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Benzophenanthridine Alkaloid

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Christopher W W Beecher – 1st expert on this subject based on the ideXlab platform

  • Angoline and Chelerythrine, Benzophenanthridine Alkaloids That Do Not Inhibit Protein Kinase C
    Journal of Biological Chemistry, 1998
    Co-Authors: Wei Guo Qing, Christopher W W Beecher, Lumonadio Luyengi, Rajendra G. Mehta, Kazuko Kawanishi, Harry H. S. Fong, A. Douglas Kinghorn, John M. Pezzuto

    Abstract:

    Abstract Starting with an extract derived from the stem ofMacleaya cordata (Papaveraceae) that was active in the process of inhibiting phorbol 12,13-dibutyrate binding to partially purified protein kinase C (PKC), the Benzophenanthridine Alkaloid angoline was isolated and identified. This discovery appeared in context, as a related Benzophenanthridine Alkaloid, chelerythrine, has been reported to mediate a variety of biological activities, including potent and selective inhibition of protein kinase C (PKC). However, in our studies, angoline was not observed to function as a potent inhibitor of PKC. Moreover, we were unable to confirm the reported inhibitory activity of chelerythrine. In a comprehensive series of studies performed with various PKC isozymes derived from a variety of mammalian species, neither chelerythrine nor angoline inhibited activity with high potency. To the contrary, chelerythrine stimulated PKC activity in the cytosolic fractions of rat and mouse brain in concentrations up to 100 μm. In addition, chelerythrine and angoline did not inhibit [3H]phorbol 12,13-dibutyrate binding to the regulatory domain of PKC at concentrations up to 40 μg/ml, and no significant alteration of PKC-α, -β, or -γ translocation was observed with human leukemia (HL-60) cells in culture. Further, chelerythrine did not inhibit 12-O-tetradecanoylphorbol 13-acetate-induced ornithine decarboxylase activity with cultured mouse 308 cells, but angoline was active in this capacity with an IC50 value of 1.0 μg/ml. A relatively large number of biological responses have been reported in studies conducted with chelerythrine, and alteration of PKC activity has been considered as a potential mechanism of action. In light of the current report, mechanisms independent of PKC inhibition should be considered as responsible for these effects.

  • involvement of protein kinase and g proteins in the signal transduction of Benzophenanthridine Alkaloid biosynthesis
    Phytochemistry, 1998
    Co-Authors: Gail B Mahady, Christopher W W Beecher

    Abstract:

    Abstract Benzophenanthridine Alkaloid biosynthesis and biosynthetic enzyme activity were induced in suspension-cells of Sanguinaria canadensis L. by compounds that stimulate the activities of protein kinase and GTP-binding proteins. The results indicate that one or more protein kinases, and putative G proteins are involved in the signal transduction pathway that mediates ABA and fungal-induced Benzophenanthridine Alkaloid biosynthesis. We have previously reported that elicitor-induced Benzophenanthridine Alkaloid biosynthesis in suspension-cell cultures of Sanguinaria canadensis L. (SCP-GM) is mediated by a signal transduction system that involves calcium and possibly protein kinase(s). In this work, a number of exogenous agents were employed to further investigate the components of the signal transduction pathway involved in the induction of Alkaloid biosynthesis by a fungal elicitor and abscisic acid (ABA). SCP-GM suspension-cells were treated with compounds that modify protein kinase activity, including phorbol esters, and 1-oleoyl-2-acetyl-rac-glycerol (OAG), a synthetic diacylglycerol analogue. Phorbol-12-myristate-13-acetate induced Alkaloid accumulation by as much as 65-fold over control values, while the negative control, phorbol-13-monoacetate, had no effect. OAG also increased Alkaloid production by approximately 25-fold as compared to controls. Likewise, pretreatment of the suspension-cell cultures with H-7 or staurosporine, significantly suppressed ABA- or fungal-induction of Benzophenanthridine Alkaloid biosynthesis. Modulators of GTP-binding protein activity were also active in this system. Treatment of the suspension-cells with cholera toxin (CHX) induced Alkaloid accumulation by 25-fold, which increased to 34-fold when CHX was combined with a fungal elicitor derived from Penicillium expansum (PE), and 32-fold when CHX was combined with ABA. Treatment of SCP-GM cells with CHX also enhanced the activities of two N -methyltransferases in the Benzophenanthridine biosynthetic pathway namely, tetrahydroberberine- N -methyltransferase and tetrahydrocoptisine- N -methyltransferase, by six and seven fold, respectively. Furthermore, Benzophenanthridine Alkaloid biosynthesis was induced by treating the suspension-cells with the G-protein activators, mastoparan, mas-7 or melittin, while the inactive homologue, mas-17, did not. Suppression of Alkaloid accumulation occurred when the susoension-cells were treated with GDPsS or pertussis toxin prior to treatment of the SCP-GM cells with either PE or ABA. The results support the hypothesis that one or more protein kinases, and putative G proteins are involved in the signal transduction pathway that mediates ABA and fungal-induced Benzophenanthridine Alkaloid biosynthesis.

