Tryptophan hydroxylase regulation. Drug-induced modifications that alter serotonin neuronal function.

Tryptophan hydroxylase is the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin. A variety of drugs are known to diminish the function of this enzyme, and possibly cause damage to serotonin neurons. These include the substituted amphetamines methamphetamine and 3,4-methylenedioxy-methamphetamine, as well as L-DOPA, the most common therapy for Parkinsons Disease. In view of the important role for dopamine in the effects of these drugs on tryptophan hydroxylase and on serotonin neurons, we tested whether dopamine could alter the activity of this important enzyme. We found that dopamine-derived quinones, but not dopamine, inactivate tryptophan hydroxylase and convert the protein to a redox-cycling quinoprotein. This posttranslational modification of tryptophan hydroxylase could play a role in the drug-induced reduction in serotonin synthesis.