Conformational influences on brain tryptophan hydroxylase by submicromolar calcium: opposite effects of equimolar lithium.

Tryptophan hydroxylase from rat midbrain, EGTA-pretreated and dialyzed, manifested allosteric properties with respect to its substrate tryptophan, cofactor tetrahydrobiopterin, and the calcium ion. Kinetic studies suggest two preferred enzyme conformations in the presence of low concentrations of the cosubstrates: a higher affinity form manifesting hyperbolic substrate kinetics, induced by submicromolar (0.4--0.8 microM) calcium in vitro and cocaine in vivo, and a lower affinity form exaggerating cooperativity with respect to substrate, induced by submicromolar (0.4 to 0.8 microM) lithium in vitro and lithium in vivo. Lithium's effect on serotonin biosynthesis may be due to its antagonism of the positive effector influence of calcium on tryptophan hydroxylase, either as a negative effector or by blocking the calcium site.