  • quercetin induced Benzophenanthridine Alkaloid production in suspension cell cultures of sanguinaria canadensis
    Planta Medica, 1994
    Co-Authors: Gail B Mahady, Christopher W W Beecher

    Abstract:

    Addition of micromolar concentrations of quercetin or rutin to suspension cell cultures of Sanguinaria canadensis L. (bloodroot) induced the biosynthesis of sanguinarine and chelerythrine in a dose-dependent manner. In contrast, related compounds : baicalein, naringin, naringenin, catechin, caffeic acid and benzoic acid displayed very weak inductive activity. Off the two active flavonoids, quercetin was the most effective for inducing Benzophenanthridine Alkaloid biosynthesis, with dose of 100 μM increasing Alkaloid production over 375% as compared to negative controls

Toni M Kutchan – 2nd expert on this subject based on the ideXlab platform

  • barbiturate induced Benzophenanthridine Alkaloid formation proceeds by gene transcript accumulation in the california poppy
    Biochemical and Biophysical Research Communications, 1997
    Co-Authors: Georg Haider, Thomas Kislinger, Toni M Kutchan

    Abstract:

    Abstract Four barbiturates, barbituric acid, butethal, phenobarbital, and 2-thiobarbituric acid, of fourteen tested were found to induce accumulation of Benzophenanthridine Alkaloids in cell suspension cultures of the California poppy Eschscholzia californica. When the plant cell suspension cultures were treated with 1 mM barbiturate, Alkaloids accumulated to 100 mg/l within four days. This is a level comparable to that achieved with 300 μM concentration of the established secondary metabolite inducer methyl jasmonate. In contrast to methyl jasmonate, barbituric acid, and 2-thiobarbituric acid, butethal and phenobarbital treatment resulted in a different Alkaloid profile, suggesting that only select cytochrome P-450 genes were activated by these latter two barbiturates. RNA gel blot analysis of barbiturate induced cell cultures confirmed that transcripts of at least two Benzophenanthridine Alkaloid biosynthetic genes cyp80b1 (encoding the cytochrome P-450-dependent monooxygenase ( S )- N -methylcoclaurine 3′-hydroxylase) and bbe1 (encoding the covalently flavinylated berberine bridge enzyme) increased up to 5- to 7-fold over control values.

