Tetrahydropterins interfere with the G protein pathway in Dictyostelium 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. Gütlich et al., Biochem. J. 314, 95-101 (1996)]. We now find that cyclic AMP stimulated binding of GTPgammaS to the membrane fraction is inhibited by tetrahydrodictyopterin and tetrahydrobiopterin. Inhibition was a function of GTPgammaS 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 GTPgammaS- 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.