The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
David W. Christianson - One of the best experts on this subject based on the ideXlab platform.
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Substitution of Aromatic Residues with Polar Residues in the Active Site Pocket of epi-Isozizaene Synthase Leads to the Generation of New Cyclic Sesquiterpenes
Biochemistry, 2017Co-Authors: Patrick N. Blank, David E. Cane, Golda H. Barrow, Wayne K. W. Chou, Lian Duan, David W. ChristiansonAbstract:The sesquiterpene cyclase epi-isozizaene synthase (EIZS) catalyzes the cyclization of farnesyl diphosphate to form the tricyclic hydrocarbon precursor of the antibiotic albaflavenone. The hydrophobic active site pocket of EIZS serves as a template as it binds and chaperones the flexible substrate and carbocation intermediates through the conformations required for a multistep reaction sequence. We previously demonstrated that the substitution of hydrophobic residues with other hydrophobic residues remolds the template and expands product Chemodiversity [Li, R., Chou, W. K. W., Himmelberger, J. A., Litwin, K. M., Harris, G. G., Cane, D. E., and Christianson, D. W. (2014) Biochemistry 53, 1155–1168]. Here, we show that the substitution of hydrophobic residues—specifically, Y69, F95, F96, and W203—with polar side chains also yields functional enzyme catalysts that expand product Chemodiversity. Fourteen new EIZS mutants are reported that generate product arrays in which eight new sesquiterpene products have ...
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exploring the influence of domain architecture on the catalytic function of diterpene synthases
Biochemistry, 2017Co-Authors: Travis A Pemberton, David E. Cane, Wayne K. W. Chou, Mengbin Chen, Golda G. Harris, Alex S. Genshaft, L Duan, Mustafa Koksal, David W. ChristiansonAbstract:Terpenoid synthases catalyze isoprenoid cyclization reactions underlying the generation of more than 80,000 natural products. Such dramatic Chemodiversity belies the fact that these enzymes generally consist of only three domain folds designated as α, β, and γ. Catalysis by class I terpenoid synthases occurs exclusively in the α domain, which is found with α, αα, αβ, and αβγ domain architectures. Here, we explore the influence of domain architecture on catalysis by taxadiene synthase from Taxus brevifolia (TbTS, αβγ), fusicoccadiene synthase from Phomopsis amygdali (PaFS, (αα)6), and ophiobolin F synthase from Aspergillus clavatus (AcOS, αα). We show that the cyclization fidelity and catalytic efficiency of the α domain of TbTS are severely compromised by deletion of the βγ domains; however, retention of the β domain preserves significant cyclization fidelity. In PaFS, we previously demonstrated that one α domain similarly influences catalysis by the other α domain [Chen, M., Chou, W. K. W., Toyomasu, T.,...
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Substitution of Aromatic Residues with Polar Residues in the Active Site Pocket of epi-Isozizaene Synthase Leads to the Generation of New Cyclic Sesquiterpenes
2017Co-Authors: Patrick N. Blank, David E. Cane, Golda H. Barrow, Wayne K. W. Chou, Lian Duan, David W. ChristiansonAbstract:The sesquiterpene cyclase epi-isozizaene synthase (EIZS) catalyzes the cyclization of farnesyl diphosphate to form the tricyclic hydrocarbon precursor of the antibiotic albaflavenone. The hydrophobic active site pocket of EIZS serves as a template as it binds and chaperones the flexible substrate and carbocation intermediates through the conformations required for a multistep reaction sequence. We previously demonstrated that the substitution of hydrophobic residues with other hydrophobic residues remolds the template and expands product Chemodiversity [Li, R., Chou, W. K. W., Himmelberger, J. A., Litwin, K. M., Harris, G. G., Cane, D. E., and Christianson, D. W. (2014) Biochemistry 53, 1155–1168]. Here, we show that the substitution of hydrophobic residuesspecifically, Y69, F95, F96, and W203with polar side chains also yields functional enzyme catalysts that expand product Chemodiversity. Fourteen new EIZS mutants are reported that generate product arrays in which eight new sesquiterpene products have been identified. Of note, some mutants generate acyclic and cyclic hydroxylated products, suggesting that the introduction of polarity in the hydrophobic pocket facilitates the binding of water capable of quenching carbocation intermediates. Furthermore, the substitution of polar residues for F96 yields high-fidelity sesquisabinene synthases. Crystal structures of selected mutants reveal that residues defining the three-dimensional contour of the hydrophobic pocket can be substituted without triggering significant structural changes elsewhere in the active site. Thus, more radical nonpolar–polar amino acid substitutions should be considered when terpenoid cyclase active sites are remolded by mutagenesis with the goal of exploring and expanding product Chemodiversity