  • Heterologous expression of Alkaloid biosynthetic genes — a review☆
    Gene, 1996
    Co-Authors: Toni M Kutchan

    Abstract:

    Abstract Tetrahydrobenzylisoquinoline Alkaloids comprise a diverse class of secondary metabolites with many pharmacologically active members. The biosynthesis at the enzyme level of at least two tetrahydrobenzylisoquinoline Alkaloids, the Benzophenanthridine Alkaloid sanguinarine in the California poppy, Eschscholtzia californica , and the bisbenzylisoquinoline Alkaloid berbamunine in barberry, Berberis stolonifera , has been elucidated in detail starting from the aromatic amino acid (aa) l -tyrosine. In an initial attempt to develop alternate systems for the production of medicinally important Alkaloids, one enzyme from each pathway (BBE, a covalently flavinylated enzyme of Benzophenanthridine Alkaloid biosynthesis and CYP80, a phenol coupling cytochrome P-450 -dependent oxidase of bisbenzylisoquinoline Alkaloid biosynthesis) has been purified to homogeneity, a partial aa sequence determined, and the corresponding cDNAs isolated with aid of synthetic oligos based on the aa sequences. The recombinant enzymes were actively expressed in Spodoptera frugiperda Sf9 cells using a baculovirus vector, purified and then characterized. Insect cell culture has proven to be a powerful system for the overexpression of Alkaloid biosynthetic genes.

  • characterization and mechanism of the berberine bridge enzyme a covalently flavinylated oxidase of Benzophenanthridine Alkaloid biosynthesis in plants
    Journal of Biological Chemistry, 1995
    Co-Authors: Toni M Kutchan, Heinz Dittrich

    Abstract:

    Abstract The berberine bridge enzyme ((S)-reticuline:oxygen oxidoreductase (methylene-bridge-forming), EC 1.5.3.9) catalyzes the oxidative cyclization of the N-methyl moiety of (S)-reticuline into the berberine bridge carbon, C-8, of (S)-scoulerine. This is a reaction that has neither an equivalent in organic chemistry nor a parallel in nature. The uniqueness of this catalytic reaction prompted an in depth study that began with the isolation of the cDNA encoding the berberine bridge enzyme followed by the overexpression of this cDNA in insect cell culture. The heterologously expressed enzyme has herein been shown to contain covalently attached FAD in a molar ratio of cofactor to protein of 1:1.03. Site-directed mutagenesis and laser desorption time-of-flight mass spectrometry suggest that the site of covalent attachment is at His-104. The holoenzyme exhibited absorbance maxima at 380 and 442 nm and a fluorescence emission maximum at 628 nm (310 nm excitation). Enzymic transformation of a series of (S)-reticuline derivatives modified with respect to the stereochemistry at C-1 or in the aromatic ring substitution suggests that ring closure proceeds in two steps: formation of the methylene iminium ion and subsequent ring closure via an ionic mechanism.

Gail B Mahady – 3rd expert on this subject based on the ideXlab platform

  • involvement of protein kinase and g proteins in the signal transduction of Benzophenanthridine Alkaloid biosynthesis
    Phytochemistry, 1998
    Co-Authors: Gail B Mahady, Christopher W W Beecher

    Abstract:

