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Abstract
Natural products from plants are useful as lead compounds in drug discovery. Plant benzylisoquinoline alkaloids (BIAs) exhibit various pharmaceutical activities. Although unidentified BIAs are expected to be of medicinal value, sufficient quantities of such BIAs, for biological assays, are sometimes difficult to obtain due to their low content in natural sources. Here, we showed that high productivity of BIAs in engineered Escherichia coli could be exploited for drug discovery. First, we improved upon the previous microbial production system producing (S)-reticuline, an important BIA intermediate, to obtain yields of around 160 mg/L, which was 4-fold higher than those of the previously reported highest production system. Subsequently, we synthesised non-natural BIAs (O-sulphated (S)-reticulines) by introducing human sulphotransferases into the improved (S)-reticuline production system. Analysis of human primary cells treated with these BIAs demonstrated that they affected a biomarker expression in a manner different from that by the parent compound (S)-reticuline, suggesting that simple side-chain modification altered the characteristic traits of BIA. These results indicated that highly productive microbial systems might facilitate the production of scarce or novel BIAs and enable subsequent evaluation of their biological activities. The system developed here could be applied to other rare natural products and might contribute to the drug-discovery process as a next-generation strategy.
Highlights
Many medicinal compounds have been discovered from natural resources, with some in wide use as popular medications
Similar to other natural compounds, unknown and scarce Benzylisoquinoline alkaloids (BIAs) are expected to be a source for drug discovery; BIAs with novel functions have been demonstrated as promising anticancer drug candidates, including novel bisbenzylisoquinoline alkaloids used as ingredients for crude drugs[4,5]
In the yeast system used for BIA production, tyrosine hydroxylase (TH) was successfully used for l-DOPA synthesis via the tetrahydrobiopterin (BH4)-synthetic pathway[9]
Summary
Many medicinal compounds have been discovered from natural resources, with some in wide use as popular medications. The active components of these pharmaceuticals accumulate in sufficient amounts in nature to enable scientific evaluation; it is relatively easy to harvest the source and assess the possibilities for medical use. Certain natural compounds anticipated as novel drug candidates occur in low concentrations in nature, making identification of the useful activities of these rare natural products difficult. The low content of some target compounds makes drug discovery from natural products difficult[1]. Advances in biotechnology and synthetic biology allow microbial production of difficult-to-obtain compounds, including plant secondary metabolites[2]. Engineered microbes can produce appreciable amounts of scarce natural compounds, thereby enabling the synthesis of the derived novel and synthetic compounds, as well as the validation of their activities. We assessed the biological activity of these BIAs by treating human primary cells and measuring the levels of biomarkers associated with various disease models[12,13]
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