EzCatDB: S00232

DB codeS00232
RLCP classification4.12.642320.458
5.201.2781500.453
CATH domainDomain 13.20.20.140Catalytic domain
E.C.3.5.4.4
CSA1a4l

CATH domainRelated DB codes (homologues)
3.20.20.140S00231,M00186,D00673,D00675,D00801,D00873,M00030,M00225,M00226

Enzyme Name
Swiss-protKEGG

P03958P56658
Protein nameAdenosine deaminaseAdenosine deaminaseadenosine deaminase
deoxyadenosine deaminase
SynonymsEC 3.5.4.4
Adenosine aminohydrolase
EC 3.5.4.4
Adenosine aminohydrolase

KEGG pathways
MAP codePathways
MAP00230Purine metabolism

Swiss-prot:Accession NumberP03958P56658
Entry nameADA_MOUSEADA_BOVIN
ActivityAdenosine + H(2)O = inosine + NH(3).Adenosine + H(2)O = inosine + NH(3).
Subunit

Subcellular location

Cofactor



CofactorsSubstratesProductsintermediates
KEGG-idC00038C00212C00001C00294C00014I00018
CompoundZincAdenosineH2OInosineNH36-Hydroxy-adenosine
Typeheavy metalamine group,nucleosideH2Oamide group,nucleosideamine group,organic ion
1a4lABound:_ZNUnbound
UnboundUnboundIntermediate-analogue:DCF
1a4lBBound:_ZNUnbound
UnboundUnboundIntermediate-analogue:DCF
1a4lCBound:_ZNUnbound
UnboundUnboundIntermediate-analogue:DCF
1a4lDBound:_ZNUnbound
UnboundUnboundIntermediate-analogue:DCF
1a4mABound:_ZNUnbound
UnboundUnboundIntermediate-analogue:PRH
1a4mBBound:_ZNUnbound
UnboundUnboundIntermediate-analogue:PRH
1a4mCBound:_ZNUnbound
UnboundUnboundIntermediate-analogue:PRH
1a4mDBound:_ZNUnbound
UnboundUnboundIntermediate-analogue:PRH
1addABound:_ZNAnalogue:1DABound:HOH 461UnboundUnboundUnbound
1fkwABound:_ZNAnalogue:PUR
UnboundUnboundUnbound
1fkxABound:_ZNUnbound
UnboundUnboundIntermediate-analogue:PRH
1uioABound:_ZNUnbound
UnboundUnboundIntermediate-analogue:HPR
1uipABound:_ZNAnalogue:PUR
UnboundUnboundUnbound
2adaABound:_ZNUnbound
UnboundUnboundIntermediate-analogue:HPR
1krmABound:_ZNUnbound
UnboundUnboundIntermediate-analogue:PRH
1ndvABound:_ZNUnbound
UnboundUnboundUnbound
1ndwABound:_ZNUnbound
UnboundUnboundUnbound
1ndyABound:_ZNUnbound
UnboundUnboundUnbound
1ndzABound:_ZNUnbound
UnboundUnboundUnbound
1o5rABound:_ZNUnbound
UnboundUnboundUnbound
1qxlABound:_ZNUnbound
UnboundUnboundUnbound
1umlABound:_ZNUnbound
UnboundUnboundUnbound
1v78ABound:_ZNUnbound
UnboundUnboundUnbound
1v79ABound:_ZNUnbound
UnboundUnboundUnbound
1v7aABound:_ZNUnbound
UnboundUnboundUnbound
1w1iEBound:_ZNUnbound
UnboundUnboundUnbound
1w1iFBound:_ZNUnbound
UnboundUnboundUnbound
1w1iGBound:_ZNUnbound
UnboundUnboundUnbound
1w1iHBound:_ZNUnbound
UnboundUnboundUnbound
2bgnEBound:_ZNUnbound
UnboundUnboundUnbound
2bgnFBound:_ZNUnbound
UnboundUnboundUnbound
2bgnGBound:_ZNUnbound
UnboundUnboundUnbound
2bgnHBound:_ZNUnbound
UnboundUnboundUnbound

