Benzophenanthridine Alkaloid

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Christopher W W Beecher - One of the best experts 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

  • 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.

Toni M Kutchan - One of the best experts 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.

  • Enzymology and molecular biology of Alkaloid biosynthesis
    Tetrahedron, 1991
    Co-Authors: Toni M Kutchan, Heinz Dittrich, D. Bracher, Meinhart H. Zenk
    Abstract:

    Abstract The biosynthetic pathways leading to the Benzophenanthridine Alkaloid, sanguinarine, and the indole Alkaloids, ajmalicine and ajmaline, have been solved at the level of the individual enzymes involved. The cDNA for two of the key enzymes has been cloned and the enzymes subsequently actively expressed in heterologous organisms.

Gail B Mahady - One of the best experts 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.

Peter J Facchini - One of the best experts on this subject based on the ideXlab platform.

  • Modulation of berberine bridge enzyme levels in transgenic root cultures of California poppy alters the accumulation of Benzophenanthridine Alkaloids
    Plant Molecular Biology, 2003
    Co-Authors: Sangun Park, Min Yu, Peter J Facchini
    Abstract:

    California poppy ( Eschscholzia californica Cham.) root cultures produce a variety of Benzophenanthridine Alkaloids, such as sanguinarine, chelirubine and macarpine, with potent biological activity. Sense and antisense constructs of genes encoding the berberine bridge enzyme (BBE) were introduced into California poppy root cultures. Transgenic roots expressing BBE from opium poppy ( Papaver somniferum L.) displayed higher levels of BBE mRNA, protein and enzyme activity, and increased accumulation of Benzophenanthridine Alkaloids compared to control roots transformed with a β-glucuronidase gene. In contrast, roots transformed with an antisense- BBE construct from California poppy had lower levels of BBE mRNA and enzyme activity, and reduced Benzophenanthridine Alkaloid accumulation, relative to controls. Pathway intermediates were not detected in any transgenic root lines. Suppression of Benzophenanthridine Alkaloid biosynthesis using antisense- BBE also reduced the growth rate of the root cultures. Two-dimensional ^1H-NMR spectroscopy showed no difference in the abundance of carbohydrate metabolites in the various transgenic roots lines. However, transformed roots with low levels of Benzophenanthridine Alkaloids contained larger cellular pools of certain amino acids compared to controls. In contrast, cellular pools of several amino acids were reduced in transgenic roots with elevated Benzophenanthridine Alkaloid levels relative to controls. The relative abundance of tyrosine, from which Benzophenanthridine Alkaloids are derived, was only marginally altered in all transgenic root lines; thus, altering metabolic flux through Benzophenanthridine Alkaloid pathways can affect cellular pools of specific amino acids. Consideration of such interactions is important for the design of metabolic engineering strategies that target Benzophenanthridine Alkaloid biosynthesis.

  • antisense rna mediated suppression of Benzophenanthridine Alkaloid biosynthesis in transgenic cell cultures of california poppy
    Plant Physiology, 2002
    Co-Authors: Sangun Park, Min Yu, Peter J Facchini
    Abstract:

    California poppy ( Eschscholzia californica Cham.) cell cultures produce several Benzophenanthridine Alkaloids, such as sanguinarine, chelirubine, and macarpine, with potent pharmacological activity. Antisense constructs of genes encoding two enzymes involved in Benzophenanthridine Alkaloid biosynthesis, the berberine bridge enzyme (BBE) and N -methylcoclaurine 3′-hydroxylase (CYP80B1), were introduced separately into California poppy cell cultures. Transformed cell lines expressing antisense BBE or antisense CYP80B1 constructs and displaying low levels of BBE or CYP80B1 mRNAs, respectively, showed reduced accumulation of Benzophenanthridine Alkaloids compared with control cultures transformed with a β-glucuronidase gene. Pathway intermediates were not detected in any of the transformed cell lines. The suppression of Benzophenanthridine Alkaloid biosynthesis using BBE or CYP80B1 antisense RNA constructs also reduced the growth rate of the cultures. Two-dimensional 1 H-nuclear magnetic resonance and in vivo 15 N-nuclear magnetic resonance spectroscopy showed no difference in the abundance of carbohydrate metabolites in the various transgenic cell lines. However, transformed cells with reduced Benzophenanthridine Alkaloid levels contained larger cellular pools of several amino acids including alanine, leucine, phenylalanine, threonine, and valine compared with controls. The relative abundance of tyrosine, from which Benzophenanthridine Alkaloids are derived, was less than 2-fold higher in antisense-suppressed cells relative to controls. These results show that alterations in the metabolic flux through Benzophenanthridine Alkaloid biosynthesis can affect the regulation of amino acid pools. These data provide new insight into the metabolic engineering of Benzophenanthridine Alkaloid pathways.

