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Background <p>Serotonin (5-hydroxytryptamine, 5-HT) is a pivotal neurotransmitter with broad clinical relevance. However, its industrial-scale microbial production remains a significant challenge. In this study, we engineered <i>Streptomyces albulus</i> to develop an efficient enzymatic cascade for the scalable and high-yield biosynthesis of 5-HT.</p> Results <p>To enhance 5-HT production, we first overexpressed the native 5-hydroxytryptophan decarboxylase (5-OHTDC) in <i>S. albulus</i>, which strengthened the final decarboxylation step. Using 5-hydroxytryptophan as the substrate, this modification achieved a 5-HT titer of 6.87&#xa0;g/L. We then introduced <i>Escherichia coli</i> L-tryptophan permease (Mtr) to improve cellular uptake of L-tryptophan, along with <i>Actinomadura luzonensis</i> tryptophan 5-hydroxylase (Luz15) to catalyze the hydroxylation of L-tryptophan. This triple-enzyme expression system (5-OHTDC/Mtr/Luz15) enabled the direct conversion of L-tryptophan to 5-HT, yielding 3.46&#xa0;g/L. Leveraging the innate L-tryptophan biosynthesis capability of <i>S. albulus</i>, we pursued direct fermentative production from low-cost carbon sources. Mannitol was identified as the optimal substrate, supporting a maximum 5-HT titer of 6.54&#xa0;g/L in fed-batch fermentation. Finally, implementing an L-tryptophan feeding strategy further boosted the final 5-HT titer to 12.0&#xa0;g/L.</p> Conclusions <p>This work establishes <i>S. albulus</i> as an efficient microbial platform for high-level 5-HT production. The engineered strain and optimized fermentation process demonstrate strong potential for industrial application and provide a versatile chassis for synthesizing diverse tryptophan-derived bioactive compounds.</p>

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Metabolic engineering of Streptomyces albulus for de novo serotonin production

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月26日

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  • Yuan Zhang,
  • Aoxiang Liu,
  • Min Zhang,
  • Jiabei Song,
  • Qian Wang,
  • Yongxuan Liu,
  • Qingshou Yao,
  • Linghui Kong,
  • Xiuwen Wang,
  • Jiayang Qin

摘要

Background

Serotonin (5-hydroxytryptamine, 5-HT) is a pivotal neurotransmitter with broad clinical relevance. However, its industrial-scale microbial production remains a significant challenge. In this study, we engineered Streptomyces albulus to develop an efficient enzymatic cascade for the scalable and high-yield biosynthesis of 5-HT.

Results

To enhance 5-HT production, we first overexpressed the native 5-hydroxytryptophan decarboxylase (5-OHTDC) in S. albulus, which strengthened the final decarboxylation step. Using 5-hydroxytryptophan as the substrate, this modification achieved a 5-HT titer of 6.87 g/L. We then introduced Escherichia coli L-tryptophan permease (Mtr) to improve cellular uptake of L-tryptophan, along with Actinomadura luzonensis tryptophan 5-hydroxylase (Luz15) to catalyze the hydroxylation of L-tryptophan. This triple-enzyme expression system (5-OHTDC/Mtr/Luz15) enabled the direct conversion of L-tryptophan to 5-HT, yielding 3.46 g/L. Leveraging the innate L-tryptophan biosynthesis capability of S. albulus, we pursued direct fermentative production from low-cost carbon sources. Mannitol was identified as the optimal substrate, supporting a maximum 5-HT titer of 6.54 g/L in fed-batch fermentation. Finally, implementing an L-tryptophan feeding strategy further boosted the final 5-HT titer to 12.0 g/L.

Conclusions

This work establishes S. albulus as an efficient microbial platform for high-level 5-HT production. The engineered strain and optimized fermentation process demonstrate strong potential for industrial application and provide a versatile chassis for synthesizing diverse tryptophan-derived bioactive compounds.