COMPARISON OF THE INHIBITION OF YEAST, RAT, AND HUMAN SQUALENE SYNTHETASE

A comparison of the inhibition of yeast, rat, and human squalene synthetase (SQS) by zaragozic acid C and two farnesyl pyrophosphate (FPP) analogs was made. IC50 values measured at steady state revealed that zaragozic acid C was a nanomolar inhibitor of all three isozymes. The isoprenoid (phosphinylmethyl) phosphonate (266056), an FPP analog which has the allylic and anhydride oxygen atoms replaced with CH2, was a micromolar inhibitor of all three isozymes. An exception to the above trends was seen with an ether-linked (phosphinylmethyl) phosphonate (267338). This compound was between 15- and 42-fold more potent an inhibitor of the mammalian forms of SQS than it was for yeast squalene synthetase, suggesting potential differences in active-site binding residues. (C) 1994 Academic Press, Inc.