9-(Phosphonoalkyl)guanine derivatives as substrates or inhibitors of guanylate kinase.
Several 9-(phosphonoalkyl)guanines (Gua(CH2)nCH2-PO3H2; n = 4-6) and 9-(difluorophosphonoalkyl)guanines (Gua(CH2)nCF2PO3H2; n = 3-7) were studied as potential substrates and inhibitors of guanylate kinase. These compounds are inhibitors of the enzyme except 9-(5-phosphonopentyl)guanine (n = 4) which is a substrate with an efficiency of phosphorylation of about 0.3% that of GMP, as estimated from the Vmax/Km ratios. The phosphonate and difluorophosphonate derivatives with n = 5 produce optimal inhibition. These two compounds have similar affinity, both being competitive inhibitors with respect to GMP and noncompetitive inhibitors with respect to ATP. pH-dependence studies indicate that the dianionic rather than the monoanionic form of these compounds bind to the enzyme. The lack of phosphorylation of 9-(5,5-difluoro-5-phosphonopentyl)guanine by guanylate kinase is explained by the decreased nucleophilic character of the oxygen atoms of the phosphonate group rather than by inadequate binding to the GMP-binding site.
Navé
J F
JF
Marion Merrell Dow Research Institute, Strasbourg, France.
Eschbach
A
A
Halazy
S
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006157:Guanosine Monophosphate / Q000378:metabolism; D051528:Guanylate Kinases; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism* / Q000494:pharmacology; D013379:Substrate Specificity
D009943:Organophosphorus Compounds; D006147:Guanine; D006157:Guanosine Monophosphate; D000255:Adenosine Triphosphate; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases