Improvement of Reticuline Productivity from Dopamine by Using Engineered<i>Escherichia coli</i>

Kim, Ju-Sung; Nakagawa, Akira; Yamazaki, Yuya; Matsumura, Eitaro; Koyanagi, Takashi; Minami, Hiromichi; Katayama, Takane; Sato, Fumihiko; Kumagai, Hidehiko

doi:10.1271/bbb.130552

Cited by 27 publications

(25 citation statements)

References 9 publications

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“…The performance of the E. coli strain was enhanced to 54.4 mg/L reticuline by systematically optimizing the Exploiting plant alkaloids Schlä ger and Drä ger 159 Table 1 Production of BIA metabolites in yeast and in E. coli. growth temperature, medium pH and the gene copy number of the monoamine oxidase and of norcoclaurine synthase [28]. Cell-free productivity of reticuline was even higher.…”

Section: Biosynthetic Steps: Enzymes and Genesmentioning

confidence: 95%

“…A third E. coli strain expressing three methyltransferases specific for methylating the phenolic hydroxyl groups was mixed with the supernatant of the (R,S)-tetrahydropapaveroline-forming strain and produced 48 mg/L reticuline within 12 h. It is notable that in this system, the condensation of dopamine and 3,4-dihydroxyphenylacetaldehyde in the second step was left to a spontaneous reaction. It was reported however, that in the course of reticuline formation from dopamine in E. coli, gene copy number and thus expression of norcoclaurine synthase had a stronger influence on the reticuline yield than the copy gene number of monoamine oxidase [28]. Norcoclaurine synthase catalyzes a Pictet-Spengler reaction, which is a condensation of a primary arylethylamine with an aldehyde forming a new heterocycle [15,16].…”

Section: Biosynthetic Steps: Enzymes and Genesmentioning

confidence: 99%

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Exploiting plant alkaloids

Schläger

Dräger

2016

Current Opinion in Biotechnology

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Section: Biosynthetic Steps: Enzymes and Genesmentioning

confidence: 95%

Section: Biosynthetic Steps: Enzymes and Genesmentioning

confidence: 99%

Exploiting plant alkaloids

Schläger

Dräger

2016

Current Opinion in Biotechnology

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“…We have previously engineered the yeast Saccharomyces cerevisiae as a host for the production of reticuline, a branch point intermediate in the biosynthesis of several subgroups of BIAs, including the morphinan and protoberberine alkaloids, from a fed precursor 12 . Total synthesis of reticuline from tyrosine was later demonstrated in the bacterial host Escherichia coli 13-15 . However, downstream modification of reticuline to form further functionalized molecules, including scoulerine, canadine, salutaridine, magnofluorine, and corytuberine, has only been achieved in a yeast host 12,16 .…”

Section: Introductionmentioning

confidence: 99%

A microbial biomanufacturing platform for natural and semisynthetic opioids

2014

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Opiates and related molecules are medically essential, but their production via field cultivation of opium poppy Papaver somniferum leads to supply inefficiencies and insecurity. As an alternative production strategy, we developed baker's yeast Saccharomyces cerevisiae as a microbial host for the transformation of opiates. Yeast strains engineered to express heterologous genes from P. somniferum and bacterium Pseudomonas putida M10 convert thebaine to codeine, morphine, hydromorphone, hydrocodone, and oxycodone. A new biosynthetic branch to neopine and neomorphine was discovered, which diverted pathway flux from morphine and other target products. Strain titer and specificity was optimized by titrating gene copy number, enhancing cosubstrate supply, applying a spatial engineering strategy, and performing high-density fermentation, resulting in total opioid titers up to 131 mg/L. This work is an important step toward total biosynthesis of valuable benzylisoquinoline alkaloid drug molecules and demonstrates the potential for developing a sustainable and secure yeast biomanufacturing platform for opioids.

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“…For the production of S-reticuline from dopamine in E. coli, the conversion yield from dopamine to S-reticuline was increased to 11% from as low as 1.3% by optimizing the pH value of the medium to 6.0, coupled with overexpression of bottleneck enzymes. [281] Conversion efficiency from R-reticuline to thebaine in yeast was also greatly enhanced in a more alkaline condition (pH 8.5-9). [275] This was because salutaridinol-7-O-acetate, converted from salutaridinol by salutaridinol 7-O-acetyltransferase, is spontaneously converted to thebaine at alkaline conditions while rearranging to side products at lower pH.…”

Section: Fermentation Strategiesmentioning

confidence: 97%

“…[263] However, since the conversion yield from dopamine to S-reticuline was as low as 1.3%, additional works were done to enhance this yield up to 11% by optimization of fermentation conditions including optimization of pH and increasing the NCS expression level by adjusting the gene copy number. [281] Metabolic flux balancing can be done in a step-by-step manner. Trenchard et al applied this strategy for the production of sanguinarine in yeast.…”

Section: Balancing Metabolic Fluxmentioning

confidence: 99%

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

Park

Yang

et al. 2017

Adv. Biosys.

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Natural products have been attracting much interest around the world for their diverse applications, especially in drug and food industries. Plants have been a major source of many different natural products. However, plants are affected by weather and environmental conditions and their successful extraction is rather limited. Chemical synthesis is inefficient due to the complexity of their chemical structures involving enantioselectivity and regioselectivity. For these reasons, an alternative means of overproducing valuable natural products using microorganisms has emerged. In recent years, various metabolic engineering strategies have been developed for the production of natural products by microorganisms. Here, the strategies taken to produce natural products are reviewed. For convenience, natural products are classified into four main categories: terpenoids, phenylpropanoids, polyketides, and alkaloids. For each product category, the strategies for establishing and rewiring the metabolic network for heterologous natural product biosynthesis, systems approaches undertaken to optimize production hosts, and the strategies for fermentation optimization are reviewed. Taken together, metabolic engineering has enabled microorganisms to serve as a prominent platform for natural compounds production. This article examines both the conventional and novel strategies of metabolic engineering, providing general strategies for complex natural compound production through the development of robust microbial‐cell factories.

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Improvement of Reticuline Productivity from Dopamine by Using EngineeredEscherichia coli

Cited by 27 publications

References 9 publications

Exploiting plant alkaloids

Exploiting plant alkaloids

A microbial biomanufacturing platform for natural and semisynthetic opioids

Metabolic Engineering of Microorganisms for the Production of Natural Compounds

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