Active-site residues
resource
literature [10], [12], [14], [15], [27]
pdbCatalytic residuesCofactor-binding residuescomment
1a4lAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1a4lBGLU  717;HIS  738;ASP  795
HIS  515;HIS  517;HIS  714;ASP  795(Zinc binding)

1a4lCGLU 1217;HIS 1238;ASP 1295
HIS 1015;HIS 1017;HIS 1214;ASP 1295(Zinc binding)

1a4lDGLU 1717;HIS 1738;ASP 1795
HIS 1515;HIS 1517;HIS 1714;ASP 1795(Zinc binding)

1a4mAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1a4mBGLU  717;HIS  738;ASP  795
HIS  515;HIS  517;HIS  714;ASP  795(Zinc binding)

1a4mCGLU 1217;HIS 1238;ASP 1295
HIS 1015;HIS 1017;HIS 1214;ASP 1295(Zinc binding)

1a4mDGLU 1717;HIS 1738;ASP 1795
HIS 1515;HIS 1517;HIS 1714;ASP 1795(Zinc binding)

1addAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1fkwAGLU  217;HIS  238;        
HIS   15;HIS   17;HIS  214;        (Zinc binding)
mutant D295E
1fkxAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)
mutant D296A
1uioAGLU  217;        ;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)
mutant H238A
1uipAGLU  217;        ;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)
mutant H238E
2adaAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1krmAGLU  214;HIS  235;ASP  292
HIS   12;HIS   14;HIS  211;ASP  292(Zinc binding)

1ndvAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1ndwAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1ndyAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1ndzAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1o5rAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1qxlAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1umlAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1v78AGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1v79AGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1v7aAGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1w1iEGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1w1iFGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1w1iGGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

1w1iHGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

2bgnEGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

2bgnFGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

2bgnGGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)

2bgnHGLU  217;HIS  238;ASP  295
HIS   15;HIS   17;HIS  214;ASP  295(Zinc binding)


References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[1]p.8455-8456
[2]p.7382-7383
[4]p.1246-1247
[6]Fig.4, p.1282-1283
[7]p.7364-7365
[10]Fig.3, p.1692-1693
[11]p.693
[12]

[13]Scheme 1
[14]Fig.1, p.7863, p.7871
[15]Fig.1, p.15027-15028
[19]p.4974-4975
[20]p.8322-8323
[22]p.2589-2590

