EzCatDB: M00200
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DB codeM00200
RLCP classification3.103.90020.1136 : Transfer
CATH domainDomain 1-.-.-.-
Domain 2-.-.-.-
Domain 33.30.70.1230 : Alpha-Beta PlaitsCatalytic domain
Domain 4-.-.-.-
Domain 53.30.70.1230 : Alpha-Beta PlaitsCatalytic domain
E.C.4.6.1.1
CSA1ab8
MACiEM0058

CATH domainRelated DB codes (homologues)
3.30.70.1230 : Alpha-Beta PlaitsM00201

Enzyme Name
UniProtKBKEGG

P30803P26769
Protein nameAdenylate cyclase type 5Adenylate cyclase type 2adenylate cyclase
adenylylcyclase
adenyl cyclase
3',5'-cyclic AMP synthetase
ATP diphosphate-lyase (cyclizing)
SynonymsEC 4.6.1.1
Adenylate cyclase type V
ATP pyrophosphate-lyase 5
Adenylyl cyclase 5
Ca(2+)-inhibitable adenylyl cyclase
EC 4.6.1.1
Adenylate cyclase type II
ATP pyrophosphate-lyase 2
Adenylyl cyclase 2
RefSeqNP_001161932.1 (Protein)
NM_001168460.1 (DNA/RNA sequence)
NP_112269.1 (Protein)
NM_031007.1 (DNA/RNA sequence)
PfamPF06327 (DUF1053)
PF00211 (Guanylate_cyc)
[Graphical view]
PF06327 (DUF1053)
PF00211 (Guanylate_cyc)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00230Purine metabolism

UniProtKB:Accession NumberP30803P26769
Entry nameADCY5_CANFAADCY2_RAT
ActivityATP = 3'',5''-cyclic AMP + diphosphate.ATP = 3'',5''-cyclic AMP + diphosphate.
Subunit

Subcellular locationMembrane, Multi-pass membrane protein.Membrane, Multi-pass membrane protein.
CofactorBinds 2 magnesium ions per subunit.Binds 2 magnesium ions per subunit (By similarity).

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00305C00002C00131C00575C00968C00013
CompoundMagnesiumATPdATP3',5'-Cyclic AMP3',5'-Cyclic dAMPPyrophosphate
Typedivalent metal (Ca2+, Mg2+)amine group,nucleotideamine group,nucleotideamine group,nucleotideamine group,nucleotidephosphate group/phosphate ion
ChEBI18420
15422
16284
17489
28074
29888
PubChem888
5957
15993
6076
188955
21961011
1023
              
1azsAUnboundUnboundUnboundUnboundUnboundUnbound
1cjkAAnalogue:_MG-_MNAnalogue:AGSUnboundUnboundUnboundUnbound
1cjtAAnalogue:_MG-_MNUnboundAnalogue:DADUnboundUnboundUnbound
1cjuABound:2x_MGUnboundAnalogue:DADUnboundUnboundUnbound
1cjvAAnalogue:_MG-_ZNUnboundAnalogue:DADUnboundUnboundUnbound
1cs4ABound:_MGUnboundUnboundUnboundUnboundBound:POP
1culABound:2x_MGUnboundUnboundUnboundUnboundAnalogue:3PO
1tl7AAnalogue:2x_MNAnalogue:ONMUnboundUnboundUnboundUnbound
1u0hABound:2x_MGAnalogue:ONMUnboundUnboundUnboundUnbound
2gvdAAnalogue:2x_MNAnalogue:128UnboundUnboundUnboundUnbound
2gvzAAnalogue:2x_MNAnalogue:ONAUnboundUnboundUnboundUnbound
1ab8AUnboundUnboundUnboundUnboundUnboundUnbound
1ab8BUnboundUnboundUnboundUnboundUnboundUnbound
1azsBUnboundUnboundUnboundUnboundUnboundUnbound
1cjkBUnboundUnboundUnboundUnboundUnboundUnbound
1cjtBUnboundUnboundUnboundUnboundUnboundUnbound
1cjuBUnboundUnboundUnboundUnboundUnboundUnbound
1cjvBUnboundUnboundUnboundUnboundUnboundUnbound
1cs4BUnboundUnboundUnboundUnboundAnalogue:101Unbound
1culBUnboundUnboundUnboundUnboundAnalogue:103Unbound
1tl7BUnboundUnboundUnboundUnboundUnboundUnbound
1u0hBUnboundUnboundUnboundUnboundUnboundUnbound
2gvdBUnboundUnboundUnboundUnboundUnboundUnbound
2gvzBUnboundUnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
literature [12]
pdbCatalytic residuesCofactor-binding residuescomment
           
1azsAARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
mutant V476M
1cjkAARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
1cjtAARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
1cjuAARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
1cjvAARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
1cs4AARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
1culAARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
1tl7AARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
1u0hAARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
2gvdAARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
2gvzAARG 484
ASP 396;ILE 397;ASP 440(Magnesium binding)
 
1ab8AARG 1029;        
 
invisible 1059-1073
1ab8BARG 1029;        
 
invisible 1059-1073
1azsBARG 1029;LYS 1065
 
 
1cjkBARG 1029;LYS 1065
 
 
1cjtBARG 1029;LYS 1065
 
 
1cjuBARG 1029;LYS 1065
 
 
1cjvBARG 1029;LYS 1065
 
 
1cs4BARG 1029;LYS 1065
 
 
1culBARG 1029;LYS 1065
 
 
1tl7BARG 1029;LYS 1065
 
 
1u0hBARG 1029;LYS 1065
 
 
2gvdBARG 1029;LYS 1065
 
 
2gvzBARG 1029;LYS 1065
 
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[9]p.33
[7]Fig.7, p.13419
[10]Fig.6, p1914-1915
[12]Fig.3, p.715-716
[14]Fig.4, p.196541
[15]p.237
[17]Fig.2, p.76003
[18]Fig.1, p.757-759

