Inhibition of adenylate kinase by P1-(lin-benzo-5'-adenosyl)-P4-(5'-adenosyl) tetraphosphate and P1-(lin-benzo-5'-adenosyl)-P5-(5'-adenosyl pentaphosphate.
P1-(lin-Benzo-5'-adenosyl)-P5-(5'-adenosyl) penraphosphate and P1-(lin-benzo-5'-adenosyl)-P4-(5'-adenosyl) tetraphosphate have been synthesized from lin-benzoadenosine 5'-monophosphoromorpholidate and adenosine 5'-tetraphosphate and adenosine 5'-triphosphate. These mixed dinucleoside polyphosphates are potent inhibitors of porcine muscle adenylate kinase, with association constants of 2 x 10(5) M-1 for the pentaphosphate and 2 x 10(6) M-1 for the tetraphosphate, respectively, as determined by kinetics and fluorescence experiments. The increase in fluorescence intensities and fluorescence lifetimes of both inhibitors upon binding to adenylate kinase results from a breaking of the intramolecular stacking interaction observed when these ligands are free in solution and implicates their binding to the enzyme in an "open" or "extended" form. These results and the dimensional requirements of these inhibitors are discussed in relation to our current knowledge of the active site of adenylate kinase and to the known inhibitors of adenylate kinase, P1,P5-bis(5'-adenosyl) pentaphosphate and P1,P4-bis-(5'-adenosyl) tetraphosphate.
D000227:Adenine Nucleotides / Q000494:pharmacology*; D000263:Adenylate Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009132:Muscles / Q000201:enzymology; D009841:Oligonucleotides / Q000494:pharmacology*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013552:Swine
D000227:Adenine Nucleotides; D009841:Oligonucleotides; D010770:Phosphotransferases; D000263:Adenylate Kinase