Synthetic pathways and processes for effective production of 5-hydroxytryptophan and serotonin from glucose in Escherichia coli

José-Aníbal Mora-Villalobos,An-Ping Zeng

doi:10.1186/s13036-018-0094-7

José-Aníbal Mora-Villalobos, An-Ping Zeng

Open Access

https://doi.org/10.1186/s13036-018-0094-7

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Abstract

BackgroundTryptophan derivatives such as 5-hydroxytryptophan (5HTP) and serotonin are valuable molecules with pharmaceutical interest. 5HTP is presently mainly obtained by extraction from the plant Griffonia simplicifolia and serotonin is produced by chemical synthesis. A simple biotechnological method for the production of these compounds is desired.ResultsIn a first attempt to synthesize serotonin from glucose, we used a single engineered Escherichia coli strain and observed a low production of maximal 0.8 ± 0.2 mg/L of serotonin, probably due to the undesired site-reaction of direct decarboxylation of tryptophan and the consequent decrease of the precursor 5HTP. To circumvent this problem, we have constructed a stepwise system in which the 5HTP production and the serotonin conversion are separated. 962 ± 58 mg/L of 5HTP was produced in the first step using a recombinant strain with a semi-rationally engineered aromatic amino acid hydroxylase, the highest concentration reported so far. In a subsequent step of 5HTP bioconversion using a recombinant strain harboring a tryptophan decarboxylase, 154.3 ± 14.3 mg/L of serotonin was produced.ConclusionsWe present results of a two-stage fermentation process for the production of 5HTP and serotonin. The first strain is a highly efficient 5HTP producer, and after fermentation the supernatant is separated and used for the production of serotonin. This is the first report for the microbial production of serotonin from glucose.

Highlights

Tryptophan derivatives such as 5-hydroxytryptophan (5HTP) and serotonin are valuable molecules with pharmaceutical interest. 5HTP is presently mainly obtained by extraction from the plant Griffonia simplicifolia and serotonin is produced by chemical synthesis
Potential therapeutic agents have stimulated the interest in the design and synthesis of tryptophan-related structures, which could have direct health benefits or may work as key biosynthetic precursors for other molecules. 5-Hydroxytryptophan (5HTP) and serotonin are two important tryptophan derivatives. 5HTP is an intermediate molecule in the biosynthesis of serotonin, and over the last 30 years, it has been used to treat a wide variety of conditions related to serotonin
We engineered an aromatic amino acid hydroxylase from C. taiwanensis (CtAAAH-W192F, from here on referred as CtAAAH-F) with which 2.5 mM of 5HTP was produced in E. coli in media supplied with 5 mM of tryptophan [20]

Summary

Introduction

Tryptophan derivatives such as 5-hydroxytryptophan (5HTP) and serotonin are valuable molecules with pharmaceutical interest. 5HTP is presently mainly obtained by extraction from the plant Griffonia simplicifolia and serotonin is produced by chemical synthesis. Tryptophan derivatives such as 5-hydroxytryptophan (5HTP) and serotonin are valuable molecules with pharmaceutical interest. Tryptophan is an essential amino acid with medical, industrial and pharmaceutical importance. Potential therapeutic agents have stimulated the interest in the design and synthesis of tryptophan-related structures, which could have direct health benefits or may work as key biosynthetic precursors for other molecules. 5-Hydroxytryptophan (5HTP) and serotonin are two important tryptophan derivatives. The indole aromatic heterocyclic backbone, present in 5HTP and serotonin, is a valuable molecular framework that provides a plethora of opportunities for medical chemistry and drug discovery. Biotechnology itself presents as a tempting promise for the production of these molecules with high yields, in short time with low costs [13]

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