Conformational basis for the activation of adenylate cyclase by adenosine.
The ability of adenosine to stimulate adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] and increase adenosine 3':5'-cyclic monophosphate (cAMP) levels has important biochemical consequences. These include the suppression of immune responses and cardiovascular effects. Recent investigations involving the ability of adenosine and adenosine analogs to stimulate adenylate cyclase provided experimental data that appear to be correlated with the ability of adenosine and analogs of adenosine to exist in the glycosidic high anti conformation. 9-beta-D-Arabinofuranosyladenine, which is not stable in the high anti conformation, is inactive as a stimulator of adenylate cyclase. 2'-Deoxyadenosine is also not stable in the high anti conformation but its instability may be significantly decreased by intramolecular adjustments promoted by receptor or active site interactions. 2'-Deoxyadenosine does not activate adenylate cyclase in lymphocytes when ATP is the substrate but is able to activate adenylate cyclase when 2-fluoro ATP is the substrate. The inability of certain analogs of adenosine, with bulky groups substituted for hydrogen at the 8 position of the adenine base, to activate adenylate cyclase and increase either lymphocyte or cardiac cell cAMP levels is consistent with the designation of the high anti conformation as being the conformation required for the activation of adenylate cyclase. An understanding of the glycosidic conformation required by the extracellular adenosine receptor of the adenosine molecule provides the basis for designing nucleoside analogs of adenosine that will exert a desired effect on cAMP levels. The avoidance of unwanted immunosuppressive or cardiotoxic effects can be arranged by structural changes that prohibit the high anti conformation.
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000262:Adenylyl Cyclases / Q000378:metabolism*; D004789:Enzyme Activation; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D000262:Adenylyl Cyclases; D000241:Adenosine
J Biol Chem. 1974 Aug 25;249(16):5296-303
4369127
Proc Natl Acad Sci U S A. 1976 Jan;73(1):213-7
1061119
Antimicrob Agents Chemother (Bethesda). 1968;8:180-9
5735360
J Biol Chem. 1974 Oct 10;249(19):6119-24
4425095
J Biol Chem. 1974 Jan 10;249(1):59-65
4358641
Biochemistry. 1974 Apr 23;13(9):1920-4
4365250
J Biol Chem. 1971 Mar 25;246(6):1877-82
4926550
Life Sci II. 1972 Dec 8;11(23):1143-54
4351979
Lancet. 1972 Dec 16;2(7790):1316
4117846
J Infect Dis. 1974 Nov;130(5):549-52
4371532
Eur J Biochem. 1974 Feb 1;41(3):421-30
4361644
J Immunol. 1972 Jun;108(6):1526-34
4337966
Mol Pharmacol. 1970 Jan;6(1):13-23
4354003
Biochem Pharmacol. 1969 Sep;18(9):2115-22
4310276
J Biol Chem. 1976 Jul 25;251(14):4239-46
932031
Biochim Biophys Acta. 1975 Oct 9;404(2):202-13
170974
J Biol Chem. 1975 Jun 10;250(11):4239-45
1126949
J Biol Chem. 1975 Jul 10;250(13):5003-8
1171095
Prog Allergy. 1972;16:300-449
4564107
Fed Proc. 1974 Aug;33(8):1882-5
4602113
Biochemistry. 1973 Aug 14;12(17):3294-302
4542512
Cancer Res. 1974 Dec;34(12):3197-202
4547679
Cancer Res. 1973 Jan;33(1):94-103
4509125
FEBS Lett. 1976 Jul 1;66(1):102-6
179893
Proc Natl Acad Sci U S A. 1975 Mar;72(3):888-91
165492
Science. 1975 Mar 14;187(4180):957-9
167434
Mol Pharmacol. 1975 Sep;11(5):528-44
170501
J Neurochem. 1975 Dec;25(6):895-6
173803
J Clin Invest. 1976 Feb;57(2):274-82
176177
Biochem Pharmacol. 1974 Oct 1;23(19):2761-7
4423608
Biochem Biophys Res Commun. 1974 Apr 8;57(3):590-5
4827825
J Pediatr. 1974 Feb;84(2):173-7
4810724
J Clin Invest. 1974 Apr;53(4):1194-6
4815083
Science. 1973 Nov 23;182(4114):836-7
4795749
Antimicrob Agents Chemother. 1973 Apr;3(4):534-5
4790608
Biochem Biophys Res Commun. 1973 Nov 16;55(2):410-6
4767309
J Cell Sci. 1973 Sep;13(2):429-39
4760594
Transplant Proc. 1973 Mar;5(1):943-7
4735211
J Biol Chem. 1973 Jul 10;248(13):4782-5
4718743
Biochem Pharmacol. 1973 Feb 1;22(3):341-8
4687131
Cancer. 1971 Jul;28(1):89-98
4938894
Circ Res. 1971 Oct;29(4):375-84
5315522
FEBS Lett. 1975 Oct 1;57(3):223-33
1102331
J Clin Invest. 1976 Sep;58(3):654-66
956393
Science. 1976 Aug 13;193(4253):587-8
959817
Proc Natl Acad Sci U S A. 1976 Jan;73(1):104-8
1061104
Cancer Res. 1975 Jan;35(1):68-70
1053696
Ann N Y Acad Sci. 1975 Aug 8;255:380-9
1059366
Br J Cancer. 1975 May;31(5):544-9
1057444
J Biol Chem. 1976 Jul 10;251(13):4055-61
932021
Biochim Biophys Acta. 1976 Jun 18;435(2):132-44
938674
Am J Physiol. 1963 Feb;204:317-22
13971060
J Biol Chem. 1976 Nov 10;251(21):6791-7
185219
J Biol Chem. 1976 Nov 10;251(21):6757-66
185217
Biochem Pharmacol. 1976 Dec 15;25(24):2713-9
188424
Proc Natl Acad Sci U S A. 1976 Dec;73(12):4257-60
1069980
J Biol Chem. 1976 Oct 10;251(19):5839-44
972142
Lancet. 1972 Nov 18;2(7786):1067-9
4117384
Science. 1974 Apr 5;184(4132):19-28
4131281
Chem Pharm Bull (Tokyo). 1975 Apr;23(4):759-74
1182861
Antimicrob Agents Chemother. 1975 Feb;7(2):203-7
1137371
J Med Chem. 1971 May;14(5):415-20
5117688
J Immunol. 1971 Apr;106(4):917-26
5553718
Biochim Biophys Acta. 1971 Jun 30;240(2):170-9
5559973
Cancer Chemother Rep 2. 1968 Oct;1(1):1-272
5743752
Br J Pharmacol Chemother. 1966 Nov;28(2):218-27
5972628
Acta Crystallogr. 1965 Jul 10;19(1):111-24
5896865
J Exp Med. 1972 Jul 1;136(1):112-27
4402392
Life Sci. 1975 Oct 10;17(7):1021-38
172752
Eur J Pharmacol. 1972 Aug;19(2):246-50
4403675
Drug Metab Dispos. 1973 Jul-Aug;1(4):645-52
4149639
Biochem Biophys Res Commun. 1974 Feb 27;56(4):934-9
4363643
Life Sci. 1974 Feb 1;14(3):489-503
4363081