Inhibitory action of certain cyclophosphate derivatives of cAMP on cAMP‐dependent protein kinases

• DOI: 10.1111/j.1432-1033.1984.tb08279.x
• Publication Date: 2005-03-04T01:14:19Z
• Authors: René J. W. DE WIT; Doeke HEKSTRA; Bernd JASTORFF; Wojciech J. STEC; Janina BARANIAK; Roel VAN DRIEL; Peter J. M. VAN H...
• Keywords: Moiety; Ribose

A series cAMP derivatives with modifications in the adenine, ribose and cyclophosphate moiety were screened for their binding affinity two types of cAMP‐binding sites mammalian protein kinase type I. In addition, activation by these analogs was monitored. The data indicate that is bound to both a comparable manner: adenine appears have no hydrogen‐bond interactions sites, whereas may be three hydrogen bonds involving 2′, 3′ 5′ positions cAMP. are not conclusive about nature interaction exocyclic oxygen atoms on phosphorus, though charge seems absent. molecule syn conformation. results experiments show do affect maximal level, while alteration exocydic result reduced level one case, ( R p )‐adenosine 3′, 5′‐monophosphorothioate [ −cAMPS], total absence even at concentrations, which analog saturates sites. Since occupancy this derivative apparently did lead enzyme, we examined whether compound could antagonize Indeed )‐cAMPS found inhibit stimulated activity concentrations compatible its affinity. Also II showed antagonistic activity, cAMP‐dependent from Dictyostelium discoideum partial agonistic observed. Previously mechanism I proposed between equatorial atom site [De Wit et al. (1982) Eur. J. Biochem. 122 , 95‐99]. This based measurements impure preparations S isomers adenosine 5′‐monophosphodimethylamidate, cAMPN(CH 3 ) 2 . present work using highly purified compounds suggests interaction, since uncharged )‐cAMPN(CH activates effectively. seem an model formation covalent bond phosphorus