alpha helix|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.


==Reactions==
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.<ref name="four" /> Zinc is the only [[Cofactor (biochemistry)|cofactor]] necessary for activity.
ADA irreversibly deaminates adenosine, converting it to the related [[nucleoside]] [[inosine]] by the removal of an [[amino]] group.  


<gallery>
The substrate, adenosine, is stabilized and bound to the active site by nine hydrogen bonds.<ref name="four" /> 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 Zn<sup>2+</sup> 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.
Image:A chemical structure.png|[[Adenosine]]
 
Image:Inosine.svg|[[Inosine]] (observe missing nitrogen in upper left)
Due to the recessing of the active site inside the enzyme, the substrate, once bound, is almost completely sequestered from solvent.<ref name="four" /> The surface exposure of the substrate to solvent when bound is 0.5% the surface exposure of the substrate in the free state.
</gallery>
 
== Reactions ==
 
ADA irreversibly [[deamination|deaminates]] adenosine, converting it to the related [[nucleoside]] [[inosine]] by the substitution of the [[amino]] group for a keto group.
 
[[Image:Adenosin.svg|thumb|Adenosine]]
[[Image:Inosin.svg|thumb|Inosine]]


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


==Pathology==
== Mechanism of catalysis ==
Mutations in the gene for adenosine deaminase causing it to not be expressed are one cause of [[severe combined immunodeficiency]] (SCID).<ref name="pmid17181544">{{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}}</ref>


[[Mutation]]s causing it to be overexpressed are one cause of [[hemolytic anemia]].<ref name="pmid3029177">{{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=}}</ref>
Two proposed mechanisms exist for ADA-catalyzed deamination: 1) stereospecific addition-elimination via tetrahedral intermediate or 2) an S<sub>N</sub>2 reaction.<ref name = "eight"/><ref name = "five">{{cite journal | vauthors = Glader BE, Backer K, Diamond LK | title = Elevated erythrocyte adenosine deaminase activity in congenital hypoplastic anemia | journal = The New England Journal of Medicine | volume = 309 | issue = 24 | pages = 1486–1490 | date = Dec 1983 | pmid = 6646173 | pmc =  | doi = 10.1056/NEJM198312153092404 }}</ref> By either mechanism, Zn<sup>2+</sup> as a strong electrophile activates a water molecule, which is deprotonated by the basic Asp295 to form the attacking hydroxide.<ref name = "four"/> 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.


There is some evidence that a different allelle (ADA2) may lead to [[autism]].<ref name="pmid11121182">{{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=}}</ref>
The reaction is [[stereospecificity|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.<ref name = "four"/>


==Isoforms==
Competitive inhibition has been observed for ADA, where the product inosine acts at the competitive inhibitor to enzymatic activity.<ref name = "six">{{cite journal | vauthors = Saboury AA, Divsalar A, Jafari GA, Moosavi-Movahedi AA, Housaindokht MR, Hakimelahi GH | title = A product inhibition study on adenosine deaminase by spectroscopy and calorimetry | journal = Journal of Biochemistry and Molecular Biology | volume = 35 | issue = 3 | pages = 302–305 | date = May 2002 | pmid = 12297022 | doi = 10.5483/BMBRep.2002.35.3.302 }}</ref>
There are 2 [[isoforms]] of ADA: ADA1 and ADA2.  


* ADA1 is found in most body cells, particularly [[lymphocyte]]s and [[macrophage]]s, 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).
== Function ==


* ADA2 was first identified in human thymus. 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.
ADA is considered one of the key enzymes of purine metabolism.<ref name = "five"/> The enzyme has been found in bacteria, plants, invertebrates, vertebrates, and mammals, with [[conserved sequence|high conservation of amino acid sequence]].<ref name = "eight"/> The high degree of amino acid sequence conservation suggests the crucial nature of ADA in the purine salvage pathway.