references
[1]
PubMed ID3442668
JournalBiochemistry
Year1987
Volume26
Pages8450-7
AuthorsKurz LC, Frieden C
TitleAdenosine deaminase converts purine riboside into an analogue of a reactive intermediate: a 13C NMR and kinetic study.
[2]
PubMed ID3427079
JournalBiochemistry
Year1987
Volume26
Pages7378-84
AuthorsWeiss PM, Cook PF, Hermes JD, Cleland WW
TitleEvidence from nitrogen-15 and solvent deuterium isotope effects on the chemical mechanism of adenosine deaminase.
[3]
PubMed ID3398052
JournalJ Mol Biol
Year1988
Volume200
Pages613-4
AuthorsWilson DK, Rudolph FB, Harrison ML, Kellems RE, Quiocho FA
TitlePreliminary X-ray analysis of crystals of murine adenosine deaminase.
[4]
PubMed ID2713361
JournalBiochemistry
Year1989
Volume28
Pages1242-7
AuthorsJones W, Kurz LC, Wolfenden R
TitleTransition-state stabilization by adenosine deaminase: 1,6-addition of water to purine ribonucleoside, the enzyme's affinity for 6-hydroxy-1,6-dihydropurine ribonucleoside, and the effective concentration of substrate water at the active site.
[5]
PubMed ID2275794
JournalJ Biomol Struct Dyn
Year1990
Volume8
Pages199-212
AuthorsCox MB, Arjunan P, Arora SK
TitleStructural and conformational analysis of pentostatin (2'-deoxycoformycin), a potent inhibitor of adenosine deaminase.
[6]
CommentsX-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
Medline ID92022516
PubMed ID1925539
JournalScience
Year1991
Volume252
Pages1278-84
AuthorsWilson DK, Rudolph FB, Quiocho FA
TitleAtomic structure of adenosine deaminase complexed with a transition-state analog: understanding catalysis and immunodeficiency mutations.
Related PDB2ada
Related Swiss-protP03958
[7]
PubMed ID1510925
JournalBiochemistry
Year1992
Volume31
Pages7356-66
AuthorsKati WM, Acheson SA, Wolfenden R
TitleA transition state in pieces: major contributions of entropic effects to ligand binding by adenosine deaminase.
[8]
PubMed ID1731884
JournalBiochemistry
Year1992
Volume31
Pages39-48
AuthorsKurz LC, Moix L, Riley MC, Frieden C
TitleThe rate of formation of transition-state analogues in the active site of adenosine deaminase is encounter-controlled: implications for the mechanism.
[9]
PubMed ID1518061
JournalJ Mol Biol
Year1992
Volume226
Pages917-21
AuthorsSharff AJ, Wilson DK, Chang Z, Quiocho FA
TitleRefined 2.5 A structure of murine adenosine deaminase at pH 6.0.
[10]
CommentsX-ray crystallography
PubMed ID8439534
JournalBiochemistry
Year1993
Volume32
Pages1689-94
AuthorsWilson DK, Quiocho FA
TitleA pre-transition-state mimic of an enzyme: X-ray structure of adenosine deaminase with bound 1-deazaadenosine and zinc-activated water.
Related PDB1add
[11]
PubMed ID7634072
JournalNat Struct Biol
Year1994
Volume1
Pages691-4
AuthorsWilson DK, Quiocho FA
TitleCrystallographic observation of a trapped tetrahedral intermediate in a metalloenzyme.
[12]
PubMed ID8634299
JournalBiochemistry
Year1996
Volume35
Pages1672-80
AuthorsMohamedali KA, Kurz LC, Rudolph FB
TitleSite-directed mutagenesis of active site glutamate-217 in mouse adenosine deaminase.
[13]
PubMed ID8664259
JournalBiochemistry
Year1996
Volume35
Pages4697-703
AuthorsShih P, Wolfenden R
TitleEnzyme-substrate complexes of adenosine and cytidine deaminases: absence of accumulation of water adducts.
[14]
CommentsX-ray crystallography
PubMed ID8672487
JournalBiochemistry
Year1996
Volume35
Pages7862-72
AuthorsSideraki V, Mohamedali KA, Wilson DK, Chang Z, Kellems RE, Quiocho FA, Rudolph FB
TitleProbing the functional role of two conserved active site aspartates in mouse adenosine deaminase.
Related PDB1fkw,1fkx
[15]
CommentsX-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
Medline ID97098127
PubMed ID8942668
JournalBiochemistry
Year1996
Volume35
Pages15019-28
AuthorsSideraki V, Wilson DK, Kurz LC, Quiocho FA, Rudolph FB
TitleSite-directed mutagenesis of histidine 238 in mouse adenosine deaminase: substitution of histidine 238 does not impede hydroxylate formation.
Related PDB1uio,1uip
Related Swiss-protP03958
[16]
PubMed ID9442929
JournalBiochem Mol Biol Int
Year1997
Volume43
Pages1339-52
AuthorsLupidi G, Marmocchi F, Venardi G, Cristalli G
TitleFunctional residues at the active site of bovine brain adenosine deaminase.
[17]
PubMed ID9361033
JournalHum Mol Genet
Year1997
Volume6
Pages2271-8
AuthorsJiang C, Hong R, Horowitz SD, Kong X, Hirschhorn R
TitleAn adenosine deaminase (ADA) allele contains two newly identified deleterious mutations (Y97C and L106V) that interact to abolish enzyme activity.
[18]
PubMed ID9341908
JournalJ Med Chem
Year1997
Volume40
Pages3336-45
AuthorsGroziak MP, Huan ZW, Ding H, Meng Z, Stevens WC, Robinson PD
