Tetrahydropterins Interfere with the G Protein Pathway inDictyostelium discoideum

The cellular slime mold Dictyostelium discoideum produces tetrahydrodictyopterin, the D-threo-isomer of tetrahydrobiopterin. During cyclic AMP coordinated aggregation, the G protein linked signalling pathway is involved in the regulation of the initial enzyme GTP cyclohydrolase I [M. Gutlich et at, Biochem, J. 314, 95-101 (1995)]. We now find that cyclic AMP stimulated binding of GTP gamma S to the membrane fraction is inhibited by tetrahydrodictyopterin and tetrahydrobiopterin. Inhibition was a function of GTP gamma S concentration and the analysis of the kinetic data pointed to a competitive type of inhibition. The inhibition of G protein activation was accompanied by a loss of adenylyl cyclase activation. Because the GTP gamma S- and G protein-dependent reduction of receptor affinity for cyclic AMP was also attenuated, we conclude that tetrahydrodictyopterin and tetrahydrobiopterin interfere with activation of G proteins by inhibiting GDP-GTP exchange. (C) 1996 Academic Press. Inc.