* {{Gene|ADAR}} is an RNA-specific ADA.<ref>{{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}}</ref>
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 [[cellular differentiation|differentiation]], [[neurotransmission]], and [[gestation]] maintenance.<ref name = "seven">{{cite journal | vauthors = Moriwaki Y, Yamamoto T, Higashino K | title = Enzymes involved in purine metabolism--a review of histochemical localization and functional implications | journal = Histology and Histopathology | volume = 14 | issue = 4 | pages = 1321–1340 | date = Oct 1999 | pmid = 10506947 }}</ref> It has also been proposed that ADA, in addition to adenosine breakdown, stimulates release of [[excitatory amino acid]]s and is necessary to the coupling of A1 adenosine receptors and [[heterotrimeric G protein]]s.<ref name = "eight"/>  Adenosine deaminase deficiency leads to pulmonary fibrosis,<ref name="pmid12559769">{{cite journal | vauthors = Blackburn MR | title = Too much of a good thing: adenosine overload in adenosine-deaminase-deficient mice | journal = Trends in Pharmacological Sciences | volume = 24 | issue = 2 | pages = 66–70 | year = 2003 | pmid = 12559769 | doi = 10.1016/S0165-6147(02)00045-7 }}</ref> suggesting that chronic exposure to high levels of adenosine can exacerbate inflammation responses rather than suppressing them.  It has also been recognized that adenosine deaminase protein and activity is upregulated in mouse hearts that overexpress [[HIF1A|HIF-1 alpha]], which in part explains the attenuated levels of adenosine in HIF-1 alpha expressing hearts during [[ischemic]] stress.<ref name="pmid25681585">{{cite journal | vauthors = Wu J, Bond C, Chen P, Chen M, Li Y, Shohet RV, Wright G | title = HIF-1α in the heart: remodeling nucleotide metabolism | journal = Journal of Molecular and Cellular Cardiology | volume = 82 | issue = | pages = 194–200 | year = 2015 | pmid = 25681585 | doi = 10.1016/j.yjmcc.2015.01.014 | pmc=4405794}}</ref>


* ADAT ({{Gene|ADAT1}}, {{Gene|ADAT2}}, {{Gene|ADAT3}}) is a [[tRNA]]-specific ADA, changing the tRNA to allow for a [[Wobble base pair|wobble base pairing]].
== Pathology ==


==Clinical significance==
Some [[mutation]]s in the gene for adenosine deaminase cause it not to be expressed.  The resulting deficiency is one cause of {{SWL|type=mutation_results_in|target=severe combined immunodeficiency}} (SCID), particularly of autosomal recessive inheritance.<ref name="pmid17181544">{{cite journal | vauthors = 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 = Annals of Human Genetics | volume = 71 | issue = Pt 3 | pages = 336–47 | date = May 2007 | pmid = 17181544 | doi = 10.1111/j.1469-1809.2006.00338.x }}</ref> Deficient levels of ADA have also been associated with pulmonary inflammation, thymic cell death, and defective T-cell receptor signaling.<ref name = "pulmon">{{cite journal | vauthors = Blackburn MR, Kellems RE | title = Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation | journal = Advances in Immunology | volume = 86 | pages = 1–41 | year = 2005 | pmid = 15705418 | pmc =  | doi = 10.1016/S0065-2776(04)86001-2 | isbn = 9780120044863 | series = Advances in Immunology }}</ref><ref name = "thym">{{cite journal | vauthors = Apasov SG, Blackburn MR, Kellems RE, Smith PT, Sitkovsky MV | title = Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling | journal = The Journal of Clinical Investigation | volume = 108 | issue = 1 | pages = 131–141 | date = Jul 2001 | pmid = 11435465 | pmc = 209335 | doi = 10.1172/JCI10360 }}</ref>
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, [[EHNA|erythro-9-(2-hydroxy-3-nonyl) adenine]] (EHNA) is added prior to incubation so as to inhibit the enzymatic acivity of ADA1. It is the absence of ADA1 that causes SCID.
Conversely, mutations causing this enzyme to be overexpressed are one cause of {{SWL|target=hemolytic anemia|type=overexpression_results_in}}.<ref name="pmid3029177">{{cite journal | vauthors = 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 = The Journal of Clinical Investigation | volume = 79 | issue = 3 | pages = 1001–5 | date = Mar 1987 | pmid = 3029177 | pmc = 424261 | doi = 10.1172/JCI112866 }}</ref>


==See also==
There is some evidence that a different [[allele]] (ADA2) may lead to [[autism]].<ref name="pmid11121182">{{cite journal | vauthors = Persico AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S, Montecchi F, Palermo MT, Pascucci T, Puglisi-Allegra S, Reichelt KL, Conciatori M, Baldi A, Keller F | title = Adenosine deaminase alleles and autistic disorder: case-control and family-based association studies | journal = American Journal of Medical Genetics | volume = 96 | issue = 6 | pages = 784–90 | date = Dec 2000 | pmid = 11121182 | doi = 10.1002/1096-8628(20001204)96:6<784::AID-AJMG18>3.0.CO;2-7 }}</ref>
 
