5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology

Massimo E Maffei, Massimo E Maffei

Abstract

L-5-hydroxytryptophan (5-HTP) is both a drug and a natural component of some dietary supplements. 5-HTP is produced from tryptophan by tryptophan hydroxylase (TPH), which is present in two isoforms (TPH1 and TPH2). Decarboxylation of 5-HTP yields serotonin (5-hydroxytryptamine, 5-HT) that is further transformed to melatonin (N-acetyl-5-methoxytryptamine). 5-HTP plays a major role both in neurologic and metabolic diseases and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis. In this review, after an look at the main natural sources of 5-HTP, the chemical analysis and synthesis, biosynthesis and microbial production of 5-HTP by molecular engineering will be described. The physiological effects of 5-HTP are discussed in both animal studies and human clinical trials. The physiological role of 5-HTP in the treatment of depression, anxiety, panic, sleep disorders, obesity, myoclonus and serotonin syndrome are also discussed. 5-HTP toxicity and the occurrence of toxic impurities present in tryptophan and 5-HTP preparations are also discussed.

Keywords: 5-hydroxytryptophan; animal; biosynthetic pathways; human; microbial production; natural sources; physiological effects.

Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Chemical synthesis of 5-hydroxytryptophan (5-HTP). From [54], modified.
Figure 2
Figure 2
Hydroxylation of tryptophan by tryptophan hydroxylase (TPH). See text for explanation. From [58], modified.
Figure 3
Figure 3
Biosynthesis of BH4 in mammals. Modified from [61].
Figure 4
Figure 4
Biosynthetic pathway of serotonin (5-HT). Tryptophan is hydroxylated by the two forms of TPH to yield 5-HTP, which is then decarboxylated by the aromatic amino acid decarboxylase (AADC) to serotonin.
Figure 5
Figure 5
Structure formulae of some TPH inhibitors.
Figure 6
Figure 6
Chemical formula of tetrahydromonapterin.
Figure 7
Figure 7
Production of 5-HTP from tryptophan in E. coli by engineered PAH and the utilization of tetrahydromonapterin (MH4) instead of BH4. DHMR, dihydromonapterin reductase; PAH, phenylalanine 4-hydroxylase; PCD, pterin-4α-carbinolamine dehydratase; MH2, dihydromonapterin. Modified from [88].
Figure 8
Figure 8
Production of 5-HTP from glucose in engineered E. coli by using a novel salicylate 5-hydroxylase. PEP, phosphoenol pyruvate; E4P, erythrose-4-phosphate; TrpEfbrG, anthranilate synthase (from a feedback resistance mutant); SalABCD, salicylate 5-hydroxylase; TrpDCA and TrpB, E. coli native tryptophan biosynthetic enzymes. Adapted from [90].
Figure 9
Figure 9
Summary of heterologous production of 5-HTP. Chromobacterium violaceum, with the first use of PAH for tryptophan hydroxylation to 5-HTP. Escherichia coli, with a) utilization of MH4 instead of BH4 as the native pterin coenzyme for 5-HTP synthesis, b) the biosynthesis of 5-HTP with the use of a novel salicylate 5-hydroxylase that uses glucose as the substrate for the production of the non-natural substrate anthranilate to 5-hydroxyanthranilate (5-HI), c) substitution of the promoter of aroHfbr gene encoding 3-deoxy-7-phosphoheptulonate synthase to feed the biosynthetic pathway of tryptophan production. The use of yeasts with the heterologous expression of either a prokaryotic PAH or eukaryotic tryptophan 3/5-hydroxylase, together with enhanced synthesis of the two cofactors MH4 or BH4; the native Saccharomyces cerevisiae gene, DFR1, which encodes dihydrofolate reductase to catalyze tetrahydrofolate, plays a pivotal role in 5-HTP synthesis by regenerating MH4. Created with BioRender.com.
Figure 10
Figure 10
Summary of effects of 5-HTP on some animals. In terrestrial snails, 5-HTP reinstates the context memory, whereas in mice, 5-HTP produces a characteristic head twitch and tremors, induces hypoglycemia, and suppresses inflammation by inducing pro-inflammatory mediators. In rats, most of the listed effects of 5-HTP are dose dependent. In guinea pigs, 5-HTP enhances myoclonus and facilitates the luminal 5-HT release. In dogs, 5-HTP increases propulsive activity, contractive force, and mobility index. Injection of 5-HTP facilitates the stretch reflex in cats and produces a fall in temperature in rabbits. In sheep, 5-HTP increases serum melatonin and foetal breathing movements and stimulates an autocrine–paracrine adaptation to lactation in cows. Created with BioRender.com.
Figure 11
Figure 11
Summary of some effects of 5-HTP on humans. 5-HTP is a treatment of choice in the prophylaxis of migraine and headache and promotes decreased food intake and weight loss in obese patients. 5-HTP is used for treating depressive symptoms in Parkinson’s disease and may be used as a diagnostic test for Alzheimer’s disease. 5-HTP is useful to control some forms of myoclonus and significantly increases plasma human prolactin. Excessive 5-HTP generates serotonin syndrome. 5-HTP has the potential for use in the treatment of inflammatory diseases and oxidative stress. As a precursor of 5-HT, 5-HTP treatment is used to reduce depression, anxiety, and panic attacks. 5-HTP is associated with an increase in rapid eye movement (REM) sleep and reduces sleep disorder. Created with BioRender.com.

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