Microbial Synthesis of Human-Hormone Melatonin at Gram Scales

Hao Luo*, Konstantin Schneider, Ulla Christensen, Yang Lei, Markus Herrgard, Bernhard Ø. Palsson

*Corresponding author for this work

Research output: Contribution to journalLetterpeer-review


Melatonin is a commercially attractive tryptophan-derived hormone. Here we describe a bioprocess for the production of melatonin using Escherichia coli to high titers. The first engineered strain produced 0.13 g/L of melatonin from tryptophan under fed-batch fermentation conditions. A 4-fold improvement on melatonin titer was further achieved by (1) protein engineering of rate-limiting tryptophan hydroxylase to improve 5-hydroxytryptophan biosynthesis and (2) chromosomal integration of aromatic-amino-acid decarboxylase to limit byproduct formation and to minimize gene toxicity to the host cell. Fermentation optimization improved melatonin titer by an additional 2-fold. Deletion of yddG, a tryptophan exporter, exhibited an additive beneficial effect. The final engineered strain produced ∼2.0 g/L of melatonin with tryptophan supplemented externally and ∼1.0 g/L with glucose as the sole carbon source for tryptophan supply. This study lays the foundation for further developing a commercial melatonin-producing E. coli strain.
Original languageEnglish
JournalACS Synthetic Biology
Issue number6
Pages (from-to)1240-1245
Number of pages6
Publication statusPublished - 2020


  • Fermentation
  • Glucose
  • Trytophan
  • E. coli
  • High titer


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