Elevated levels of ADA has also been associated with [[AIDS]].<ref name = "pulmon" /><ref name = "AIDS">{{cite journal | vauthors = Cowan MJ, Brady RO, Widder KJ | title = Elevated erythrocyte adenosine deaminase activity in patients with acquired immunodeficiency syndrome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 4 | pages = 1089–1091 | date = Feb 1986 | pmid = 3006027 | pmc = 323016 | doi = 10.1073/pnas.83.4.1089 }}</ref>
 
== Isoforms ==
 
There are 2 [[isoforms]] of ADA: ADA1 and ADA2.
 
* ADA1 is found in most body cells, particularly [[lymphocyte]]s and [[macrophage]]s, 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).<ref name="eight"/> The interconversion of small to large forms is regulated by a 'conversion factor' in the lung.<ref name = "three">{{cite journal | vauthors = Schrader WP, Stacy AR | title = Purification and subunit structure of adenosine deaminase from human kidney | journal = The Journal of Biological Chemistry | volume = 252 | issue = 18 | pages = 6409–6415 | date = Sep 1977 | pmid = 893413 }}</ref>
* ADA2 was first identified in human spleen.<ref name="pmid24216">{{cite journal | vauthors = 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 = Proceedings of the National Academy of Sciences of the United States of America | volume = 75 | issue = 1 | pages = 446–50 | date = Jan 1978 | pmid = 24216 | pmc = 411266 | doi = 10.1073/pnas.75.1.446 }}</ref> 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 homodimer.<ref name="pmid15926889">{{cite journal | vauthors = Zavialov AV, Engström A | title = Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity | journal = The Biochemical Journal | volume = 391 | issue = Pt 1 | pages = 51–57 | date = Oct 2005 | pmid = 15926889 | pmc = 1237138 | doi = 10.1042/BJ20050683 }}</ref>
 
== 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|date=June 2009}}
 
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, [[EHNA|erythro-9-(2-hydroxy-3-nonyl) adenine]] (EHNA) is added prior to incubation so as to inhibit the enzymatic activity of ADA1.<ref name="pmid24216" /> It is the absence of ADA1 that causes [[Severe combined immunodeficiency|SCID]].
 
ADA can also be used in the workup of lymphocytic [[pleural effusion]]s or [[Ascites|peritoneal ascites]], in that such specimens with low ADA levels essentially excludes tuberculosis from consideration.<ref name="pmid12608433">{{cite journal | vauthors = Jiménez Castro D, Díaz Nuevo G, Pérez-Rodríguez E, Light RW | title = Diagnostic value of adenosine deaminase in nontuberculous lymphocytic pleural effusions | journal = Eur. Respir. J. | volume = 21 | issue = 2 | pages = 220–4 | year = 2003 | pmid = 12608433 | doi = 10.1183/09031936.03.00051603 | url = http://erj.ersjournals.com/content/21/2/220.full.pdf }}</ref>
 
[[Tuberculosis]] pleural effusions can now be diagnosed accurately by increased levels of pleural fluid adenosine deaminase, above 40 U per liter.<ref>{{cite book | first1 = F. | last1 = Brunicardi | first2 = Dana | last2 = Andersen | first3 = Timothy | last3 = Billiar | first4 = David | last4 = Dunn | first5 = John | last5 = Hunter | first6 = Raphael E. | last6 = Pollock  | title = Schwartz's principles of surgery | date = 2005 | publisher = McGraw-Hill Professional | location = New York | isbn = 978-0071410908 | edition = 8th | chapter = Chapter 18, question 16 | name-list-format = vanc }}</ref>
 
[[Cladribine]] is an anti-neoplastic agent used in the treatment of [[hairy cell leukemia]]; its mechanism of action is inhibition of adenosine deaminase.
 
[[Coformycin]] was also described as a [[adenosine deaminase inhibitor]] but is alleged to be an antibiotic.
 
