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Microbial Production of Plant Benzylisoquinoline Alkaloids

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Microbial Production of Plant Benzylisoquinoline Alkaloids Microbial production of plant benzylisoquinoline alkaloids Hiromichi Minami*, Ju-Sung Kim*, Nobuhiro Ikezawa†, Tomoya Takemura†, Takane Katayama*, Hidehiko Kumagai*, and Fumihiko Sato†‡ *Research Institute for Bioresources and Biotechnology, Ishikawa Prefectural University, Nonoichi-machi, Ishikawa 921-8836, Japan; and †Division of Integrated Life Science, Graduate School of Biostudies, Kyoto University, Oiwake-cho, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan Communicated by Yasuyuki Yamada, Nara Institute of Science and Technology, Nara, Japan, March 25, 2008 (received for review January 25, 2008) Benzylisoquinoline alkaloids, such as the analgesic compounds to alkaloid production, an enzymatic synthesis would be desir- morphine and codeine, and the antibacterial agents berberine, able for environmentally friendly and highly efficient alkaloid palmatine, and magnoflorine, are synthesized from tyrosine in the production. Papaveraceae, Berberidaceae, Ranunculaceae, Magnoliaceae, and Plant metabolic engineering often has been tried to increase many other plant families. It is difficult to produce alkaloids on a the amount of an alkaloid pathway end product, and selected large scale under the strict control of secondary metabolism in plant cells can produce sufficient quantities of metabolites for plants, and they are too complex for cost-effective chemical syn- industrial application (7). However, only a few successful exam- thesis. By using a system that combines microbial and plant ples of plant metabolic engineering have been reported, partic- enzymes to produce desired benzylisoquinoline alkaloids, we syn- ularly for the accumulation of benzylisoquinoline alkaloid me- thesized (S)-reticuline, the key intermediate in benzylisoquinoline tabolites. To date, transgenic opium poppy plant with RNAi of alkaloid biosynthesis, from dopamine by crude enzymes from codeinone reductase and transgenic California poppy cells with transgenic Escherichia coli. The final yield of (S)-reticuline was 55 RNAi of berberine bridge enzyme (BBE) have been reported for mg/liter within 1 h. Furthermore, we synthesized an aporphine the production of reticuline (1, 8). Although transgenic poppy is alkaloid, magnoflorine, or a protoberberine alkaloid, scoulerine, advantageous for the production of reticuline, the amount of from dopamine via reticuline by using different combination cul- product varies a great deal in plants and cultured cells, and plants tures of transgenic E. coli and Saccharomyces cerevisiae cells. The and cultured cells take a long time to grow (9). Furthermore, final yields of magnoflorine and scoulerine were 7.2 and 8.3 these transgenic poppies accumulate some methylated deriva- mg/liter culture medium. These results indicate that microbial tives of reticuline. Although a transgenic approach can be a very systems that incorporate plant genes cannot only enable the mass powerful tool for metabolic engineering, this technology, includ- production of scarce benzylisoquinoline alkaloids but may also ing RNAi, still needs to be further improved before it can be used open up pathways for the production of novel benzylisoquinoline for desired metabolite production. alkaloids. Recently, some attempts to reconstruct entire plant biosyn- thetic processes have been examined in microbial systems (10, (S)-reticuline ͉ magnoflorine ͉ scoulerine 11). Microbial systems may be able to improve not only the quantity but also the quality of secondary metabolites because igher plants produce divergent chemicals, such as alkaloids, they do not include other plant metabolites. Although microbial Hterpenoids, and phenolic compounds, in secondary metab- systems offer several advantages for the biotransformation of olism. Among these chemicals, alkaloids are very important in chemicals, they also have disadvantages, such as limited substrate medicine because of their high biological activities. Alkaloids are availability, particularly for plant metabolites. The combination low-molecular-weight, nitrogen-containing compounds that are of microbial and plant-derived genes would be useful for the found in Ϸ20% of plant species. Most alkaloids are derived from establishment of efficient systems for the production of various amines produced by the decarboxylation of amino acids, such as compounds. Here, we report the establishment of a microbial histidine, lysine, ornithine, tryptophan, and tyrosine. Benzyliso- system for the production of reticuline, the key intermediate for quinoline alkaloids are a large and diverse group of pharma- benzylisoquinoline alkaloids, with the use of microbes with plant ceutical alkaloids with Ϸ2,500 defined