EFFECTS OF THE INHIBITORS OF IMP DEHYDROGENASE, TIAZOFURIN AND MYCOPHENOLIC-ACID, ON GLYCOPROTEIN METABOLISM

  • 1 January 1985
    • journal article
    • research article
    • Vol. 28  (6) , 567-573
Abstract
The effects of the inhibitors of IMP dehydrogenase, tiazofurin (2-.beta.-D-ribofuranosylthiazole-4-carboxamide) and mycophenolic acid, on the synthesis of cellular glycoproteins were evaluated in Sarcoma 180 cells. Both tiazofurin and mycophenolic acid decreased the rate of incorporation of [2-3H]mannose and [2-3H]fucose into acid-precipitable glycoproteins within 4 hr of exposure; this inhibitory activity was concentration dependent and occurred in the absence of a significant effect on the incorporation of labeled glucosamine and leucine into acid-insoluble material. Interference with the utilization of [3H]mannose for the formation of glycoproteins was paralleled by an inhibition of [3H]mannose incorporation into their lipid-linked oligosaccharide precursors following treatment with cytotoxic concentrations of tiazofurin (100 .mu.M) or mycophenolic acid (10 .mu.M); these actions occurred within 3 hr of exposure to these agents, with maximal reductions being observed at 12 hr. Under these conditions, intracellular GTP levels were reduced by 80%, whereas ATP pools remained unaffected and UTP levels were markedly increased. Guanosine (100 .mu.M) prevented the cytotoxic actions of tiazofurin and mycophenolic acid and reversed the drug-induced decrease in GTP pools and in the incorporation of mannose and other metabolic precursors into acid-insoluble material. Inhibition of fucose and mannose incorporation into lipid-linked oligosaccharides and glycoproteins were preceded by decreases in the labeling of the respective guanosine nucleotide sugars and were followed sequentially by alterations in the plasma membrane as detected by both the binding and the rate of cell agglutination caused by the plant lectin, concanavalin A. The findings that tiazofurin and mycophenolic acid produce alterations in the utilization of [3H]mannose for the formation of glycoproteins and in membrane architecture are indicative of metabolic lesions induced by agents that selectively depress guanine nucleotide synthesis through inhibition of IMP dehydrogenase.

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