Potential cancer chemopreventive activity of simple isoquinolines, 1-benzylisoquinolines, and protoberberines

Cui, Wenhua; Iwasa, Kinuko; Tokuda, Harukuni; Kashihara, Akiko; Mitani, Yosuke; Hasegawa, Tomoko; Nishiyama, Yumi; Moriyasu, Masataka; Nishino, Hoyoku; Hanaoka, Miyoji; Mukai, Chisato; Takeda, Kazuyoshi

doi:10.1016/j.phytochem.2005.10.007

Cited by 37 publications

(28 citation statements)

References 19 publications

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“…Our system can provide a variety of isoquinoline alkaloid skeletons besides norlaudanosoline by the combination of other amines and aldehydes for substrates. The widespread application of our system may lead to further progress with microbial systems for use in the pharmaceutical industry, which needs a diverse chemical library to develop more advanced tools for chemical therapy, such as anticancer, antidiabetes, and antimalarial drugs (28,29). Bioengineering by using microbial, plant, and other biological resources is a novel basic tool for manufacturing a broad range of plant-derived metabolites, particularly isoquinoline alkaloids.…”

Section: Discussionmentioning

confidence: 99%

Microbial production of plant benzylisoquinoline alkaloids

Minami

Kim

Ikezawa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

312

230

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Benzylisoquinoline alkaloids, such as the analgesic compounds morphine and codeine, and the antibacterial agents berberine, palmatine, and magnoflorine, are synthesized from tyrosine in the Papaveraceae, Berberidaceae, Ranunculaceae, Magnoliaceae, and many other plant families. It is difficult to produce alkaloids on a large scale under the strict control of secondary metabolism in plants, and they are too complex for cost-effective chemical synthesis. By using a system that combines microbial and plant enzymes to produce desired benzylisoquinoline alkaloids, we synthesized (S)-reticuline, the key intermediate in benzylisoquinoline alkaloid biosynthesis, from dopamine by crude enzymes from transgenic Escherichia coli. The final yield of (S)-reticuline was 55 mg/liter within 1 h. Furthermore, we synthesized an aporphine alkaloid, magnoflorine, or a protoberberine alkaloid, scoulerine, from dopamine via reticuline by using different combination cultures of transgenic E. coli and Saccharomyces cerevisiae cells. The final yields of magnoflorine and scoulerine were 7.2 and 8.3 mg/liter culture medium. These results indicate that microbial systems that incorporate plant genes cannot only enable the mass production of scarce benzylisoquinoline alkaloids but may also open up pathways for the production of novel benzylisoquinoline alkaloids.(S)-reticuline ͉ magnoflorine ͉ scoulerine

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Section: Discussionmentioning

confidence: 99%

Microbial production of plant benzylisoquinoline alkaloids

Minami

Kim

Ikezawa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

312

230

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“…Reversed-phase HPLC was performed with a Shimadzu LC-10A system: column, TSKgel ODS-80TM (4.6 ϫ 250 mm; Tosoh); solvent system, acetonitrile/H 2 O/acetic acid (30:69:1); flow rate, 0.8 ml/min; detection, absorbance measurement at 280 nm with an SPD6A photodiode array detector. (21). Ketoconazole was purchased from Wako Pure Chemical Industries, Ltd., Japan.…”

Section: Methodsmentioning

confidence: 99%

Molecular Cloning and Characterization of CYP80G2, a Cytochrome P450 That Catalyzes an Intramolecular C–C Phenol Coupling of (S)-Reticuline in Magnoflorine Biosynthesis, from Cultured Coptis japonica Cells

Ikezawa

Iwasa

Sato

2008

Journal of Biological Chemistry

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143

122

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Cytochrome P450s (P450) play a key role in oxidative reactions in plant secondary metabolism. Some of them, which catalyze unique reactions other than the standard hydroxylation, increase the structural diversity of plant secondary metabolites. In isoquinoline alkaloid biosyntheses, several unique P450 reactions have been reported, such as methylenedioxy bridge formation, intramolecular C-C phenol-coupling and intermolecular C-O phenol-coupling reactions. We report here the isolation and characterization of a C-C phenol-coupling P450 cDNA (CYP80G2) from an expressed sequence tag library of cultured Coptis japonica cells. Structural analysis showed that CYP80G2 had high amino acid sequence similarity to Berberis stolonifera CYP80A1, an intermolecular C-O phenol-coupling P450 involved in berbamunine biosynthesis. Heterologous expression in yeast indicated that CYP80G2 had intramolecular C-C phenol-coupling activity to produce (S)-corytuberine (aporphine-type) from (S)-reticuline (benzylisoquinoline type). Despite this intriguing reaction, recombinant CYP80G2 showed typical P450 properties: its C-C phenol-coupling reaction required NADPH and oxygen and was inhibited by a typical P450 inhibitor. Based on a detailed substrate-specificity analysis, this unique reaction mechanism and substrate recognition were discussed. CYP80G2 may be involved in magnoflorine biosynthesis in C. japonica, based on the fact that recombinant C. japonica S-adenosyl-L-methionine:coclaurine N-methyltransferase could convert (S)-corytuberine to magnoflorine.Isoquinoline alkaloids are a large group of alkaloids and include many pharmacologically useful compounds; e.g. the analgesic morphinan alkaloid morphine, the anti-tussive alkaloid codeine, and the anti-microbial alkaloids berberine and sanguinarine. Due to the importance of these pharmaceutically useful alkaloids, their biosynthetic pathways have been well investigated, and several of them have been completely clarified at the enzyme level (1-3). It is now known that many isoquinoline alkaloids share a common biosynthetic pathway from L-tyrosine to the key intermediate (S)-reticuline.(S)-Reticuline is a central precursor of various types of isoquinoline alkaloids such as morphinans, aporphines, pavines, protoberberines, protopines, and benzophenanthridines (1, 4). Although the molecular origin of this chemical diversity has not yet been clarified, recent studies have shown that many of their oxidative steps are catalyzed by cytochrome P450s (P450) 2 ( Fig. 1) (1-3, 5-11). Members of the P450 family are found in a very large number of species, especially in the plant kingdom (246 and 356 species in Arabidopsis thaliana and Oryza sativa in contrast to 57 and 84 species in human and Drosophila melanogaster) (12, 13), and many of them have been shown to be involved in plant secondary metabolism (14, 15).In the biosyntheses of isoquinoline alkaloids, P450-mediated hydroxylation, methylenedioxy bridge formation, and phenolcoupling reactions have been reported. Although members of the CYP80B s...

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“…Synthesis of racemic substrate (±)-1 1-Methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (±)-1 was synthesized via Bischler-Napieralsky cyclization of the corresponding amides prepared from 3,4-dimethoxyphenylethylamine and acetic anhydride. 27 Next, CALA (immobilized on Immobead 150 from Candida antarctica), a potential alternative for the chemical resolution of (±)-1, was used as an enzyme catalyst for the enzymatic N-acylation of (±)-1.…”

Section: Resultsmentioning

confidence: 99%