Tryptophan hydroxylase (TPH) catalyzes the 5-hydroxylation of tryptophan, which is the first step in the biosynthesis of indoleamines (serotonin and melatonin). In mammals, serotonin biosynthesis occurs predominantly in neurons which originate in the raphe nuclei of the brain, and melatonin synthesis takes place within the pineal gland. Although TPH catalyzes the same reaction within the raphe nuclei and the pineal gland, TPH activity is rate-limiting for serotonin but not melatonin biosynthesis. Serotonin functions mainly as a neurotransmitter, whereas melatonin is the principal hormone secreted by the pineal gland. The activity of TPH is enhanced by phosphorylation by cAMP-dependent protein kinase (PKA) and Ca2+/calmodulin kinase II (CAM K II). Both PKA and CAM K II phosphorylate Ser58 which lies within the regulatory domain of TPH.
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