Sangivamycin, a nucleoside analogue, is a potent inhibitor of protein kinase C.
Protein kinase C functions prominently in cell regulation via its pleiotropic role in signal transduction processes. Certain oncogene products resemble elements involved in transmembrane signaling, elevate cellular sn-1,2-diacylglycerol second messenger levels, and activate protein kinase C. Sangivamycin was unique among the nucleoside compounds tested in its ability to potently inhibit protein kinase C activity. Inhibition was competitive with respect to ATP for both protein kinase C and the catalytic fragment of protein kinase C prepared by trypsin digestion. Sangivamycin was a noncompetitive inhibitor with respect to histone and lipid cofactors (phosphatidylserine and diacylglycerol). Sangivamycin inhibited native protein kinase C and the catalytic fragment identically, with apparent Ki values of 11 and 15 microM, respectively. Sangivamycin was an effective an inhibitor of protein kinase C as H-7, an isoquinolinsulfonamide. Sangivamycin did not inhibit [3H]phorbol-12,13-dibutyrate binding to protein kinase C. Sangivamycin did not exert its action through the lipid binding/regulatory domain; inhibition was not affected by the presence of lipid or detergent. Unlike H-7, sangivamycin selectively inhibited protein kinase C compared to cAMP-dependent protein kinase. The discovery that protein kinase C is inhibited by sangivamycin and other antitumor agents suggests that protein kinase C may be a target for rational design of antitumor compounds.
Loomis
C R
CR
Duke University Medical Center, Department of Biochemistry, Durham, North Carolina 27710.
Bell
R M
RM
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D009857:Oncogenes; D010718:Phosphatidylserines / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011741:Pyrimidine Nucleosides / Q000494:pharmacology; D051381:Rats; D014357:Trypsin / Q000378:metabolism
D007546:Isoquinolines; D010718:Phosphatidylserines; D010879:Piperazines; D011741:Pyrimidine Nucleosides; C005699:sangivamycin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D014357:Trypsin