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Inhibition of diacylglycerol kinase by the antitumor agent calphostin C: Evidence for similarity between the active site of diacylglycerol kinase and the regulatory site of protein kinase C



Inhibition of diacylglycerol kinase by the antitumor agent calphostin C: Evidence for similarity between the active site of diacylglycerol kinase and the regulatory site of protein kinase C



Biochemical Pharmacology 50(2): 235-241



Calphostin C is an anti-tumor agent that binds to the regulatory domain of protein kinase C and inhibits the binding of phorbol dibutyrate. Recent studies suggest that there may be structural similarities between protein kinase C (PKC) and diacylglycerol kinase (DGK). Both enzymes bind diacylglycerol and phosphatidylserine, and sequencing of the 80 kDa diacylglycerol kinase shows that it contains zinc finger-like sequences, similar to those occurring in PKC. Similarities in some enzymatic properties of PKC and DGK led us to examine whether regulatory-site inhibitors of PKC also might inhibit DGK. For these studies, the membrane-bound DGK was partially purified from porcine testis membranes. Calphostin C inhibited DGK with an IC-50 in the micromolar range. The inhibition of DGK by calphostin C was competitive with respect to diacylglycerol and was not affected by the presence or absence of phosphatidylserine. Other inhibitors of protein kinase C were without effect, with the exception of Adriamycin, which inhibited at millimolar concentrations. Staurosporine, which binds to the catalytic domain of protein kinase C, did not inhibit DGK. The results suggest that there are functional similarities between the substrate binding site of DGK and regulatory site of protein kinase C.

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Accession: 008877529

Download citation: RISBibTeXText

PMID: 7632168

DOI: 10.1016/0006-2952(95)00118-j


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