TitleEffect of a chemical modification on the hydrated adenosine intermediate produced by adenosine deaminase and a model reaction for a potential mechanism of action of 5-aminoimidazole ribonucleotide carboxylase.
[19]
PubMed ID9538015
JournalBiochemistry
Year1998
Volume37
Pages4968-76
AuthorsDeng H, Kurz LC, Rudolph FB, Callender R
TitleCharacterization of hydrogen bonding in the complex of adenosine deaminase with a transition state analogue: a Raman spectroscopic study.
[20]
CommentsX-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
Medline ID98285559
PubMed ID9622483
JournalBiochemistry
Year1998
Volume37
Pages8314-24
AuthorsWang Z, Quiocho FA
TitleComplexes of adenosine deaminase with two potent inhibitors: X-ray structures in four independent molecules at pH of maximum activity.
Related PDB1a4l,1a4m
Related Swiss-protP03958
[21]
PubMed ID9474762
JournalBiophys Chem
Year1998
Volume70
Pages41-56
AuthorsCaiolfa VR, Gill D, Parola AH
TitleProbing the active site of adenosine deaminase by a pH responsive fluorescent competitive inhibitor.
[22]
PubMed ID10704207
JournalBiochemistry
Year2000
Volume39
Pages2581-92
AuthorsFord H Jr, Dai F, Mu L, Siddiqui MA, Nicklaus MC, Anderson L, Marquez VE, Barchi JJ Jr
TitleAdenosine deaminase prefers a distinct sugar ring conformation for binding and catalysis: kinetic and structural studies.
[23]
PubMed ID10673097
JournalBioorg Med Chem Lett
Year2000
Volume10
Pages139-41
AuthorsTritsch D, Jung PM, Burger A, Biellmann JF
Title3'-Beta-ethynyl and 2'-deoxy-3'-beta-ethynyl adenosines: first 3'-beta-branched-adenosines substrates of adenosine deaminase.
[24]
PubMed ID12057661
JournalBioorg Med Chem
Year2002
Volume10
Pages2723-30
AuthorsHernandez S, Ford H Jr, Marquez VE
TitleIs the anomeric effect an important factor in the rate of adenosine deaminase catalyzed hydrolysis of purine nucleosides? A direct comparison of nucleoside analogues constructed on ribose and carbocyclic templates with equivalent heterocyclic bases selected to promote hydration.
[25]
PubMed ID11901152
JournalJ Biol Chem
Year2002
Volume277
Pages19720-6
AuthorsRichard E, Alam SM, Arredondo-Vega FX, Patel DD, Hershfield MS
TitleClustered charged amino acids of human adenosine deaminase comprise a functional epitope for binding the adenosine deaminase complexing protein CD26/dipeptidyl peptidase IV.
[26]
PubMed ID12437375
JournalJ Biomol Struct Dyn
Year2002
Volume20
Pages375-80
AuthorsAnderson E, Britt BM
TitleThe stability curve of bovine adenosine deaminase is bimodal.
[27]
CommentsX-ray crystallography
PubMed ID12554940
JournalActa Crystallogr D Biol Crystallogr
Year2003
Volume59
Pages299-303
AuthorsKinoshita T, Nishio N, Nakanishi I, Sato A, Fujii T
TitleStructure of bovine adenosine deaminase complexed with 6-hydroxy-1,6-dihydropurine riboside.
Related PDB1krm
[28]
PubMed ID12643924
JournalBioorg Med Chem Lett
Year2003
Volume13
Pages1115-8
AuthorsTerasaka T, Nakanishi I, Nakamura K, Eikyu Y, Kinoshita T, Nishio N, Sato A, Kuno M, Seki N, Sakane K
TitleStructure-based de novo design of non-nucleoside adenosine deaminase inhibitors.
[29]
CommentsX-ray crystallography
PubMed ID14709046
JournalJ Am Chem Soc
Year2004
Volume126
Pages34-5
AuthorsTerasaka T, Kinoshita T, Kuno M, Nakanishi I
TitleA highly potent non-nucleoside adenosine deaminase inhibitor: efficient drug discovery by intentional lead hybridization.
Related PDB1ndv,1ndw,1ndy,1ndz
[30]
CommentsX-ray crystallography
PubMed ID15213224
JournalJ Biol Chem
Year2004
Volume279
Pages43330-5
AuthorsWeihofen WA, Liu J, Reutter W, Saenger W, Fan H
TitleCrystal structure of CD26/dipeptidyl-peptidase IV in complex with adenosine deaminase reveals a highly amphiphilic interface.
Related PDB1w1i
[31]
CommentsX-ray crystallography
PubMed ID15239652
JournalJ Med Chem
Year2004
Volume47
Pages3730-43
AuthorsTerasaka T, Kinoshita T, Kuno M, Seki N, Tanaka K, Nakanishi I
TitleStructure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors.
Related PDB1o5r,1uml,1qxl
[32]
CommentsX-ray crystallography
PubMed ID15139750
JournalJ Med Chem
Year2004
Volume47
Pages2728-31
AuthorsTerasaka T, Okumura H, Tsuji K, Kato T, Nakanishi I, Kinoshita T, Kato Y, Kuno M, Seki N, Naoe Y, Inoue T, Tanaka K, Nakamura K
TitleStructure-based design and synthesis of non-nucleoside, potent, and orally bioavailable adenosine deaminase inhibitors.
Related PDB1v78,1v79,1v7a
[33]
CommentsX-ray crystallography
PubMed ID15695814
JournalJ Biol Chem
Year2005
Volume[Epub ahead of print]
Pages[Epub ahead of print]
AuthorsWeihofen WA, Liu J, Reutter W, Saenger W, Fan H
TitleCrystal structures of HIV-1 Tat derived nonapeptides Tat(1-9) and Trp2-Tat(1-9) bound to the active site of dipeptidyl peptidase IV (CD26).
Related PDB2bgn