== See also ==
* [[Adenosine deaminase deficiency]]
* [[Adenosine deaminase deficiency]]
* [[ADAR]], a human gene encoding a RNA-specific adenosine deaminase


==References==
== References ==
{{reflist|2}}
{{Reflist|33em}}
==Further reading==
 
{{refbegin | 2}}
== Further reading ==
{{PBB_Further_reading
{{refbegin|33em}}
| citations =
* {{cite journal | vauthors = 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=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 | vauthors = Franco R, Casadó V, Ciruela F, Saura C, Mallol J, Canela EI, Lluis C | title = Cell surface adenosine deaminase: much more than an ectoenzyme | journal = Progress in Neurobiology | volume = 52 | issue = 4 | pages = 283–94 | date = Jul 1997 | pmid = 9247966 | doi = 10.1016/S0301-0082(97)00013-0 }}
*{{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= }}
* {{cite journal | vauthors = Valenzuela A, Blanco J, Callebaut C, Jacotot E, Lluis C, Hovanessian AG, Franco R | title = HIV-1 envelope gp120 and viral particles block adenosine deaminase binding to human CD26 | journal = Advances in Experimental Medicine and Biology | volume = 421 | issue =  | pages = 185–92 | year = 1997 | pmid = 9330696 | doi = 10.1007/978-1-4757-9613-1_24 }}
*{{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 | vauthors = Moriwaki Y, Yamamoto T, Higashino K | title = Enzymes involved in purine metabolism--a review of histochemical localization and functional implications | journal = Histology and Histopathology | volume = 14 | issue = 4 | pages = 1321–40 | date = Oct 1999 | pmid = 10506947 | 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 | vauthors = 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 = Human Mutation | volume = 1 | issue = 2 | pages = 166–8 | year = 1993 | pmid = 1284479 | doi = 10.1002/humu.1380010214 }}
*{{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 | vauthors = Berkvens TM, van Ormondt H, Gerritsen EJ, Khan PM, van der Eb AJ | 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 | date = Aug 1990 | pmid = 1696926 | doi = 10.1016/0888-7543(90)90190-6 }}
*{{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= }}
* {{cite journal | vauthors = Aran JM, Colomer D, Matutes E, Vives-Corrons JL, Franco R | title = Presence of adenosine deaminase on the surface of mononuclear blood cells: immunochemical localization using light and electron microscopy | journal = The Journal of Histochemistry and Cytochemistry | volume = 39 | issue = 8 | pages = 1001–8 | date = Aug 1991 | pmid = 1856451 | doi = 10.1177/39.8.1856451 }}
*{{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 | vauthors = Bielat K, Tritsch GL | title = Ecto-enzyme activity of human erythrocyte adenosine deaminase | journal = Molecular and Cellular Biochemistry | volume = 86 | issue = 2 | pages = 135–42 | date = Apr 1989 | pmid = 2770711 | doi = 10.1007/BF00222613 }}
*{{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= }}
* {{cite journal | vauthors = 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 = The Journal of Clinical Investigation | volume = 83 | issue = 2 | pages = 497–501 | date = Feb 1989 | pmid = 2783588 | pmc = 303706 | doi = 10.1172/JCI113909 }}
*{{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= }}
* {{cite journal | vauthors = 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 = American Journal of Hematology | volume = 21 | issue = 1 | pages = 57–66 | date = Jan 1986 | pmid = 3010705 | doi = 10.1002/ajh.2830210108 }}
*{{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= }}
* {{cite journal | vauthors = Wiginton DA, Kaplan DJ, States JC, Akeson AL, Perme CM, Bilyk IJ, Vaughn AJ, Lattier DL, Hutton JJ | title = Complete sequence and structure of the gene for human adenosine deaminase | journal = Biochemistry | volume = 25 | issue = 25 | pages = 8234–44 | date = Dec 1986 | pmid = 3028473 | doi = 10.1021/bi00373a017 }}
*{{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= }}
* {{cite journal | vauthors = Akeson AL, Wiginton DA, Dusing MR, States JC, Hutton JJ | title = Mutant human adenosine deaminase alleles and their expression by transfection into fibroblasts | journal = The Journal of Biological Chemistry | volume = 263 | issue = 31 | pages = 16291–6 | date = Nov 1988 | pmid = 3182793 | doi =  }}
*{{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 | vauthors = 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 = British Journal of Haematology | volume = 68 | issue = 2 | pages = 165–8 | date = Feb 1988 | pmid = 3348976 | doi = 10.1111/j.1365-2141.1988.tb06184.x }}
*{{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= }}
* {{cite journal | vauthors = Petersen MB, Tranebjaerg L, Tommerup N, Nygaard P, Edwards H | title = New assignment of the adenosine deaminase gene locus to chromosome 20q13 X 11 by study of a patient with interstitial deletion 20q | journal = Journal of Medical Genetics | volume = 24 | issue = 2 | pages = 93–6 | date = Feb 1987 | pmid = 3560174 | pmc = 1049896 | doi = 10.1136/jmg.24.2.93 }}
*{{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 | vauthors = 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 = Molecular and Cellular Biology | volume = 5 | issue = 4 | pages = 762–7 | date = Apr 1985 | pmid = 3838797 | pmc = 366780 | 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 | vauthors = Valerio D, Duyvesteyn MG, Dekker BM, Weeda G, Berkvens TM, van der Voorn L, van Ormondt H, van der Eb AJ | title = Adenosine deaminase: characterization and expression of a gene with a remarkable promoter | journal = The EMBO Journal | volume = 4 | issue = 2 | pages = 437–43 | date = Feb 1985 | pmid = 3839456 | pmc = 554205 | 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 | vauthors = Bonthron DT, Markham AF, Ginsburg D, Orkin SH | title = Identification of a point mutation in the adenosine deaminase gene responsible for immunodeficiency | journal = The Journal of Clinical Investigation | volume = 76 | issue = 2 | pages = 894–7 | date = Aug 1985 | pmid = 3839802 | pmc = 423929 | doi = 10.1172/JCI112050 }}
*{{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= }}
* {{cite journal | vauthors = Daddona PE, Shewach DS, Kelley WN, Argos P, Markham AF, Orkin SH | title = Human adenosine deaminase. cDNA and complete primary amino acid sequence | journal = The Journal of Biological Chemistry | volume = 259 | issue = 19 | pages = 12101–6 | date = Oct 1984 | pmid = 6090454 | doi =  }}
*{{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 | vauthors = Valerio D, Duyvesteyn MG, Meera Khan P, Geurts van Kessel A, de Waard A, van der Eb AJ | title = Isolation of cDNA clones for human adenosine deaminase | journal = Gene | volume = 25 | issue = 2–3 | pages = 231–40 | date = Nov 1983 | pmid = 6198240 | doi = 10.1016/0378-1119(83)90227-5 }}
*{{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= }}
}}
{{refend}}
{{refend}}


