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Tissue-specific Expression of Functional Isoforms of Mouse Folylpoly--glutamate Synthetase: A Basis for Targeting Folate Antimetabolites¹

Departments of Pharmacology and Toxicology [F. B. T., J. L. A., R. G. M.] and Microbiology and Immunology [S. M. T.] and the Massey Cancer Center [J. F., S. T., A. T., S. M. T., R. G. M.], Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298

Folates and folate antimetabolites are metabolically trapped in mammalian cells as polyglutamates, a process catalyzed by folylpoly--glutamate synthetase (FPGS). Using 5'-rapid amplification of cDNA ends, RNase protection assays, transfection of cDNAs into FPGS-deficient cells, and kinetic analysis of recombinant enzymes expressed in insect cells, it was determined that the species of active FPGS in mouse liver and kidney was different from that in mouse tumor cells, bone marrow, and intestine. The NH₂-terminal peptide of hepatic enzyme contained 18 amino acids not found in enzyme from dividing tissues, and the specificity of the two isoforms for antifolates also differed, suggesting different architecture of the active sites. In most tissues, the expression of one isozyme or the other was an all-or-nothing event. The exclusive use of one of two alternative sets of initial coding exons in different tissues underlies this phenomenon, suggesting the design of antifolates specific for activation by individual FPGS isoforms and hence tissue-selective targeting of antifolate therapy for cancer, arthritis, or psoriasis.

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