DB code: M00200

RLCP classification 3.103.90020.1136 : Transfer
CATH domain -.-.-.- :
-.-.-.- :
3.30.70.1230 : Alpha-Beta Plaits Catalytic domain
-.-.-.- :
3.30.70.1230 : Alpha-Beta Plaits Catalytic domain
E.C. 4.6.1.1
CSA 1ab8
M-CSA 1ab8
MACiE M0058

CATH domain Related DB codes (homologues)
3.30.70.1230 : Alpha-Beta Plaits M00201

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P30803 Adenylate cyclase type 5
EC 4.6.1.1
Adenylate cyclase type V
ATP pyrophosphate-lyase 5
Adenylyl cyclase 5
Ca(2+)-inhibitable adenylyl cyclase
NP_001161932.1 (Protein)
NM_001168460.1 (DNA/RNA sequence)
PF06327 (DUF1053)
PF00211 (Guanylate_cyc)
[Graphical View]
P26769 Adenylate cyclase type 2
EC 4.6.1.1
Adenylate cyclase type II
ATP pyrophosphate-lyase 2
Adenylyl cyclase 2
NP_112269.1 (Protein)
NM_031007.1 (DNA/RNA sequence)
PF06327 (DUF1053)
PF00211 (Guanylate_cyc)
[Graphical View]

KEGG enzyme name
adenylate cyclase
adenylylcyclase
adenyl cyclase
3',5'-cyclic AMP synthetase
ATP diphosphate-lyase (cyclizing)

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P30803 ADCY5_CANFA ATP = 3'',5''-cyclic AMP + diphosphate. Membrane, Multi-pass membrane protein. Binds 2 magnesium ions per subunit.
P26769 ADCY2_RAT ATP = 3'',5''-cyclic AMP + diphosphate. Membrane, Multi-pass membrane protein. Binds 2 magnesium ions per subunit (By similarity).

KEGG Pathways
Map code Pathways E.C.
MAP00230 Purine metabolism

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00305 C00002 C00131 C00575 C00968 C00013
E.C.
Compound Magnesium ATP dATP 3',5'-Cyclic AMP 3',5'-Cyclic dAMP Pyrophosphate
Type divalent metal (Ca2+, Mg2+) amine group,nucleotide amine group,nucleotide amine group,nucleotide amine group,nucleotide phosphate group/phosphate ion
ChEBI 18420
 18420
 		15422
 15422
 		16284
 16284
 		17489
 17489
 		28074
 28074
 		29888
 29888
PubChem 888
 888
 		5957
 5957
 		15993
 15993
 		6076
 6076
 		188955
 188955
 		1023
 21961011
 1023
 21961011
1azsA Unbound Unbound Unbound Unbound Unbound Unbound
1cjkA Analogue:_MG-_MN Analogue:AGS Unbound Unbound Unbound Unbound
1cjtA Analogue:_MG-_MN Unbound Analogue:DAD Unbound Unbound Unbound
1cjuA Bound:2x_MG Unbound Analogue:DAD Unbound Unbound Unbound
1cjvA Analogue:_MG-_ZN Unbound Analogue:DAD Unbound Unbound Unbound
1cs4A Bound:_MG Unbound Unbound Unbound Unbound Bound:POP
1culA Bound:2x_MG Unbound Unbound Unbound Unbound Analogue:3PO
1tl7A Analogue:2x_MN Analogue:ONM Unbound Unbound Unbound Unbound
1u0hA Bound:2x_MG Analogue:ONM Unbound Unbound Unbound Unbound
2gvdA Analogue:2x_MN Analogue:128 Unbound Unbound Unbound Unbound
2gvzA Analogue:2x_MN Analogue:ONA Unbound Unbound Unbound Unbound
1ab8A Unbound Unbound Unbound Unbound Unbound Unbound
1ab8B Unbound Unbound Unbound Unbound Unbound Unbound
1azsB Unbound Unbound Unbound Unbound Unbound Unbound
1cjkB Unbound Unbound Unbound Unbound Unbound Unbound
1cjtB Unbound Unbound Unbound Unbound Unbound Unbound
1cjuB Unbound Unbound Unbound Unbound Unbound Unbound
1cjvB Unbound Unbound Unbound Unbound Unbound Unbound
1cs4B Unbound Unbound Unbound Unbound Analogue:101 Unbound
1culB Unbound Unbound Unbound Unbound Analogue:103 Unbound
1tl7B Unbound Unbound Unbound Unbound Unbound Unbound
1u0hB Unbound Unbound Unbound Unbound Unbound Unbound
2gvdB Unbound Unbound Unbound Unbound Unbound Unbound
2gvzB Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
literature [12]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1azsA ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding) mutant V476M
1cjkA ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
1cjtA ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
1cjuA ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
1cjvA ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
1cs4A ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
1culA ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
1tl7A ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
1u0hA ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
2gvdA ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
2gvzA ARG 484 ASP 396;ILE 397;ASP 440(Magnesium binding)
1ab8A ARG 1029; invisible 1059-1073
1ab8B ARG 1029; invisible 1059-1073
1azsB ARG 1029;LYS 1065
1cjkB ARG 1029;LYS 1065
1cjtB ARG 1029;LYS 1065
1cjuB ARG 1029;LYS 1065
1cjvB ARG 1029;LYS 1065
1cs4B ARG 1029;LYS 1065
1culB ARG 1029;LYS 1065
1tl7B ARG 1029;LYS 1065
1u0hB ARG 1029;LYS 1065
2gvdB ARG 1029;LYS 1065
2gvzB ARG 1029;LYS 1065

