Abstract C71: Inhibition of polyisoprenylated methylated protein methylesterase by anticancer drugs

Abstract

Abstract Polyisoprenylated methylated protein methylesterase (PMPMEase) is a little explored enzyme of the polyisoprenylation (isoprenylation) pathway (PP). Polyisoprenylation is a post-translational modification that is important for the function of such proteins as the heterotrimeric G proteins, Ras and Rab families of proteins. PMPMEase hydrolyzes a methyl ester formed by the S-adenosyl-L-methionine (SAM)-dependent enzyme, polyisoprenylated protein methyltransferase (PPMTase). PMPMEase's regulatory role is suggested by the fact it hydrolyzes the ester products of PPMTase. PMPMEase is a serine hydrolase, a class of hydrolytic enzymes that attack electron-deficient carbons of amide and ester bonds with the alkoxide ion of their catalytic serines. Because alkylating agents function through an aziridinium ion with an electron-deficient carbon atom, it is hypothesized that they may inhibit PMPMEase through active site adduct formation. Alkylating agents have been suspected of having other mechanisms of action against cells besides impeding replication via the cross-linking of DNA strands. The crystal structure of the human form of PMPMEase, human carboxylesterase 1, with tamoxifen bound to its active site has been solved, also suggesting its possible inhibition. Polyisoprenylated proteins are involved in processes that regulate cell viability. Mutations and overexpression of such proteins are implicated in about 30% of cancers. This study considers the possibility that the agents also reduce malignant cell growth by disrupting growth signaling pathways. Cyclophosphamide is an organophosphorous alkylating agent. Organophosphorous compounds irreversibly inhibit PMPMEase and other serine esterases. Busulfan, cyclophosphamide, mechlorethamine and tamoxifen were tested for porcine liver PMPMEase inhibition. At 1 mM concentrations, cyclophosphamide, mechlorethamine and tamoxifen inhibited 62, 35 and 55% of the PMPMEase activity. The results show that the anticancer drugs may owe part of their pharmacological activity to their modulation of oncogenic polyisoprenylated protein function through their inhibition of PMPMEase. Citation Information: Cancer Res 2009;69(23 Suppl):C71.