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Exploring the Influence of Domain Architecture on the Catalytic Function of Diterpene Synthases
2017Co-Authors: Travis A. Pemberton, David E. Cane, Wayne K. W. Chou, Lian Duan, Mengbin Chen, Golda G. Harris, Mustafa Köksal, Alex S. Genshaft, David W. ChristiansonAbstract:Terpenoid synthases catalyze isoprenoid cyclization reactions underlying the generation of more than 80,000 natural products. Such dramatic Chemodiversity belies the fact that these enzymes generally consist of only three domain folds designated as α, β, and γ. Catalysis by class I terpenoid synthases occurs exclusively in the α domain, which is found with α, αα, αβ, and αβγ domain architectures. Here, we explore the influence of domain architecture on catalysis by taxadiene synthase from Taxus brevifolia (TbTS, αβγ), fusicoccadiene synthase from Phomopsis amygdali (PaFS, (αα)6), and ophiobolin F synthase from Aspergillus clavatus (AcOS, αα). We show that the cyclization fidelity and catalytic efficiency of the α domain of TbTS are severely compromised by deletion of the βγ domains; however, retention of the β domain preserves significant cyclization fidelity. In PaFS, we previously demonstrated that one α domain similarly influences catalysis by the other α domain [Chen, M., Chou, W. K. W., Toyomasu, T., Cane, D. E., and Christianson, D. W. (2016) ACS Chem. Biol. 11, 889−899]. Here, we show that the hexameric quaternary structure of PaFS enables cluster channeling. We also show that the α domains of PaFS and AcOS can be swapped so as to make functional chimeric αα synthases. Notably, both cyclization fidelity and catalytic efficiency are altered in all chimeric synthases. Twelve newly formed and uncharacterized C20 diterpene products and three C25 sesterterpene products are generated by these chimeras. Thus, engineered αβγ and αα terpenoid cyclases promise to generate Chemodiversity in the greater family of terpenoid natural products
Da-cheng Hao - One of the best experts on this subject based on the ideXlab platform.
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ethnopharmacology Chemodiversity and bioactivity of cephalotaxus medicinal plants
Chinese Journal of Natural Medicines, 2021Co-Authors: Da-cheng Hao, Xudong Hou, Pei-gen XiaoAbstract:Cephalotaxus is the only genus of Cephalotaxaceae family, and its natural resources are declining due to habitat fragmentation, excessive exploitation and destruction. In many areas of China, folk herbal doctors traditionally use Cephalotaxus plants to treat innominate swollen poison, many of which are cancer. Not only among Han people, but also among minority ethnic groups, Cephalotaxus is used to treat various diseases, e.g., cough, internal bleeding and cancer in Miao medicine, bruises, rheumatism and pain in Yao medicine, and ascariasis, hookworm disease, scrofula in She medicine, etc. Medicinal values of some Cephalotaxus species and compounds are acknowledged officially. However, there is a lack of comprehensive review summarizing the ethnomedicinal knowledge of Cephalotaxus, relevant medicinal phytometabolites and their bioactivities. The research progresses in ethnopharmacology, Chemodiversity, and bioactivities of Cephalotaxus medicinal plants are reviewed and commented here. Knowledge gaps are pinpointed and future research directions are suggested. Classic medicinal books, folk medicine books, herbal manuals and ethnomedicinal publications were reviewed for the genus Cephalotaxus (Sanjianshan in Chinese). The relevant data about ethnobotany, phytochemistry, and pharmacology were collected as comprehensively as possible from online databases including Scopus, NCBI PubMed, Bing Scholar, and China National Knowledge Infrastructure (CNKI). "Cephalotaxus", and the respective species name were used as keywords in database search. The obtained articles of the past six decades were collated and analyzed. Four Cephalotaxus species are listed in the official medicinal book in China. They are used as ethnomedicines by many ethnic groups such as Miao, Yao, Dong, She and Han. Inspirations are obtained from traditional applications, and Cephalotaxus phytometabolites are developed into anticancer reagents. Cephalotaxine-type alkaloids, homoerythrina-type alkaloids and homoharringtonine (HHT) are abundant in Cephalotaxus, e.g., C. lanceolata, C. fortunei var. alpina, C. griffithii, and C. hainanensis, etc. New methods of alkaloid analysis and purification are continuously developed and applied. Diterpenoids, sesquiterpenoids, flavonoids, lignans, phenolics, and other components are also identified and isolated in various Cephalotaxus species. Alkaloids such as HHT, terpenoids and other compounds have anticancer activities against multiple types of human cancer. Cephalotaxus extracts and compounds showed anti-inflammatory and antioxidant activities, immunomodulatory activity, antimicrobial activity and nematotoxicity, antihyperglycemic effect, and bone effect, etc. Drug metabolism and pharmacokinetic studies of Cephalotaxus are increasing. We should continue to collect and sort out folk medicinal knowledge of Cephalotaxus and associated organisms, so as to obtain new enlightenment to translate traditional tips into great therapeutic drugs. Transcriptomics, genomics, metabolomics and proteomics studies can contribute massive information for bioactivity and phytochemistry of Cephalotaxus medicinal plants. We should continue to strengthen the application of state-of-the-art technologies in more Cephalotaxus species and for more useful compounds and pharmacological activities.
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Anticancer Chemodiversity of Ranunculaceae Medicinal Plants
Ranunculales Medicinal Plants, 2019Co-Authors: Da-cheng HaoAbstract:Various medicinal compounds have been found in Ranunculaceae plants, many of which, such as alkaloids, terpenoids, saponins, and polysaccharides, have shown anticancer activities during in vitro and in vivo studies. Most concerns have been raised for two epiphany molecules, the monoterpene thymoquinone and the isoquinoline alkaloid berberine. At least 17 genera have been found to be rich in anticancer compounds. Some Ranunculaceae compounds induce the cell cycle arrest and apoptosis of cancer cells or enhance immune activities, while others inhibit the proliferation, invasion, angiogenesis, and metastasis, or reverse the multi-drug resistance of cancer cells. In fact, Ranunculaceae phytometabolites regulate all ten cancer hallmarks defined by Hanahan and Weinberg. The same class of phytometabolite could exert the anticancer activity via multiple pathways. In addition, absorption, distribution, metabolism, and excretion/toxicity properties and structure activity relationships of some phytometabolites have been revealed and are useful in the early drug discovery and development pipelines. However, a comprehensive review of the molecular mechanisms and functions of Ranunculaceae anticancer compounds is lacking. In this chapter, the recent progress of the anticancer Chemodiversity and pharmacological diversity of Ranunculaceae medicinal plants is summarized, focusing on the emerging molecular machineries and functions of anticancer compounds. Gene expression profiling and relevant omics platforms could reveal differential effects of phytometabolites on the phenotypically heterogeneous cancer cells. Genomics, transcriptomics, proteomics, and metabolomics are highlighted as Rosetta Stone in deciphering novel anticancer mechanisms and utilities of Ranunculaceae phytometabolites.
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biodiversity Chemodiversity and pharmacotherapy of thalictrum medicinal plants
2018Co-Authors: Da-cheng HaoAbstract:The Ranunculaceae genus Thalictrum has a variety of medicinal plants, with its roots, flowers, and whole herbs used in traditional medicine. The genus contains flavonoids, alkaloids (especially structurally diverse benzylisoquinoline), terpene, saponin, essential oils, etc. The biological activities manifest as antimicrobial, antiinflammatory, cardiovascular, and anticancer effects. This chapter reviews the research progress of chemical constituents and bioactivities of Thalictrum and constructs the molecular phylogenetic tree of the genus; its similarities and differences with morphological classification and chemical classification are discussed. This chapter provides reference for the study of medicinal kinship and the sustainable use of drug resources.
