(E)-3-Cyanophosphoenolpyruvate, a new inhibitor of phosphoenolpyruvate-dependent enzymes

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Abstract
(E)-3-Cyanophosphoenolpyruvate has been synthesized by reacting dimethyl chlorophosphate with the potassium enolate of ethyl cyanopyruvate. The resulting trialkyl ester was deesterified with bromotrimethylsilane followed by potassium hydroxide. Subsequent treatment with Dowex-50-H+ resin and cyclohexylamine afforded the tricyclohexylammonium salt; only the E geometric isomer was obtained. This compound can be photoisomerized to a 70:30 E:Z mixture. (E)-3-Cyanophosphoenolpyruvate is an excellent competitive inhibitor of phosphoenolpyruvate carboxylase [KI(Mn2+) = 16 .mu.M, KI(Mg2+) = 1360 .mu.M], pyruvate kinase [KI(Mn2+) = 0.085 .mu.M, Ki(Mg2+) = 0.76 .mu.M], and enolase [KI(Mn2+) = 360 .mu.M, KI(Mg2+) = 280 .mu.M]. The compound is a substrate for pyruvate kinase (Vmax .apprx. 1% of phosphoenolpyruvate rate), but not for the other two enzymes. No irreversible inactivation is observed with phosphoenolpyruvate carboxylase or pyruvate kinase.
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