N-dibenzylphospho-N'-3-(2,6-dichlorophenyl)propyl-guanidine is a bisubstrate-analog for creatine kinase.
We describe a new compound, N-dibenzylphospho-N'-3-(2,6-dichlorophenyl)-propylguanidine (DPPG), and our study of its interaction with cytosolic CK. To our knowledge, it is the most potent inhibitor known for CK: the Ki value versus ADP was 330 nM and 110 nM for CK-MM and BB respectively. In view of the inhibition pattern, Ki(app) dependencies on the second substrate, and very low Ki values, we conclude that DPPG binds to the active site as a bisubstrate-type analog. This bisubstrate analog confirms different mechanisms for CK-MM and BB: in spite of a more than 80% similarity in amino-acid sequences, both isoenzymes are random at pH 8.6 but CK-BB has an ordered mechanism at pH 6.6.
Min
K L
KL
Laboratoire de Biochimie C, Hôpital Edouard Herriot, Lyon, France.
Steghens
J P
JP
Henry
R
R
Doutheau
A
A
Collombel
C
C
D000244:Adenosine Diphosphate / Q000494:pharmacology; D001921:Brain / Q000201:enzymology; D003402:Creatine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006146:Guanidines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007527:Isoenzymes; D007700:Kinetics; D008956:Models, Chemical; D018482:Muscle, Skeletal / Q000201:enzymology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D006146:Guanidines; D007527:Isoenzymes; C109097:N-dibenzylphospho-N'-3-(2,6-dichlorophenyl)propylguanidine; D000244:Adenosine Diphosphate; D003402:Creatine Kinase