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Anticancer Chemodiversity of Ranunculaceae Medicinal Plants: Molecular Mechanisms and Functions.
Current genomics, 2016Co-Authors: Da-cheng Hao, Jie Shen, Pei-gen XiaoAbstract:The buttercup family, Ranunculaceae, comprising more than 2,200 species in at least 62 genera, mostly herbs, has long been used in folk medicine and worldwide ethnomedicine since the beginning of human civilization. Various medicinal phytometabolites have been found in Ranunculaceae plants, many of which, such as alkaloids, terpenoids, saponins, and polysaccharides, have shown anti-cancer activities in vitro and in vivo. Most concerns have been raised for two epiphany molecules, the monoterpene thymoquinone and the isoquinoline alkaloid berberine. At least 17 genera have been enriched with anti-cancer phytometabolites. Some Ranunculaceae phytometabolites induce the cell cycle arrest and apoptosis of cancer cells or enhance immune activities, while others inhibit the proliferation, invasion, angiogenesis, and metastasis, or reverse the multi-drug resistance of cancer cells thereby regulating all known hallmarks of cancer. These phytometabolites could exert their anti-cancer activities via multiple signaling pathways. In addition, absorption, distribution, metabolism, and excretion/toxicity properties and structure/activity relationships of some phytometabolites have been revealed assisting in the early drug discovery and development pipelines. However, a comprehensive review of the molecular mechanisms and functions of Ranunculaceae anti-cancer phytometabolites is lacking. Here, we summarize the recent progress of the anti-cancer chemo- and pharmacological diversity of Ranunculaceae medicinal plants, focusing on the emerging molecular machineries and functions of anti-cancer phytometabolites. Gene expression profiling and relevant omics platforms (e.g. genomics, transcriptomics, proteomics, and metabolomics) could reveal differential effects of phytometabolites on the phenotypically heterogeneous cancer cells.
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Mining Chemodiversity from biodiversity: pharmacophylogeny of medicinal plants of Ranunculaceae.
Chinese journal of natural medicines, 2015Co-Authors: Da-cheng Hao, Pei-gen Xiao, Yong PengAbstract:This paper reports a pharmacophylogenetic study of a medicinal plant family, Ranunculaceae, investigating the correlations between their phylogeny, chemical constituents, and pharmaceutical properties. Phytochemical, ethnopharmacological, and pharmacological data were integrated in the context of the systematics and molecular phylogeny of the Ranunculaceae. The chemical components of this family included several representative metabolic groups: benzylisoquinoline alkaloids, ranunculin, triterpenoid saponin, and diterpene alkaloids, among others. Ranunculin and magnoflorine were found to coexist in some genera. The pharmacophylogenetic analysis, integrated with therapeutic information, agreed with the taxonomy proposed previously, in which the family Ranunculaceae was divided into five sub-families: Ranunculoideae, Thalictroideae, Coptidoideae, Hydrastidoideae, and Glaucidioideae. It was plausible to organize the sub-family Ranunculoideae into ten tribes. The chemical constituents and therapeutic efficacy of each taxonomic group were reviewed, revealing the underlying connections between phylogeny, chemical diversity, and clinical use, which should facilitate the conservation and sustainable utilization of the pharmaceutical resources derived from the Ranunculaceae.
Jennifer M. Duringer - One of the best experts on this subject based on the ideXlab platform.
