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(biochemistry) a nucleoside that is a structural component of nucleic acids; it is present in all living cells in a combined form as a constituent of DNA and RNA and ADP and ATP and AMP

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/04 02:19:18」(JST)

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Adenosine deaminase (editase) domain

Identifiers

Symbol

A_deamin

Pfam

PF02137

InterPro

IPR002466

PROSITE

PDOC00419

SCOP

1add

SUPERFAMILY

1add

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

Adenosine/AMP deaminase N-terminal

Identifiers

Symbol

A_deaminase_N

Pfam

PF08451

InterPro

IPR013659

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure 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.^[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 hydroxyl 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

Two proposed mechanisms exist for ADA-catalyzed deamination: 1) stereospecific addition-elimination via tetrahedral intermediate or 2) an S_N2 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).^[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.

References

^ ^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): 1278–1284. doi:10.1126/science.1925539. PMID 1925539.
^ ^a ^b ^c ^d ^e ^f 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.
^ Daddona PE, Kelley WN (Jan 1977). "Human adenosine deaminase. Purification and subunit structure". The Journal of Biological Chemistry 252 (1): 110–115. PMID 13062.
^ ^a ^b 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.
^ 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.
^ 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.
^ 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.
^ 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. PMID 25681585.
^ 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.
^ ^a ^b 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ ^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. doi:10.1073/pnas.75.1.446. PMC 411266. PMID 24216.
^ 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.
^ 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.
^ 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.

External links

ADA human gene location in the UCSC Genome Browser.
ADA human gene details in the UCSC Genome Browser.

Molecular and Cellular Biology portal

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 成人における胸水の診断的評価：初期検査 diagnostic evaluation of a pleural effusion in adults initial testing
2. アデノシンデアミナーゼ欠損症：病因、臨床症状、および診断 adenosine deaminase deficiency pathogenesis clinical manifestations and diagnosis
3. アデノシンデアミナーゼ欠損症：治療 adenosine deaminase deficiency treatment
4. 結核性腹膜炎 tuberculous peritonitis
5. HIV陰性患者における結核性胸水 tuberculous pleural effusions in hiv negative patients

English Journal

Dual Effect of Adenosine A1 Receptor Activation on Renal O2 Consumption.

Babich V1,2,3, Vadnagara K2, Di Sole F1,2,3.
Journal of cellular physiology.J Cell Physiol.2015 Dec;230(12):3093-104. doi: 10.1002/jcp.25050.
The high requirement of O2 in the renal proximal tubule stems from a high rate of Na(+) transport. Adenosine A1 receptor (A1R) activation regulates Na(+) transport in this nephron segment. Thus, the effect of the acute activation and the mechanisms of A1R on the rate of O2 consumption were evaluated
PMID 26010290

Case-control study of ADARB1 and ADARB2 gene variants in migraine.

Gasparini CF1, Sutherland HG, Maher B, Rodriguez-Acevedo AJ, Khlifi E, Haupt LM, Griffiths LR.
The journal of headache and pain.J Headache Pain.2015 Dec;16:511. doi: 10.1186/s10194-015-0511-y. Epub 2015 Apr 3.
BACKGROUND: Migraine causes crippling attacks of severe head pain along with associated nausea, vomiting, photophobia and/or phonophobia. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in the adenosine deaminase, RNA-specific, B1 (ADARB1) and adenosine deaminase, RNA
PMID 25916332

A Five Years Study of Tuberculous Meningitis in Iran.

Hajia M1, Amirzargar AA2, Nazari M3, Razavi Davodi N3, Karami Zarandi M3.
Iranian journal of pathology.Iran J Pathol.2015 Fall;10(4):290-4.
BACKGROUND: Tuberculous meningitis (TBM) is a severe form of extra pulmonary tuberculosis with high mortality and morbidity rate in all age group patients specific in adults and children. The incidence and prevalence are not exactly known in Iran. In this study, we tried to evaluate the role of rapi
PMID 26351499

Japanese Journal

Different mechanisms of extracellular adenosine accumulation by reduction of the external Ca2+ concentration and inhibition of adenosine metabolism in spinal astrocytes

Journal of pharmacological sciences 128(1), 47-53, 2015-05
NAID 120005661436

P3-33-2 Adenosine deaminase活性値の測定と組織診断により,癌性腹膜炎と鑑別診断を行った結核性腹膜炎の2症例(Group135 感染症,一般演題,公益社団法人日本産科婦人科学会第67回学術講演会)

日本産科婦人科學會雜誌 67(2), 902, 2015-02-01
NAID 110009941778

局所麻酔下胸腔鏡検査にて確定診断が得られた胸水ADA低値高齢者結核性胸膜炎の1例

気管支学 : 日本気管支研究会雑誌 37(1), 76-81, 2015-01-25
NAID 110009922662

Related Pictures

★リンクテーブル★

リンク元	「アデノシンデアミナーゼ」「ADA」
拡張検索	「adenosine deaminase deficiency」
関連記事	「deaminase」

「アデノシンデアミナーゼ」

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

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

Adenosine deaminase
	Ribbon diagram of bovine adenosine deaminase. Zinc ion visible at center. From PDB: 1VFL
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1M7M, 3IAR
Identifiers
Symbol	ADA
External IDs	OMIM: 608958 MGI: 87916 HomoloGene: 37249 ChEMBL: 1910 GeneCards: ADA Gene
EC number	3.5.4.4
Gene ontology
Molecular function	• purine nucleoside binding; • adenosine deaminase activity; • protein binding; • zinc ion binding;
Cellular component	• extracellular space; • cytoplasm; • lysosome; • cytosol; • plasma membrane; • external side of plasma membrane; • cell surface; • membrane; • cell junction; • dendrite cytoplasm; • neuronal cell body; • cytoplasmic membrane-bounded vesicle lumen;
Biological process	• response to hypoxia; • histamine secretion; • trophectodermal cell differentiation; • liver development; • placenta development; • germinal center B cell differentiation; • positive regulation of germinal center formation; • negative regulation of leukocyte migration; • negative regulation of mature B cell apoptotic process; • purine nucleobase metabolic process; • adenosine catabolic process; • deoxyadenosine catabolic process; • aging; • purine ribonucleoside monophosphate biosynthetic process; • positive regulation of heart rate; • positive regulation of B cell proliferation; • purine nucleotide salvage; • positive regulation of T cell differentiation in thymus; • response to vitamin E; • regulation of cell-cell adhesion mediated by integrin; • T cell activation; • negative regulation of circadian sleep/wake cycle, non-REM sleep; • response to drug; • response to hydrogen peroxide; • purine-containing compound salvage; • hypoxanthine salvage; • response to morphine; • small molecule metabolic process; • positive regulation of smooth muscle contraction; • dATP catabolic process; • inosine biosynthetic process; • xanthine biosynthetic process; • positive regulation of alpha-beta T cell differentiation; • lung alveolus development; • Peyer's patch development; • embryonic digestive tract development; • negative regulation of inflammatory response; • positive regulation of calcium-mediated signaling; • positive regulation of T cell receptor signaling pathway; • nucleobase-containing small molecule metabolic process; • negative regulation of adenosine receptor signaling pathway; • negative regulation of penile erection; • negative regulation of thymocyte apoptotic process; • negative regulation of mucus secretion;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;