    Abstract Benzophenanthridine Alkaloid biosynthesis and biosynthetic enzyme activity were induced in suspension-cells of Sanguinaria canadensis L. by compounds that stimulate the activities of protein kinase and GTP-binding proteins. The results indicate that one or more protein kinases, and putative G proteins are involved in the signal transduction pathway that mediates ABA and fungal-induced Benzophenanthridine Alkaloid biosynthesis. We have previously reported that elicitor-induced Benzophenanthridine Alkaloid biosynthesis in suspension-cell cultures of Sanguinaria canadensis L. (SCP-GM) is mediated by a signal transduction system that involves calcium and possibly protein kinase(s). In this work, a number of exogenous agents were employed to further investigate the components of the signal transduction pathway involved in the induction of Alkaloid biosynthesis by a fungal elicitor and abscisic acid (ABA). SCP-GM suspension-cells were treated with compounds that modify protein kinase activity, including phorbol esters, and 1-oleoyl-2-acetyl-rac-glycerol (OAG), a synthetic diacylglycerol analogue. Phorbol-12-myristate-13-acetate induced Alkaloid accumulation by as much as 65-fold over control values, while the negative control, phorbol-13-monoacetate, had no effect. OAG also increased Alkaloid production by approximately 25-fold as compared to controls. Likewise, pretreatment of the suspension-cell cultures with H-7 or staurosporine, significantly suppressed ABA- or fungal-induction of Benzophenanthridine Alkaloid biosynthesis. Modulators of GTP-binding protein activity were also active in this system. Treatment of the suspension-cells with cholera toxin (CHX) induced Alkaloid accumulation by 25-fold, which increased to 34-fold when CHX was combined with a fungal elicitor derived from Penicillium expansum (PE), and 32-fold when CHX was combined with ABA. Treatment of SCP-GM cells with CHX also enhanced the activities of two N -methyltransferases in the Benzophenanthridine biosynthetic pathway namely, tetrahydroberberine- N -methyltransferase and tetrahydrocoptisine- N -methyltransferase, by six and seven fold, respectively. Furthermore, Benzophenanthridine Alkaloid biosynthesis was induced by treating the suspension-cells with the G-protein activators, mastoparan, mas-7 or melittin, while the inactive homologue, mas-17, did not. Suppression of Alkaloid accumulation occurred when the susoension-cells were treated with GDPsS or pertussis toxin prior to treatment of the SCP-GM cells with either PE or ABA. The results support the hypothesis that one or more protein kinases, and putative G proteins are involved in the signal transduction pathway that mediates ABA and fungal-induced Benzophenanthridine Alkaloid biosynthesis.

  • quercetin induced Benzophenanthridine Alkaloid production in suspension cell cultures of sanguinaria canadensis
    Planta Medica, 1994
    Co-Authors: Gail B Mahady, Christopher W W Beecher

    Abstract:

    Addition of micromolar concentrations of quercetin or rutin to suspension cell cultures of Sanguinaria canadensis L. (bloodroot) induced the biosynthesis of sanguinarine and chelerythrine in a dose-dependent manner. In contrast, related compounds : baicalein, naringin, naringenin, catechin, caffeic acid and benzoic acid displayed very weak inductive activity. Off the two active flavonoids, quercetin was the most effective for inducing Benzophenanthridine Alkaloid biosynthesis, with dose of 100 μM increasing Alkaloid production over 375% as compared to negative controls

  • elicitor stimulated Benzophenanthridine Alkaloid biosynthesis in bloodroot suspension cultures is mediated by calcium
    Phytochemistry, 1994
    Co-Authors: Gail B Mahady, Christopher W W Beecher

    Abstract:

    Abstract Addition of an elicitor derived from the fungus Penicillium expansum Link (PE-elicitor) or the calcium ionophore A23187, to a suspension-cell culture of Sanguinaria canadensis induced the production of the Benzophenanthridine Alkaloids, sanguinarine and chelerythrine, in a dose-dependent manner. Pretreatment of the cells with the specific calcium chelatant EGTA (3 mM) or the calcium channel inhibitor verapamil (100 μM), for 1 hr prior to the addition of the PE-elicitor, decreased the accumulation of both sanguinarine and chelerythrine. Moreover, A23187-stimulated Alkaloid accumulation was almost completely inhibited by pretreating the suspension cells with EGTA (3 mM) for 1 hr and this suppression was reversed by the readdition of calcium ions to the medium. Furthermore, addition of trifluoperazine (100 μM) to the suspension-cell cultures 1 hr before the PE-elicitor (35 μg Glc equ ml −1 ) treatment suppressed the accumulation of Benzophenanthridine Alkaloids by 51% as compared to suspension cells treated with PE-elicitor alone. These results demonstrate that an external source of calcium ions is required for elicitor-induced Benzophenanthridine Alkaloid accumulation and suggest that calcium and possibly calmodulin and/or protein kinase C may participate in a signal transduction system that mediates this process.