[[Category:EC 3.5.4]]
== External links ==
* {{UCSC genome browser|ADA}}
* {{UCSC gene details|ADA}}


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{{PDB Gallery|geneid=100}}
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[[ja:アデノシンデアミナーゼ]]
[[Category:EC 3.5.4]]
[[pt:Adenosina deaminase]]
[[Category:Immunostimulants]]
[[Category:Enzymes]]

Revision as of 22:22, 20 May 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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UniProt

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View/Edit Human
Adenosine/AMP deaminase
File:PDB 2amx EBI.jpg
crystal structure of plasmodium yoelii adenosine deaminase (py02076)
Identifiers
SymbolA_deaminase
PfamPF00962
Pfam clanCL0034
InterProIPR001365
PROSITEPDOC00419
SCOP1add
SUPERFAMILY1add
Adenosine deaminase (editase) domain
Identifiers
SymbolA_deamin
PfamPF02137
InterProIPR002466
PROSITEPDOC00419
SCOP1add
SUPERFAMILY1add
Adenosine/AMP deaminase N-terminal
Identifiers
SymbolA_deaminase_N
PfamPF08451
InterProIPR013659

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.[1] However, the full physiological role of ADA is not yet completely understood.[2]

Structure

ADA exists in both small form (as a monomer) and large form (as a dimer-complex).[2] In the monomer form, the enzyme is a polypeptide chain,[3] folded into eight strands of parallel α/β barrels, which surround a central deep pocket that is the active site.[1] 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.[1] Zinc is the only cofactor necessary for activity.

The substrate, adenosine, is stabilized and bound to the active site by nine hydrogen bonds.[1] 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.[1] The surface exposure of the substrate to solvent when bound is 0.5% the surface exposure of the substrate in the free state.

