THE IMMUNOSUPPRESSANT SR-31747 BLOCKS CELL-PROLIFERATION BY INHIBITING A STEROID ISOMERASE IN SACCHAROMYCES-CEREVISIAE

SIR 31747 is a novel immunosuppressant agent that arrests cell prolife ration in the yeast Saccharomyces cerevisiae. SR 31747-treated cells a ccumulate the same aberrant sterols as those found in a mutant impaire d in Delta 8-Delta 7-sterol isomerase. Sterol isomerase activity is al so inhibited by SR 31747 in in vitro assays. Overexpression of the ste rol isomerase-encoding gene, ERG2, confers enhanced SR resistance. Cel ls growing anaerobically on ergosterol-containing medium are not sensi tive to SR Disruption of the sterol isomerase-encoding gene is lethal in cells growing in the absence of exogenous ergosterol, except in SR- resistant mutants lacking either the SUR4 or the FEN1 gene product. Th ese results suggest that sterol isomerase is the target of SR 31747 an d that both the SUR4 and FEN1 gene products are required to mediate th e proliferation arrest induced by ergosterol depletion.