Inhibition of cGMP-dependent protein kinase by (Rp)-guanosine 3',5'-monophosphorothioates.
The activation of the cGMP-dependent protein kinase and cAMP-dependent protein kinase by the diastereomers of guanosine 3',5'-monophosphorothioate, (Sp)-cGMPS and (Rp)-cGMPS, and 8-chloroguanosine 3',5'-monophosphorothioate, (Sp)-8-Cl-cGMPS and (Rp)-8-Cl-cGMPS, was investigated using the peptide Kemptide as substrate. The (Sp)-diastereomers, which have an axial exocyclic sulfur atom, bound to the cGMP-dependent protein kinase and stimulated its phosphotransferase activity. In contrast, the (Rp)-isomers, which have an equatorial exocyclic sulfur atom, bound to the enzyme without stimulation of its activity. (Rp)-cGMPS and (Rp)-8-Cl-cGMPS antagonized the activation of the cGMP-dependent protein kinase with a Ki of 20 microM and 1.5 microM, respectively. (Rp)-cGMPS also antagonized the activation of cAMP-dependent protein kinase with a Ki of 20 microM. In contrast, (Rp)-8-cGMPS ws a weak inhibitor of the cAMP-dependent protein kinase with a Ki of 100 microM. (Rp)-8-Cl-cGMPS appears to be a rather selective inhibitor of the cGMP-dependent protein kinase and may be a useful tool for studying the role of cGMP in broken and intact cell systems.
Butt
E
E
Universität Bremen, Fachbereich Chemie, FRG.
van Bemmelen
M
M
Fischer
L
L
Walter
U
U
Jastorff
B
B
D000818:Animals; D002417:Cattle; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation; D007700:Kinetics; D008168:Lung / Q000201:enzymology; D015394:Molecular Structure; D009206:Myocardium / Q000201:enzymology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013873:Thionucleotides / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D013873:Thionucleotides; D011494:Protein Kinases; D006152:Cyclic GMP