structures. In the ben- enzyme genes. Furthermore, we propose that a system that zylisoquinoline alkaloid pathway, aporphine-type alkaloids, such combines two different microbes with different biosynthetic potentials to produce more divergent chemicals may be a as magnoflorine and corydine, and protoberberine-type alka- universal system. This advanced system is shown to produce two loids, such as berberine and coptisine, are produced via (S)- kinds of benzylisoquinoline alkaloids, magnoflorine and scoulerine. reticuline from tyrosine. (S)-Reticuline is a branch-point inter- mediate in the biosynthesis of many types of benzylisoquinoline Results and Discussion alkaloids and also a nonnarcotic alkaloid of pharmaceutical Experimental Design for Benzylisoquinoline Alkaloid Production in significance that is useful in the development of antimalarial and Microbes. Whereas our advanced system consisted of a two-step anticancer drugs (ref. 1 and references therein). Recent studies synthesis of alkaloids with Escherichia coli and Saccharomyces have also suggested that these alkaloids may be useful as novel cerevisiae cells, we first tried to produce reticuline, which is an medicines. For example, the aporphine-type alkaloid magnoflo- important intermediate in benzylisoquinoline alkaloid biosyn- SCIENCES rine has been reported to protect HDL during oxidant stress to prevent the development of atherosclerotic disease and to inhibit APPLIED BIOLOGICAL human lymphoblastoid cell-killing by HIV-1 (2–4). A recent Author contributions: H.M. and F.S. designed research; H.M. and J.-S.K. performed re- report stated that the antimicrobial agent berberine had choles- search; N.I., T.T., T.K., and H.K. contributed new reagents/analytic tools; H.M., N.I., T.T., T.K., terol-lowering activity (5). H.K., and F.S. analyzed data; and H.M. and F.S. wrote the paper. Because of the high interest in their potential for medicinal The authors declare no conflict of interest. use, some benzylisoquinoline alkaloids have been chemically ‡To whom correspondence should be addressed. E-mail: [email protected]. synthesized via total synthesis. For example, the total synthesis This article contains supporting information online at www.pnas.org/cgi/content/full/ of the narcotic analgesic morphine has been reported by Gates 0802981105/DCSupplemental. and Tschudi (6). Although chemical synthesis has been applied © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0802981105 PNAS ͉ May 27, 2008 ͉ vol. 105 ͉ no. 21 ͉ 7393–7398 Downloaded by guest on October 2, 2021 NH 2 synthesize reticuline from dopamine in E. coli (18–21). The MAO HOHO HO O coupling of dopamine and 3,4-dihydroxyphenylacetaldehyde H (3,4-DHPAA) enabled us to skip the step of the cytochrome HO HO P450 hydroxylase (CYP80B). Because MAO does not appear to Dopamine 3,4-DHPAA play a role in the biosynthesis of alkaloids in opium poppy (22), NCS microbial MAO was incorporated into reticuline biosynthesis to synthesize 3,4-DHPAA by the deamination of dopamine. In our HO previous study, two kinds of NCS, CjNCS1 and CjPR10A, have NH HO H been isolated from C. japonica cells and characterized (18). OHOH CjPR10A is sufficiently expressed in an active form in E. coli OH cells, whereas CjNCS1 forms a larger complex in plant cells, and (S)-Norlaudanosoline the recombinant enzyme expressed in E. coli cells has consid- 6OMT erably lower activity than that of native enzyme. Because HCO CjPR10A was more suitable than CjNCS1 in the microbial highly HCO 3 3 efficient production system, CjPR10A was used as NCS enzyme NCH NH 3 HO HO in reticuline biosynthesis. H H OHOH OH In the second step of aporphine-type alkaloid biosynthesis, the CNMT OH OH recently identified P450 enzyme (CYP80G2), corytuberine syn- (S)-3'-Hydroxycoclaurine (S)-3'-Hydroxy-N-methylcoclaurine thase (23), was used in S. cerevisiae with C. japonica CNMT, 4'OMT which has a relatively broad substrate specificity and can N- methylate corytuberine to synthesize magnoflorine (Fig. 1). HC 3 O C. japonica S. cerevisiae HC3 O Similarly, BBE of was expressed in to NCH N 3 produce scoulerine from reticuline. HO HO H H OH OH Reticuline Production in E. coli. BBE First, we examined high reticuline OCH3 OCH3 production as a key intermediate of benzylisoquinoline alkaloid S (S)-Reticuline ( )-Scoulerine in E. coli. For in vivo production, transgenic E. coli-expressing biosynthetic genes (i.e., MAO, NCS, 6OMT, CNMT, and CYP80G2 Ј HCO 4 OMT) necessary to produce reticuline from dopamine were 3 cultured with 2 mM dopamine in the medium. This culture N CH HO 3 HC3 O produced mainly (R,S)-reticuline at a yield of 2.0 mg/liter HO O + CH N 3 medium within 28 h (Fig. 2A and Fig. S2). Dopamine and the N HO + Corytuberine- - CH N HCO 3 resultant reticuline did not inhibit the growth of E. coli cells. An O 3 methyltransferase HO OCH3 (CNMT?)
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