References for Catalytic Mechanism
References Sections No. 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.19654 1
[15]
p.237
[17]
Fig.2, p.7600 3
[18]
Fig.1, p.757-759

References
[1]
Resource
Comments
Medline ID
PubMed ID 1525824
Journal Cell
Year 1992
Volume 70
Pages 869-72
Authors Tang WJ, Gilman AG
Title Adenylyl cyclases.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 8418825
Journal Adv Second Messenger Phosphoprotein Res
Year 1993
Volume 27
Pages 109-62
Authors Danchin A
Title Phylogeny of adenylyl cyclases.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 9048648
Journal Circ Res
Year 1997
Volume 80
Pages 297-304
Authors Ishikawa Y, Homcy CJ
Title The adenylyl cyclases as integrators of transmembrane signal transduction.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 9346923
Journal J Biol Chem
Year 1997
Volume 272
Pages 27787-95
Authors Dessauer CW, Gilman AG
Title The catalytic mechanism of mammalian adenylyl cyclase. Equilibrium binding and kinetic analysis of P-site inhibition.
Related PDB
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 9214499
Journal Nature
Year 1997
Volume 388
Pages 33-4
Authors Artymiuk PJ, Poirrette AR, Rice DW, Willett P
Title A polymerase I palm in adenylyl cyclase?
Related PDB
Related UniProtKB
[6]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.58 ANGSTROMS) OF 871-1090.
Medline ID 97222132
PubMed ID 9069282
Journal Nature
Year 1997
Volume 386
Pages 247-53
Authors Zhang G, Liu Y, Ruoho AE, Hurley JH
Title Structure of the adenylyl cyclase catalytic core.
Related PDB 1ab8
Related UniProtKB P26769
[7]
Resource
Comments
Medline ID
PubMed ID 9391039
Journal Proc Natl Acad Sci U S A
Year 1997
Volume 94
Pages 13414-9
Authors Liu Y, Ruoho AE, Rao VD, Hurley JH
Title Catalytic mechanism of the adenylyl and guanylyl cyclases: modeling and mutational analysis.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 9098900
Journal Protein Sci
Year 1997
Volume 6
Pages 903-8
Authors Zhang G, Liu Y, Qin J, Vo B, Tang WJ, Ruoho AE, Hurley JH
Title Characterization and crystallization of a minimal catalytic core domain from mammalian type II adenylyl cyclase.
Related PDB
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 9417637
Journal Science
Year 1997
Volume 278
Pages 1898-9
Authors Bourne HR
Title Pieces of the true grail: a G protein finds its target.
Related PDB
Related UniProtKB
[10]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 870-1081 OF COMPLEX WITH G(S)-ALPHA.
Medline ID 98072190
PubMed ID 9417641
Journal Science
Year 1997
Volume 278
Pages 1907-16
Authors Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR
Title Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS.
Related PDB 1azs
Related UniProtKB P26769 P30803
[11]
Resource
Comments
Medline ID
PubMed ID 9819210
Journal Biochemistry
Year 1998
Volume 37
Pages 16183-91
Authors Mitterauer T, Hohenegger M, Tang WJ, Nanoff C, Freissmuth M
Title The C2 catalytic domain of adenylyl cyclase contains the second metal ion (Mn2+) binding site.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 9914249
Journal Curr Opin Struct Biol
Year 1998
Volume 8
Pages 713-9
Authors Tesmer JJ, Sprang SR
Title The structure, catalytic mechanism and regulation of adenylyl cyclase.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 9632695
Journal J Biol Chem