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volatile metabolomic composition of vitex species Chemodiversity insights and acaricidal activity
Frontiers in Plant Science, 2017Co-Authors: José G. De Sena Filho, Ighor C. Barreto, Adenir V. Teodoro, Haroudo S. Xavier, Allívia R. C. Rabbani, Daniel J. Spakowicz, Avaldo De Oliveira Soares Filho, Paulo Cesar De Lima Nogueira, Ana Veruska Cruz Da Silva, Jennifer M. DuringerAbstract:The Vitex genus (Lamiaceae) produces a plethora of metabolites that include ecdysteroids and terpenoids, some of which have demonstrated insect repellent properties. The volatile composition of several members of this genus has not been chemically defined, as many taxa are endemic to remote ecosystems. In this study, leaves were collected from the northeast of Brazil from Vitex capitata, V. megapotamica, V. gardneriana and V. rufescens plants and examined for their chemical profile via GC-MS/FID of essential oil extracts. The analyses showed a diversity of terpenoids. Of particular note were seven-member ring sesquiterpenes which were present in great abundance; a dendrogram showed clades separating by the production of (+)-bicyclogermacrene, aromadendrane and 5,10-cycloaromadendrane sesquiterpenoids for the four species. Comparison of volatile metabolite profiles to 13 other Vitex species showed strong similarities in the production of some monoterpenes, but varied by their production of larger terpenes, especially those with gem-dimethylcyclopropyl subunits on seven-member ring compounds. From this work, we suggest that the sesquiterpene skeleton with seven member rings is a good chemosystematic biomarker candidate for the Vitex genus. Separation using this biomarker was then validated using Inter-Simple Sequence Repeat (ISSR) profiling. Lastly, experiments examining the toxicity of these four oils against the coconut mite A. guerreronis showed that only the oil of V. gardneriana had strong acaricidal activity, with an LC50 of 0.85 mg/mL, thus demonstrating its potential for use as a natural pesticide.
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Volatile Metabolomic Composition of Vitex Species: Chemodiversity Insights and Acaricidal Activity
Frontiers Media S.A., 2017Co-Authors: José G. De Sena Filho, Ighor C. Barreto, Avaldo Soares O. Filho, Paulo C. L. Nogueira, Adenir V. Teodoro, Ana Cruz V. Da Silva, Haroudo S. Xavier, Allívia R. C. Rabbani, Daniel J. Spakowicz, Jennifer M. DuringerAbstract:The Vitex genus (Lamiaceae) produces a plethora of metabolites that include ecdysteroids and terpenoids, some of which have demonstrated insect repellent properties. The volatile composition of several members of this genus has not been chemically defined, as many taxa are endemic to remote ecosystems. In this study, leaves were collected from the northeast of Brazil from Vitex capitata, V. megapotamica, V. gardneriana, and V. rufescens plants and examined for their chemical profile via GC-MS/FID of essential oil extracts. The analyses showed a diversity of terpenoids. Of particular note were seven-member ring sesquiterpenes which were present in great abundance; a dendrogram showed clades separating by the production of bicyclogermacrene, aromadendrane and 5,10-cycloaromadendrane sesquiterpenoids for the four species. Comparison of volatile metabolite profiles to 13 other Vitex species showed strong similarities in the production of some monoterpenes, but varied by their production of larger terpenes, especially those with gem-dimethylcyclopropyl subunits on seven-member ring compounds. From this work, we suggest that the sesquiterpene skeleton with seven member rings is a good chemosystematic biomarker candidate for the Vitex genus. Separation using this biomarker was then validated using Inter-Simple Sequence Repeat profiling. Lastly, experiments examining the toxicity of these four oils against the coconut mite Aceria guerreronis showed that only the oil of V. gardneriana had strong acaricidal activity, with an LC50 of 0.85 mg/mL, thus demonstrating its potential for use as a natural pesticide
Pei-gen Xiao - One of the best experts on this subject based on the ideXlab platform.