references
[1]
PubMed ID1525824
JournalCell
Year1992
Volume70
Pages869-72
AuthorsTang WJ, Gilman AG
TitleAdenylyl cyclases.
[2]
PubMed ID8418825
JournalAdv Second Messenger Phosphoprotein Res
Year1993
Volume27
Pages109-62
AuthorsDanchin A
TitlePhylogeny of adenylyl cyclases.
[3]
PubMed ID9048648
JournalCirc Res
Year1997
Volume80
Pages297-304
AuthorsIshikawa Y, Homcy CJ
TitleThe adenylyl cyclases as integrators of transmembrane signal transduction.
[4]
PubMed ID9346923
JournalJ Biol Chem
Year1997
Volume272
Pages27787-95
AuthorsDessauer CW, Gilman AG
TitleThe catalytic mechanism of mammalian adenylyl cyclase. Equilibrium binding and kinetic analysis of P-site inhibition.
[5]
PubMed ID9214499
JournalNature
Year1997
Volume388
Pages33-4
AuthorsArtymiuk PJ, Poirrette AR, Rice DW, Willett P
TitleA polymerase I palm in adenylyl cyclase?
[6]
CommentsX-RAY CRYSTALLOGRAPHY (2.58 ANGSTROMS) OF 871-1090.
Medline ID97222132
PubMed ID9069282
JournalNature
Year1997
Volume386
Pages247-53
AuthorsZhang G, Liu Y, Ruoho AE, Hurley JH
TitleStructure of the adenylyl cyclase catalytic core.
Related PDB1ab8
Related UniProtKBP26769
[7]
PubMed ID9391039
JournalProc Natl Acad Sci U S A
Year1997
Volume94
Pages13414-9
AuthorsLiu Y, Ruoho AE, Rao VD, Hurley JH
TitleCatalytic mechanism of the adenylyl and guanylyl cyclases: modeling and mutational analysis.
[8]
PubMed ID9098900
JournalProtein Sci
Year1997
Volume6
Pages903-8
AuthorsZhang G, Liu Y, Qin J, Vo B, Tang WJ, Ruoho AE, Hurley JH
TitleCharacterization and crystallization of a minimal catalytic core domain from mammalian type II adenylyl cyclase.
[9]
PubMed ID9417637
JournalScience
Year1997
Volume278
Pages1898-9
AuthorsBourne HR
TitlePieces of the true grail: a G protein finds its target.
[10]
CommentsX-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 870-1081 OF COMPLEX WITH G(S)-ALPHA.
Medline ID98072190
PubMed ID9417641
JournalScience
Year1997
Volume278
Pages1907-16
AuthorsTesmer JJ, Sunahara RK, Gilman AG, Sprang SR
TitleCrystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS.
Related PDB1azs
Related UniProtKBP26769,P30803
[11]
PubMed ID9819210
JournalBiochemistry
Year1998
Volume37
Pages16183-91
AuthorsMitterauer T, Hohenegger M, Tang WJ, Nanoff C, Freissmuth M
TitleThe C2 catalytic domain of adenylyl cyclase contains the second metal ion (Mn2+) binding site.
[12]
PubMed ID9914249
JournalCurr Opin Struct Biol
Year1998
Volume8
Pages713-9
AuthorsTesmer JJ, Sprang SR
TitleThe structure, catalytic mechanism and regulation of adenylyl cyclase.
[13]
PubMed ID9632695
JournalJ Biol Chem
Year1998
Volume273
Pages16332-8
AuthorsSunahara RK, Beuve A, Tesmer JJ, Sprang SR, Garbers DL, Gilman AG
TitleExchange of substrate and inhibitor specificities between adenylyl and guanylyl cyclases.
[14]
PubMed ID9677392
JournalJ Biol Chem
Year1998
Volume273
Pages19650-5
AuthorsZimmermann G, Zhou D, Taussig R
TitleMutations uncover a role for two magnesium ions in the catalytic mechanism of adenylyl cyclase.
[15]
PubMed ID9687563
JournalMol Pharmacol
Year1998
Volume54
Pages231-40
AuthorsTang WJ, Hurley JH
TitleCatalytic mechanism and regulation of mammalian adenylyl cyclases.
[16]
PubMed ID10600134
JournalBiochemistry
Year1999
Volume38
Pages16706-13
AuthorsTepe NM, Lorenz JN, Yatani A, Dash R, Kranias EG, Dorn GW 2nd, Liggett SB
TitleAltering the receptor-effector ratio by transgenic overexpression of type V adenylyl cyclase: enhanced basal catalytic activity and function without increased cardiomyocyte beta-adrenergic signalling.
[17]
PubMed ID10075642
JournalJ Biol Chem
Year1999
Volume274
Pages7599-602
AuthorsHurley JH
TitleStructure, mechanism, and regulation of mammalian adenylyl cyclase.
[18]
CommentsX-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 870-1081 OF COMPLEX WITH G(S)-ALPHA.
Medline ID99357873
PubMed ID10427002
JournalScience
Year1999
Volume285
Pages756-60
AuthorsTesmer JJ, Sunahara RK, Johnson RA, Gosselin G, Gilman AG, Sprang SR
TitleTwo-metal-Ion catalysis in adenylyl cyclase.
Related PDB1cjk,1cjt,1cju,1cjv
Related UniProtKBP26769,P30803
[19]
PubMed ID10354616
JournalTrends Pharmacol Sci
Year1999
Volume20
Pages205-10
AuthorsDessauer CW, Tesmer JJ, Sprang SR, Gilman AG
TitleThe interactions of adenylate cyclases with P-site inhibitors.
[20]
PubMed ID10101967
JournalTrends Pharmacol Sci
Year1999
Volume20
Pages66-73
AuthorsSimonds WF
TitleG protein regulation of adenylate cyclase.
[21]
CommentsX-ray crystallography
PubMed ID11087399
JournalBiochemistry
Year2000
Volume39
Pages14464-71
AuthorsTesmer JJ, Dessauer CW, Sunahara RK, Murray LD, Johnson RA, Gilman AG, Sprang SR
TitleMolecular basis for P-site inhibition of adenylyl cyclase.
Related PDB1cs4,1cul
[22]
PubMed ID11327830
JournalBiochemistry
Year2001
Volume40
Pages1702-9
AuthorsTan CM, Kelvin DJ, Litchfield DW, Ferguson SS, Feldman RD
TitleTyrosine kinase-mediated serine phosphorylation of adenylyl cyclase.
[23]
PubMed ID11535062
JournalBiochemistry
Year2001
Volume40
Pages10853-8
AuthorsWeitmann S, Schultz G, Kleuss C
TitleAdenylyl cyclase type II domains involved in Gbetagamma stimulation.
[24]
PubMed ID11461898
JournalJ Biol Chem
Year2001
Volume276
Pages35450-7
AuthorsWu GC, Lai HL, Lin YW, Chu YT, Chern Y
TitleN-glycosylation and residues Asn805 and Asn890 are involved in the functional properties of type VI adenylyl cyclase.
[25]
PubMed ID12372507
JournalBioorg Med Chem Lett
Year2002
Volume12
Pages3085-8
AuthorsLevy D, Marlowe C, Kane-Maguire K, Bao M, Cherbavaz D, Tomlinson J, Sedlock D, Scarborough R
TitleHydroxamate based inhibitors of adenylyl cyclase. Part 1: the effect of acyclic linkers on P-site binding.
[26]
PubMed ID12372508
JournalBioorg Med Chem Lett
Year2002
Volume12
Pages3089-92
AuthorsLevy D, Bao M, Tomlinson J, Scarborough R
TitleHydroxamate based inhibitors of adenylyl cyclase. Part 2: the effect of cyclic linkers on P-site binding.
[27]
PubMed ID12019229
JournalGenetics
Year2002
Volume161
Pages133-42
AuthorsMoorman C, Plasterk RH
TitleFunctional characterization of the adenylyl cyclase gene sgs-1 by analysis of a mutational spectrum in Caenorhabditis elegans.
[28]
PubMed ID12058044
JournalJ Biol Chem
Year2002
Volume277
Pages28823-9
AuthorsDessauer CW, Chen-Goodspeed M, Chen J
TitleMechanism of Galpha i-mediated inhibition of type V adenylyl cyclase.
[29]
PubMed ID12065575
JournalJ Biol Chem
Year2002
Volume277
Pages33139-47
AuthorsHu B, Nakata H, Gu C, De Beer T, Cooper DM
TitleA critical interplay between Ca2+ inhibition and activation by Mg2+ of AC5 revealed by mutants and chimeric constructs.
[30]
PubMed ID11877398
JournalJ Biol Chem
Year2002
Volume277
Pages15721-8
AuthorsLin TH, Lai HL, Kao YY, Sun CN, Hwang MJ, Chern Y
TitleProtein kinase C inhibits type VI adenylyl cyclase by phosphorylating the regulatory N domain and two catalytic C1 and C2 domains.
[31]
PubMed ID11665600
JournalMethods Enzymol
Year2002
Volume345
Pages127-40
AuthorsHatley ME, Gilman AG, Sunahara RK
TitleExpression, purification, and assay of cytosolic (catalytic) domains of membrane-bound mammalian adenylyl cyclases.
[32]
PubMed ID11665605
JournalMethods Enzymol
Year2002
Volume345
Pages198-206
AuthorsTesmer JJ, Sunahara RK, Fancy DA, Gilman AG, Sprang SR
TitleCrystallization of complex between soluble domains of adenylyl cyclase and activated Gs alpha.
[33]
PubMed ID16766715
JournalMol Pharmacol
Year2006
Volume70
Pages878-86
AuthorsMou TC, Gille A, Suryanarayana S, Richter M, Seifert R, Sprang SR
TitleBroad specificity of mammalian adenylyl cyclase for interaction with 2',3'-substituted purine- and pyrimidine nucleotide inhibitors.
Related PDB1tl7,1u0h
[34]
PubMed ID15591060
JournalJ Biol Chem
Year2005
Volume280
Pages7253-61
AuthorsMou TC, Gille A, Fancy DA, Seifert R, Sprang SR
TitleStructural basis for the inhibition of mammalian membrane adenylyl cyclase by 2'(3')-O-(N-Methylanthraniloyl)-guanosine 5 '-triphosphate.
Related PDB2gvd,2gvz