Year 1998
Volume 273
Pages 16332-8
Authors Sunahara RK, Beuve A, Tesmer JJ, Sprang SR, Garbers DL, Gilman AG
Title Exchange of substrate and inhibitor specificities between adenylyl and guanylyl cyclases.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 9677392
Journal J Biol Chem
Year 1998
Volume 273
Pages 19650-5
Authors Zimmermann G, Zhou D, Taussig R
Title Mutations uncover a role for two magnesium ions in the catalytic mechanism of adenylyl cyclase.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 9687563
Journal Mol Pharmacol
Year 1998
Volume 54
Pages 231-40
Authors Tang WJ, Hurley JH
Title Catalytic mechanism and regulation of mammalian adenylyl cyclases.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 10600134
Journal Biochemistry
Year 1999
Volume 38
Pages 16706-13
Authors Tepe NM, Lorenz JN, Yatani A, Dash R, Kranias EG, Dorn GW 2nd, Liggett SB
Title Altering the receptor-effector ratio by transgenic overexpression of type V adenylyl cyclase: enhanced basal catalytic activity and function without increased cardiomyocyte beta-adrenergic signalling.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 10075642
Journal J Biol Chem
Year 1999
Volume 274
Pages 7599-602
Authors Hurley JH
Title Structure, mechanism, and regulation of mammalian adenylyl cyclase.
Related PDB
Related UniProtKB
[18]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 870-1081 OF COMPLEX WITH G(S)-ALPHA.
Medline ID 99357873
PubMed ID 10427002
Journal Science
Year 1999
Volume 285
Pages 756-60
Authors Tesmer JJ, Sunahara RK, Johnson RA, Gosselin G, Gilman AG, Sprang SR
Title Two-metal-Ion catalysis in adenylyl cyclase.
Related PDB 1cjk 1cjt 1cju 1cjv
Related UniProtKB P26769 P30803
[19]
Resource
Comments
Medline ID
PubMed ID 10354616
Journal Trends Pharmacol Sci
Year 1999
Volume 20
Pages 205-10
Authors Dessauer CW, Tesmer JJ, Sprang SR, Gilman AG
Title The interactions of adenylate cyclases with P-site inhibitors.
Related PDB
Related UniProtKB
[20]
Resource
Comments
Medline ID
PubMed ID 10101967
Journal Trends Pharmacol Sci
Year 1999
Volume 20
Pages 66-73
Authors Simonds WF
Title G protein regulation of adenylate cyclase.
Related PDB
Related UniProtKB
[21]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 11087399
Journal Biochemistry
Year 2000
Volume 39
Pages 14464-71
Authors Tesmer JJ, Dessauer CW, Sunahara RK, Murray LD, Johnson RA, Gilman AG, Sprang SR
Title Molecular basis for P-site inhibition of adenylyl cyclase.
Related PDB 1cs4 1cul
Related UniProtKB
[22]
Resource
Comments
Medline ID
PubMed ID 11327830
Journal Biochemistry
Year 2001
Volume 40
Pages 1702-9
Authors Tan CM, Kelvin DJ, Litchfield DW, Ferguson SS, Feldman RD
Title Tyrosine kinase-mediated serine phosphorylation of adenylyl cyclase.
Related PDB
Related UniProtKB
[23]
Resource
Comments
Medline ID
PubMed ID 11535062
Journal Biochemistry
Year 2001
Volume 40
Pages 10853-8
Authors Weitmann S, Schultz G, Kleuss C
Title Adenylyl cyclase type II domains involved in Gbetagamma stimulation.
Related PDB
Related UniProtKB
[24]
Resource
Comments
Medline ID
PubMed ID 11461898
Journal J Biol Chem
Year 2001
Volume 276
Pages 35450-7
Authors Wu GC, Lai HL, Lin YW, Chu YT, Chern Y
Title N-glycosylation and residues Asn805 and Asn890 are involved in the functional properties of type VI adenylyl cyclase.