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ethnopharmacology Chemodiversity and bioactivity of cephalotaxus medicinal plants
Chinese Journal of Natural Medicines, 2021Co-Authors: Da-cheng Hao, Xudong Hou, Pei-gen XiaoAbstract:Cephalotaxus is the only genus of Cephalotaxaceae family, and its natural resources are declining due to habitat fragmentation, excessive exploitation and destruction. In many areas of China, folk herbal doctors traditionally use Cephalotaxus plants to treat innominate swollen poison, many of which are cancer. Not only among Han people, but also among minority ethnic groups, Cephalotaxus is used to treat various diseases, e.g., cough, internal bleeding and cancer in Miao medicine, bruises, rheumatism and pain in Yao medicine, and ascariasis, hookworm disease, scrofula in She medicine, etc. Medicinal values of some Cephalotaxus species and compounds are acknowledged officially. However, there is a lack of comprehensive review summarizing the ethnomedicinal knowledge of Cephalotaxus, relevant medicinal phytometabolites and their bioactivities. The research progresses in ethnopharmacology, Chemodiversity, and bioactivities of Cephalotaxus medicinal plants are reviewed and commented here. Knowledge gaps are pinpointed and future research directions are suggested. Classic medicinal books, folk medicine books, herbal manuals and ethnomedicinal publications were reviewed for the genus Cephalotaxus (Sanjianshan in Chinese). The relevant data about ethnobotany, phytochemistry, and pharmacology were collected as comprehensively as possible from online databases including Scopus, NCBI PubMed, Bing Scholar, and China National Knowledge Infrastructure (CNKI). "Cephalotaxus", and the respective species name were used as keywords in database search. The obtained articles of the past six decades were collated and analyzed. Four Cephalotaxus species are listed in the official medicinal book in China. They are used as ethnomedicines by many ethnic groups such as Miao, Yao, Dong, She and Han. Inspirations are obtained from traditional applications, and Cephalotaxus phytometabolites are developed into anticancer reagents. Cephalotaxine-type alkaloids, homoerythrina-type alkaloids and homoharringtonine (HHT) are abundant in Cephalotaxus, e.g., C. lanceolata, C. fortunei var. alpina, C. griffithii, and C. hainanensis, etc. New methods of alkaloid analysis and purification are continuously developed and applied. Diterpenoids, sesquiterpenoids, flavonoids, lignans, phenolics, and other components are also identified and isolated in various Cephalotaxus species. Alkaloids such as HHT, terpenoids and other compounds have anticancer activities against multiple types of human cancer. Cephalotaxus extracts and compounds showed anti-inflammatory and antioxidant activities, immunomodulatory activity, antimicrobial activity and nematotoxicity, antihyperglycemic effect, and bone effect, etc. Drug metabolism and pharmacokinetic studies of Cephalotaxus are increasing. We should continue to collect and sort out folk medicinal knowledge of Cephalotaxus and associated organisms, so as to obtain new enlightenment to translate traditional tips into great therapeutic drugs. Transcriptomics, genomics, metabolomics and proteomics studies can contribute massive information for bioactivity and phytochemistry of Cephalotaxus medicinal plants. We should continue to strengthen the application of state-of-the-art technologies in more Cephalotaxus species and for more useful compounds and pharmacological activities.
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Anticancer Chemodiversity of Ranunculaceae Medicinal Plants: Molecular Mechanisms and Functions.
Current genomics, 2016Co-Authors: Da-cheng Hao, Jie Shen, Pei-gen XiaoAbstract:The buttercup family, Ranunculaceae, comprising more than 2,200 species in at least 62 genera, mostly herbs, has long been used in folk medicine and worldwide ethnomedicine since the beginning of human civilization. Various medicinal phytometabolites have been found in Ranunculaceae plants, many of which, such as alkaloids, terpenoids, saponins, and polysaccharides, have shown anti-cancer activities in vitro and in vivo. Most concerns have been raised for two epiphany molecules, the monoterpene thymoquinone and the isoquinoline alkaloid berberine. At least 17 genera have been enriched with anti-cancer phytometabolites. Some Ranunculaceae phytometabolites induce the cell cycle arrest and apoptosis of cancer cells or enhance immune activities, while others inhibit the proliferation, invasion, angiogenesis, and metastasis, or reverse the multi-drug resistance of cancer cells thereby regulating all known hallmarks of cancer. These phytometabolites could exert their anti-cancer activities via multiple signaling pathways. In addition, absorption, distribution, metabolism, and excretion/toxicity properties and structure/activity relationships of some phytometabolites have been revealed assisting in the early drug discovery and development pipelines. However, a comprehensive review of the molecular mechanisms and functions of Ranunculaceae anti-cancer phytometabolites is lacking. Here, we summarize the recent progress of the anti-cancer chemo- and pharmacological diversity of Ranunculaceae medicinal plants, focusing on the emerging molecular machineries and functions of anti-cancer phytometabolites. Gene expression profiling and relevant omics platforms (e.g. genomics, transcriptomics, proteomics, and metabolomics) could reveal differential effects of phytometabolites on the phenotypically heterogeneous cancer cells.
