Biochemistry of 5-hydroxytryptophan (5-HTP)

Introduction
5-Hydroxytryptophan (5-HTP) is the immediate precursor to the production of serotonin (5-hydroxytryptamine). 5-HTP is made from the amino acid tryptophan through the action of an enzyme known as tryptophan hydroxylase, which adds a hydroxyl group (-OH) to tryptophan. Next, the enzyme 5-hydroxytrytophan decarboxylase removes a carboxyl group (-COOH) from 5-HTP to generate serotonin. Serotonergic neurons of the Raphe synthesize and store serotonin whereas the pineal gland further processes serotonin into melatonin. The life cycle of serotonin ends with the actions of monoamine oxidases (MAOs), which produce the breakdown (oxidation) product 5-hydroxy indole acetic acid (5-HIAA).

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Tryptophan hydroxylase and 5-HTP
Synthesis of 5-HTP is the rate limiting step in the production of serotonin. This means that brain levels of tryptophan largely determine how much serotonin is made. For example, decreased levels of serotonin could be attained through a diet with limited amounts of tryptophan or inhibitors of tryptophan hydroxylase. In contrast, artificially increasing the amount of 5-HTP in serotonergic neurons would bypass the rate limiting step and enhance levels of serotonin.

There are caveats for any strategy to increase neuronal levels of serotonin. First, serotonin is present throughout the body, not just the brain. For example, the gut is rich in serotonergic neurons that control bowel functions (1). Second, serotonin is involved in many behaviors including sleep (2,3). Third, brain levels of serotonin vary throughout the day (4,5). Fourth, the blood brain barrier regulates chemical access to the brain. Therefore, the effectiveness of a particular supplement or drug largely depends on how well it can pass the blood brain barrier in addition to its biochemical/pharmacological mechanism(s) of action.

References
(1) Gershon MD (2004) Review article: serotonin receptors and transporters -- roles in normal and abnormal gastrointestinal motility. Alimentary Pharmacology & Therapeutics 20:(s7) 3-14.
(2) Alexandre C, Popa D, Fabre V, Bouali S, Venault P, Lesch KP, Hamon M, Adrien J. (2006) Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter. Journal of Neuroscience 26:5554-64.
(3) Portas CM, Bjorvatn B, Ursin R. (2000) Serotonin and the sleep/wake cycle: special emphasis on microdialysis studies. Progress in Neurobiology 60:13-35.
(4) Birkett M, Fite KV. (2005) Diurnal variation in serotonin immunoreactivity in the dorsal raphe nucleus. Brain Research 1034:180-4.
(5) Sun X, Deng J, Liu T, Borjigin J. (2002) Circadian 5-HT production regulated by adrenergic signaling. Proceedings of the National Academy of Science (PNAS) USA 99:4686-91.

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