Related PDB
Related UniProtKB
[25]
Resource
Comments
Medline ID
PubMed ID 12372507
Journal Bioorg Med Chem Lett
Year 2002
Volume 12
Pages 3085-8
Authors Levy D, Marlowe C, Kane-Maguire K, Bao M, Cherbavaz D, Tomlinson J, Sedlock D, Scarborough R
Title Hydroxamate based inhibitors of adenylyl cyclase. Part 1: the effect of acyclic linkers on P-site binding.
Related PDB
Related UniProtKB
[26]
Resource
Comments
Medline ID
PubMed ID 12372508
Journal Bioorg Med Chem Lett
Year 2002
Volume 12
Pages 3089-92
Authors Levy D, Bao M, Tomlinson J, Scarborough R
Title Hydroxamate based inhibitors of adenylyl cyclase. Part 2: the effect of cyclic linkers on P-site binding.
Related PDB
Related UniProtKB
[27]
Resource
Comments
Medline ID
PubMed ID 12019229
Journal Genetics
Year 2002
Volume 161
Pages 133-42
Authors Moorman C, Plasterk RH
Title Functional characterization of the adenylyl cyclase gene sgs-1 by analysis of a mutational spectrum in Caenorhabditis elegans.
Related PDB
Related UniProtKB
[28]
Resource
Comments
Medline ID
PubMed ID 12058044
Journal J Biol Chem
Year 2002
Volume 277
Pages 28823-9
Authors Dessauer CW, Chen-Goodspeed M, Chen J
Title Mechanism of Galpha i-mediated inhibition of type V adenylyl cyclase.
Related PDB
Related UniProtKB
[29]
Resource
Comments
Medline ID
PubMed ID 12065575
Journal J Biol Chem
Year 2002
Volume 277
Pages 33139-47
Authors Hu B, Nakata H, Gu C, De Beer T, Cooper DM
Title A critical interplay between Ca2+ inhibition and activation by Mg2+ of AC5 revealed by mutants and chimeric constructs.
Related PDB
Related UniProtKB
[30]
Resource
Comments
Medline ID
PubMed ID 11877398
Journal J Biol Chem
Year 2002
Volume 277
Pages 15721-8
Authors Lin TH, Lai HL, Kao YY, Sun CN, Hwang MJ, Chern Y
Title Protein kinase C inhibits type VI adenylyl cyclase by phosphorylating the regulatory N domain and two catalytic C1 and C2 domains.
Related PDB
Related UniProtKB
[31]
Resource
Comments
Medline ID
PubMed ID 11665600
Journal Methods Enzymol
Year 2002
Volume 345
Pages 127-40
Authors Hatley ME, Gilman AG, Sunahara RK
Title Expression, purification, and assay of cytosolic (catalytic) domains of membrane-bound mammalian adenylyl cyclases.
Related PDB
Related UniProtKB
[32]
Resource
Comments
Medline ID
PubMed ID 11665605
Journal Methods Enzymol
Year 2002
Volume 345
Pages 198-206
Authors Tesmer JJ, Sunahara RK, Fancy DA, Gilman AG, Sprang SR
Title Crystallization of complex between soluble domains of adenylyl cyclase and activated Gs alpha.
Related PDB
Related UniProtKB
[33]
Resource
Comments
Medline ID
PubMed ID 16766715
Journal Mol Pharmacol
Year 2006
Volume 70
Pages 878-86
Authors Mou TC, Gille A, Suryanarayana S, Richter M, Seifert R, Sprang SR
Title Broad specificity of mammalian adenylyl cyclase for interaction with 2',3'-substituted purine- and pyrimidine nucleotide inhibitors.
Related PDB 1tl7 1u0h
Related UniProtKB
[34]
Resource
Comments
Medline ID
PubMed ID 15591060
Journal J Biol Chem
Year 2005
Volume 280
Pages 7253-61
Authors Mou TC, Gille A, Fancy DA, Seifert R, Sprang SR
Title Structural basis for the inhibition of mammalian membrane adenylyl cyclase by 2'(3')-O-(N-Methylanthraniloyl)-guanosine 5 '-triphosphate.
Related PDB 2gvd 2gvz
Related UniProtKB

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.

Created Updated
2004-04-12 2009-02-26