comments
This enzyme belongs to the adenosine and AMP deaminase family.
This enzyme is homologous to guanine deaminase (EC 3.5.4.3; D00873 in EzCatDB) and cytosine deaminase (EC 3.5.4.1; D00675 in EzCatDB), sharing a similar catalytic site.
This enzyme catalyzes two successive reactions (as in cytidine deaminase (D00406 in EzCatDB), according to the literature [6], [10] & [20].
(A) Additive double-bond deformation; Addition of water to purine C6-carbon to form a tetrahedral intermediate (I00018).
(B) Eliminative double-bond formation; Elimination of amine group from the intermediate, forming a carbonyl group.
####
Although literature [10] suggested that His238 is a general base to activate the water in the first reaction (A), other papers gave the evidence against it. Instead of His238, Asp295 seems more likely base (see [6], [14] & [15]). Moreover, in the second reaction, some papers ([14] & [15]) suggested that His238 might act as a general acid to protonate the eliminated amine group, it is too distant from the group. Instead of the residue, hydrophobic cluster composed of Leu58, Phe61, Thr269 & Phe300 seems to facilitate the elimination (see [20]). However, these hydrophobic residues are not so conserved among the homologous enzymes (guanine deaminase and cytosine deaminase).
In analogy with cytosine deaminase (D00675 in EzCatDB), which adopts Fe2+ ion as cofactor, and guanine deaminase, which uses the same cofactor, zinc ion, as this enzyme, this enzyme may catalyzes the following reactions (addition and elimination):
(A) Additive double-bond deformation; Addition of water to purine C6-carbon, forming a tetrahedral intermediate (I00018):
(A1) Asp295 acts as a general base to deprotonate the Zinc-bound water. Here, the positive charge of His238 seems to stabilize the activated water.
(A2) The activated water makes a nucleophilic attack on the C6 atom, whilst Glu217 acts as a general acid to protonate the N1 atom (protonation site) of the purine. This reaction leads to the formation of tetrahedral intermediate at the C6 atom, transforming the N1-C6 bond from double bond to single bond (I00018).
(B) Eliminative double-bond formation; Elimination of amine group from the intermediate, forming a carbonyl group.
(B1) Asp295 acts as a general acid to protonate the eliminated amine group, releasing the ammonia.
(B2) Asp295 acts as a general base to deprotonate the hydroxyl group, bound to the zinc ion and His238. (Here, His238 may assist the catalytic function of Asp295 as well.) This reaction leads to the enol form of the product, inosine. (This may be an E1-like reaction, as amine elimination occurs prior to deprotonation.)

createdupdated
2005-03-222012-10-17
Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2010)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)

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