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Mining Chemodiversity from biodiversity: pharmacophylogeny of medicinal plants of Ranunculaceae.
Chinese journal of natural medicines, 2015Co-Authors: Da-cheng Hao, Pei-gen Xiao, Yong PengAbstract:This paper reports a pharmacophylogenetic study of a medicinal plant family, Ranunculaceae, investigating the correlations between their phylogeny, chemical constituents, and pharmaceutical properties. Phytochemical, ethnopharmacological, and pharmacological data were integrated in the context of the systematics and molecular phylogeny of the Ranunculaceae. The chemical components of this family included several representative metabolic groups: benzylisoquinoline alkaloids, ranunculin, triterpenoid saponin, and diterpene alkaloids, among others. Ranunculin and magnoflorine were found to coexist in some genera. The pharmacophylogenetic analysis, integrated with therapeutic information, agreed with the taxonomy proposed previously, in which the family Ranunculaceae was divided into five sub-families: Ranunculoideae, Thalictroideae, Coptidoideae, Hydrastidoideae, and Glaucidioideae. It was plausible to organize the sub-family Ranunculoideae into ten tribes. The chemical constituents and therapeutic efficacy of each taxonomic group were reviewed, revealing the underlying connections between phylogeny, chemical diversity, and clinical use, which should facilitate the conservation and sustainable utilization of the pharmaceutical resources derived from the Ranunculaceae.
David E. Cane - One of the best experts on this subject based on the ideXlab platform.
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Substitution of Aromatic Residues with Polar Residues in the Active Site Pocket of epi-Isozizaene Synthase Leads to the Generation of New Cyclic Sesquiterpenes
Biochemistry, 2017Co-Authors: Patrick N. Blank, David E. Cane, Golda H. Barrow, Wayne K. W. Chou, Lian Duan, David W. ChristiansonAbstract:The sesquiterpene cyclase epi-isozizaene synthase (EIZS) catalyzes the cyclization of farnesyl diphosphate to form the tricyclic hydrocarbon precursor of the antibiotic albaflavenone. The hydrophobic active site pocket of EIZS serves as a template as it binds and chaperones the flexible substrate and carbocation intermediates through the conformations required for a multistep reaction sequence. We previously demonstrated that the substitution of hydrophobic residues with other hydrophobic residues remolds the template and expands product Chemodiversity [Li, R., Chou, W. K. W., Himmelberger, J. A., Litwin, K. M., Harris, G. G., Cane, D. E., and Christianson, D. W. (2014) Biochemistry 53, 1155–1168]. Here, we show that the substitution of hydrophobic residues—specifically, Y69, F95, F96, and W203—with polar side chains also yields functional enzyme catalysts that expand product Chemodiversity. Fourteen new EIZS mutants are reported that generate product arrays in which eight new sesquiterpene products have ...
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exploring the influence of domain architecture on the catalytic function of diterpene synthases
Biochemistry, 2017Co-Authors: Travis A Pemberton, David E. Cane, Wayne K. W. Chou, Mengbin Chen, Golda G. Harris, Alex S. Genshaft, L Duan, Mustafa Koksal, David W. ChristiansonAbstract:Terpenoid synthases catalyze isoprenoid cyclization reactions underlying the generation of more than 80,000 natural products. Such dramatic Chemodiversity belies the fact that these enzymes generally consist of only three domain folds designated as α, β, and γ. Catalysis by class I terpenoid synthases occurs exclusively in the α domain, which is found with α, αα, αβ, and αβγ domain architectures. Here, we explore the influence of domain architecture on catalysis by taxadiene synthase from Taxus brevifolia (TbTS, αβγ), fusicoccadiene synthase from Phomopsis amygdali (PaFS, (αα)6), and ophiobolin F synthase from Aspergillus clavatus (AcOS, αα). We show that the cyclization fidelity and catalytic efficiency of the α domain of TbTS are severely compromised by deletion of the βγ domains; however, retention of the β domain preserves significant cyclization fidelity. In PaFS, we previously demonstrated that one α domain similarly influences catalysis by the other α domain [Chen, M., Chou, W. K. W., Toyomasu, T.,...