comments
There is a variety of adenylyl cyclase enzymes. This enzyme belongs to Class-IV adenylyl cylcase family, which has two catalytic domains. The catalytic domains are homologous to each other, as well as to that of the class-III family.
This enzyme is composed of a short cytoplasmic N-terminal region, two repeats of a unit comprising a membrane-spanning region (M) and two cytoplasmic regions (C) (see [12], [17]). The membrane-spanning regions (M1 and M2) each contain six membrane-spanning helices. The two cytoplasmic regionns (C1 and C2) are subdivided into C1a and C1b; and C2a and C2b. The C1a and C2a are homologous to each other, and contain all of the catalytic apparatus, which heterodimerize with each other (see [12], [17]).
The heterodimer of the C1a and C2a domains has got one catalytic site, which binds one ATP molecule with two magnesium ions.
According to the literature [12] and [14], this enzyme catalyzes the same reaction as that of DNA polymerase, although it catalyzes an intra-molecular phosphoryl transfer reaction, instead of inter-molecular transfer reaction.
(1) The magnesium ion-A, which bound to Asp440, activate the 3'-hydroxyl group of ATP by lowering its pKa.
(2) The activated hydroxyl group makes a nucleophilic attack on alpha-phosphate group, leading to a pentavalent phosphate of the transtion-state.
(3) The transition-state of the alpha-phosphate is stabilized by Magnesium ion-A and Arg1029, whereas the leaving group, beta,gamma-phosphate groups, is stabilzed by the magnesium ion-B, which is bound to Asp440, Asp396 and mainchain carbonyl group of Ile397, as well as by Arg484 and Lys1065.

createdupdated
2004-04-122009-02-26
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 2008)
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)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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