Reactions

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

File:Adenosin.svg
Adenosine
File:Inosin.svg
Inosine

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

Mechanism of catalysis

Two proposed mechanisms exist for ADA-catalyzed deamination: 1) stereospecific addition-elimination via tetrahedral intermediate or 2) an SN2 reaction.[2][4] By either mechanism, Zn2+ as a strong electrophile activates a water molecule, which is deprotonated by the basic Asp295 to form the attacking hydroxide.[1] 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.[1]

Competitive inhibition has been observed for ADA, where the product inosine acts at the competitive inhibitor to enzymatic activity.[5]

Function

ADA is considered one of the key enzymes of purine metabolism.[4] The enzyme has been found in bacteria, plants, invertebrates, vertebrates, and mammals, with high conservation of amino acid sequence.[2] 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.[6] 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.[2] Adenosine deaminase deficiency leads to pulmonary fibrosis,[7] suggesting that chronic exposure to high levels of adenosine can exacerbate inflammation responses rather than suppressing them. It has also been recognized that adenosine deaminase protein and activity is upregulated in mouse hearts that overexpress HIF-1 alpha, which in part explains the attenuated levels of adenosine in HIF-1 alpha expressing hearts during ischemic stress.[8]

Pathology

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.[9] Deficient levels of ADA have also been associated with pulmonary inflammation, thymic cell death, and defective T-cell receptor signaling.[10][11]

Conversely, mutations causing this enzyme to be overexpressed are one cause of hemolytic anemia .[12]

There is some evidence that a different allele (ADA2) may lead to autism.[13]

Elevated levels of ADA has also been associated with AIDS.[10][14]

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). ADA1 is involved mostly in intracellular activity, and exists both in small form (monomer) and large form (dimer).[2] The interconversion of small to large forms is regulated by a 'conversion factor' in the lung.[15]
  • ADA2 was first identified in human spleen.[16] 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 homodimer.[17]

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 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.[16] 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.[18]

Tuberculosis pleural effusions can now be diagnosed accurately by increased levels of pleural fluid adenosine deaminase, above 40 U per liter.[19]

Cladribine is an anti-neoplastic agent used in the treatment of hairy cell leukemia; its mechanism of action is inhibition of adenosine deaminase.

Coformycin was also described as a adenosine deaminase inhibitor but is alleged to be an antibiotic.

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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): 1278–1284. doi:10.1126/science.1925539. PMID 1925539.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Cristalli G, Costanzi S, Lambertucci C, Lupidi G, Vittori S, Volpini R, Camaioni E (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.
  3. ↑ Daddona PE, Kelley WN (Jan 1977). "Human adenosine deaminase. Purification and subunit structure". The Journal of Biological Chemistry. 252 (1): 110–115. PMID 13062.
  4. ↑ 4.0 4.1 Glader BE, Backer K, Diamond LK (Dec 1983). "Elevated erythrocyte adenosine deaminase activity in congenital hypoplastic anemia". The New England Journal of Medicine. 309 (24): 1486–1490. doi:10.1056/NEJM198312153092404. PMID 6646173.
  5. ↑ 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): 302–305. doi:10.5483/BMBRep.2002.35.3.302. PMID 12297022.
  6. ↑ 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): 1321–1340. PMID 10506947.
  7. ↑ 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.
  8. ↑ Wu J, Bond C, Chen P, Chen M, Li Y, Shohet RV, Wright G (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.
  9. ↑ 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.
  10. ↑ 10.0 10.1 Blackburn MR, Kellems RE (2005). "Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation". Advances in Immunology. Advances in Immunology. 86: 1–41. doi:10.1016/S0065-2776(04)86001-2. ISBN 9780120044863. PMID 15705418.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ Persico AM, Militerni R, Bravaccio C, Schneider C, Melmed R, Trillo S, Montecchi F, Palermo MT, Pascucci T, Puglisi-Allegra S, Reichelt KL, Conciatori M, Baldi A, Keller F (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.
  14. ↑ 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): 1089–1091. doi:10.1073/pnas.83.4.1089. PMC 323016. PMID 3006027.
  15. ↑ Schrader WP, Stacy AR (Sep 1977). "Purification and subunit structure of adenosine deaminase from human kidney". The Journal of Biological Chemistry. 252 (18): 6409–6415. PMID 893413.
  16. ↑ 16.0 16.1 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. doi:10.1073/pnas.75.1.446. PMC 411266. PMID 24216.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ Brunicardi F, Andersen D, Billiar T, Dunn D, Hunter J, Pollock RE (2005). "Chapter 18, question 16". Schwartz's principles of surgery (8th ed.). New York: McGraw-Hill Professional. ISBN 978-0071410908.

Further reading

External links

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