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Substitution of Aromatic Residues with Polar Residues in the Active Site Pocket of epi-Isozizaene Synthase Leads to the Generation of New Cyclic Sesquiterpenes
2017Co-Authors: Patrick N. Blank, David E. Cane, Golda H. Barrow, Wayne K. W. Chou, Lian Duan, David W. ChristiansonAbstract:The sesquiterpene cyclase epi-isozizaene synthase (EIZS) catalyzes the cyclization of farnesyl diphosphate to form the tricyclic hydrocarbon precursor of the antibiotic albaflavenone. The hydrophobic active site pocket of EIZS serves as a template as it binds and chaperones the flexible substrate and carbocation intermediates through the conformations required for a multistep reaction sequence. We previously demonstrated that the substitution of hydrophobic residues with other hydrophobic residues remolds the template and expands product Chemodiversity [Li, R., Chou, W. K. W., Himmelberger, J. A., Litwin, K. M., Harris, G. G., Cane, D. E., and Christianson, D. W. (2014) Biochemistry 53, 1155–1168]. Here, we show that the substitution of hydrophobic residuesspecifically, Y69, F95, F96, and W203with polar side chains also yields functional enzyme catalysts that expand product Chemodiversity. Fourteen new EIZS mutants are reported that generate product arrays in which eight new sesquiterpene products have been identified. Of note, some mutants generate acyclic and cyclic hydroxylated products, suggesting that the introduction of polarity in the hydrophobic pocket facilitates the binding of water capable of quenching carbocation intermediates. Furthermore, the substitution of polar residues for F96 yields high-fidelity sesquisabinene synthases. Crystal structures of selected mutants reveal that residues defining the three-dimensional contour of the hydrophobic pocket can be substituted without triggering significant structural changes elsewhere in the active site. Thus, more radical nonpolar–polar amino acid substitutions should be considered when terpenoid cyclase active sites are remolded by mutagenesis with the goal of exploring and expanding product Chemodiversity
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Exploring the Influence of Domain Architecture on the Catalytic Function of Diterpene Synthases
2017Co-Authors: Travis A. Pemberton, David E. Cane, Wayne K. W. Chou, Lian Duan, Mengbin Chen, Golda G. Harris, Mustafa Köksal, Alex S. Genshaft, David W. ChristiansonAbstract:Terpenoid synthases catalyze isoprenoid cyclization reactions underlying the generation of more than 80,000 natural products. Such dramatic Chemodiversity belies the fact that these enzymes generally consist of only three domain folds designated as α, β, and γ. Catalysis by class I terpenoid synthases occurs exclusively in the α domain, which is found with α, αα, αβ, and αβγ domain architectures. Here, we explore the influence of domain architecture on catalysis by taxadiene synthase from Taxus brevifolia (TbTS, αβγ), fusicoccadiene synthase from Phomopsis amygdali (PaFS, (αα)6), and ophiobolin F synthase from Aspergillus clavatus (AcOS, αα). We show that the cyclization fidelity and catalytic efficiency of the α domain of TbTS are severely compromised by deletion of the βγ domains; however, retention of the β domain preserves significant cyclization fidelity. In PaFS, we previously demonstrated that one α domain similarly influences catalysis by the other α domain [Chen, M., Chou, W. K. W., Toyomasu, T., Cane, D. E., and Christianson, D. W. (2016) ACS Chem. Biol. 11, 889−899]. Here, we show that the hexameric quaternary structure of PaFS enables cluster channeling. We also show that the α domains of PaFS and AcOS can be swapped so as to make functional chimeric αα synthases. Notably, both cyclization fidelity and catalytic efficiency are altered in all chimeric synthases. Twelve newly formed and uncharacterized C20 diterpene products and three C25 sesterterpene products are generated by these chimeras. Thus, engineered αβγ and αα terpenoid cyclases promise to generate Chemodiversity in the greater family of terpenoid natural products