Sangun Park - One of the best experts on this subject based on the ideXlab platform.

  • Modulation of berberine bridge enzyme levels in transgenic root cultures of California poppy alters the accumulation of Benzophenanthridine Alkaloids
    Plant Molecular Biology, 2003
    Co-Authors: Sangun Park, Min Yu, Peter J Facchini
    Abstract:

    California poppy ( Eschscholzia californica Cham.) root cultures produce a variety of Benzophenanthridine Alkaloids, such as sanguinarine, chelirubine and macarpine, with potent biological activity. Sense and antisense constructs of genes encoding the berberine bridge enzyme (BBE) were introduced into California poppy root cultures. Transgenic roots expressing BBE from opium poppy ( Papaver somniferum L.) displayed higher levels of BBE mRNA, protein and enzyme activity, and increased accumulation of Benzophenanthridine Alkaloids compared to control roots transformed with a β-glucuronidase gene. In contrast, roots transformed with an antisense- BBE construct from California poppy had lower levels of BBE mRNA and enzyme activity, and reduced Benzophenanthridine Alkaloid accumulation, relative to controls. Pathway intermediates were not detected in any transgenic root lines. Suppression of Benzophenanthridine Alkaloid biosynthesis using antisense- BBE also reduced the growth rate of the root cultures. Two-dimensional ^1H-NMR spectroscopy showed no difference in the abundance of carbohydrate metabolites in the various transgenic roots lines. However, transformed roots with low levels of Benzophenanthridine Alkaloids contained larger cellular pools of certain amino acids compared to controls. In contrast, cellular pools of several amino acids were reduced in transgenic roots with elevated Benzophenanthridine Alkaloid levels relative to controls. The relative abundance of tyrosine, from which Benzophenanthridine Alkaloids are derived, was only marginally altered in all transgenic root lines; thus, altering metabolic flux through Benzophenanthridine Alkaloid pathways can affect cellular pools of specific amino acids. Consideration of such interactions is important for the design of metabolic engineering strategies that target Benzophenanthridine Alkaloid biosynthesis.

  • antisense rna mediated suppression of Benzophenanthridine Alkaloid biosynthesis in transgenic cell cultures of california poppy
    Plant Physiology, 2002
    Co-Authors: Sangun Park, Min Yu, Peter J Facchini
    Abstract:

    California poppy ( Eschscholzia californica Cham.) cell cultures produce several Benzophenanthridine Alkaloids, such as sanguinarine, chelirubine, and macarpine, with potent pharmacological activity. Antisense constructs of genes encoding two enzymes involved in Benzophenanthridine Alkaloid biosynthesis, the berberine bridge enzyme (BBE) and N -methylcoclaurine 3′-hydroxylase (CYP80B1), were introduced separately into California poppy cell cultures. Transformed cell lines expressing antisense BBE or antisense CYP80B1 constructs and displaying low levels of BBE or CYP80B1 mRNAs, respectively, showed reduced accumulation of Benzophenanthridine Alkaloids compared with control cultures transformed with a β-glucuronidase gene. Pathway intermediates were not detected in any of the transformed cell lines. The suppression of Benzophenanthridine Alkaloid biosynthesis using BBE or CYP80B1 antisense RNA constructs also reduced the growth rate of the cultures. Two-dimensional 1 H-nuclear magnetic resonance and in vivo 15 N-nuclear magnetic resonance spectroscopy showed no difference in the abundance of carbohydrate metabolites in the various transgenic cell lines. However, transformed cells with reduced Benzophenanthridine Alkaloid levels contained larger cellular pools of several amino acids including alanine, leucine, phenylalanine, threonine, and valine compared with controls. The relative abundance of tyrosine, from which Benzophenanthridine Alkaloids are derived, was less than 2-fold higher in antisense-suppressed cells relative to controls. These results show that alterations in the metabolic flux through Benzophenanthridine Alkaloid biosynthesis can affect the regulation of amino acid pools. These data provide new insight into the metabolic engineering of Benzophenanthridine Alkaloid pathways.