The role of the a-carboxyl group in methotrexate (MeAPA-Glu) and the y-glutamate derivative of methotrexate (MeAPA-Glu-Glu) in the reaction catalyzed by folylpolyglutamate synthetase (FPGS) has been investigated. MeAPA-Glu and MeAPA-Glu-Glu were accepted as substrates by the same FPGS species contained in an (NH4) pS04 precipitate of mouse liver protein, as judged by a lack of additivity of product formation at saturating ...