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627 results on '"O'Connor, Sarah E"'

1. Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast

Author

Bradley, Samuel A, Lehka, Beata J, Hansson, Frederik G, Adhikari, Khem B, Rago, Daniela, Rubaszka, Paulina, Haidar, Ahmad K, Chen, Ling, Hansen, Lea G, Gudich, Olga, Giannakou, Konstantina, Lengger, Bettina, Gill, Ryan T, Nakamura, Yoko, de Bernonville, Thomas Dugé, Koudounas, Konstantinos, Romero-Suarez, David, Ding, Ling, Qiao, Yijun, Frimurer, Thomas M, Petersen, Anja A, Besseau, Sébastien, Kumar, Sandeep, Gautron, Nicolas, Melin, Celine, Marc, Jillian, Jeanneau, Remi, O’Connor, Sarah E, Courdavault, Vincent, Keasling, Jay D, Zhang, Jie, and Jensen, Michael K

Subjects
Biological Sciences, Industrial Biotechnology, Good Health and Well Being, Saccharomyces cerevisiae, Monoterpenes, Indole Alkaloids, Plants, Pharmaceutical Preparations, Catharanthus, Plant Proteins, Medicinal and Biomolecular Chemistry, Biochemistry and Cell Biology, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medicinal and biomolecular chemistry
Abstract

Monoterpenoid indole alkaloids (MIAs) represent a large class of plant natural products with marketed pharmaceutical activities against a wide range of indications, including cancer, malaria and hypertension. Halogenated MIAs have shown improved pharmaceutical properties; however, synthesis of new-to-nature halogenated MIAs remains a challenge. Here we demonstrate a platform for de novo biosynthesis of two MIAs, serpentine and alstonine, in baker's yeast Saccharomyces cerevisiae and deploy it to systematically explore the biocatalytic potential of refactored MIA pathways for the production of halogenated MIAs. From this, we demonstrate conversion of individual haloindole derivatives to a total of 19 different new-to-nature haloserpentine and haloalstonine analogs. Furthermore, by process optimization and heterologous expression of a modified halogenase in the microbial MIA platform, we document de novo halogenation and biosynthesis of chloroalstonine. Together, this study highlights a microbial platform for enzymatic exploration and production of complex natural and new-to-nature MIAs with therapeutic potential.

Published
2023

2. A microbial supply chain for production of the anti-cancer drug vinblastine

Author

Zhang, Jie, Hansen, Lea G, Gudich, Olga, Viehrig, Konrad, Lassen, Lærke MM, Schrübbers, Lars, Adhikari, Khem B, Rubaszka, Paulina, Carrasquer-Alvarez, Elena, Chen, Ling, D’Ambrosio, Vasil, Lehka, Beata, Haidar, Ahmad K, Nallapareddy, Saranya, Giannakou, Konstantina, Laloux, Marcos, Arsovska, Dushica, Jørgensen, Marcus AK, Chan, Leanne Jade G, Kristensen, Mette, Christensen, Hanne B, Sudarsan, Suresh, Stander, Emily A, Baidoo, Edward, Petzold, Christopher J, Wulff, Tune, O’Connor, Sarah E, Courdavault, Vincent, Jensen, Michael K, and Keasling, Jay D

Subjects
Cancer, Antineoplastic Agents, Bioreactors, Biosynthetic Pathways, Catharanthus, Genes, Fungal, Genes, Plant, Metabolic Engineering, Polyisoprenyl Phosphates, Saccharomyces cerevisiae, Tryptophan, Vinblastine, Vinca Alkaloids, General Science & Technology
Abstract

Monoterpene indole alkaloids (MIAs) are a diverse family of complex plant secondary metabolites with many medicinal properties, including the essential anti-cancer therapeutics vinblastine and vincristine1. As MIAs are difficult to chemically synthesize, the world's supply chain for vinblastine relies on low-yielding extraction and purification of the precursors vindoline and catharanthine from the plant Catharanthus roseus, which is then followed by simple in vitro chemical coupling and reduction to form vinblastine at an industrial scale2,3. Here, we demonstrate the de novo microbial biosynthesis of vindoline and catharanthine using a highly engineered yeast, and in vitro chemical coupling to vinblastine. The study showcases a very long biosynthetic pathway refactored into a microbial cell factory, including 30 enzymatic steps beyond the yeast native metabolites geranyl pyrophosphate and tryptophan to catharanthine and vindoline. In total, 56 genetic edits were performed, including expression of 34 heterologous genes from plants, as well as deletions, knock-downs and overexpression of ten yeast genes to improve precursor supplies towards de novo production of catharanthine and vindoline, from which semisynthesis to vinblastine occurs. As the vinblastine pathway is one of the longest MIA biosynthetic pathways, this study positions yeast as a scalable platform to produce more than 3,000 natural MIAs and a virtually infinite number of new-to-nature analogues.

Published
2022

7. Biosynthesis of strychnine

Author

Hong, Benke, Grzech, Dagny, Caputi, Lorenzo, Sonawane, Prashant, López, Carlos E. Rodríguez, Kamileen, Mohamed Omar, Hernández Lozada, Néstor J., Grabe, Veit, and O’Connor, Sarah E.

Published
2022
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10. Biocatalytic routes to stereo-divergent iridoids

Author

Hernández Lozada, Néstor J., Hong, Benke, Wood, Joshua C., Caputi, Lorenzo, Basquin, Jérôme, Chuang, Ling, Kunert, Maritta, Rodríguez López, Carlos E., Langley, Chloe, Zhao, Dongyan, Buell, C. Robin, Lichman, Benjamin R., and O’Connor, Sarah E.

Published
2022
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17. An NPF transporter exports a central monoterpene indole alkaloid intermediate from the vacuole.

Author

Payne, Richard ME, Xu, Deyang, Foureau, Emilien, Teto Carqueijeiro, Marta Ines Soares, Oudin, Audrey, Bernonville, Thomas Dugé de, Novak, Vlastimil, Burow, Meike, Olsen, Carl-Erik, Jones, D Marc, Tatsis, Evangelos C, Pendle, Ali, Ann Halkier, Barbara, Geu-Flores, Fernando, Courdavault, Vincent, Nour-Eldin, Hussam Hassan, and O'Connor, Sarah E

Subjects
Vacuoles, Catharanthus, Monoterpenes, Vinca Alkaloids, Anion Transport Proteins, Symporters, Plant Proteins, Gene Expression Regulation, Plant, Biological Transport, Gene Expression Regulation, Plant
Abstract

Plants sequester intermediates of metabolic pathways into different cellular compartments, but the mechanisms by which these molecules are transported remain poorly understood. Monoterpene indole alkaloids, a class of specialized metabolites that includes the anticancer agent vincristine, antimalarial quinine and neurotoxin strychnine, are synthesized in several different cellular locations. However, the transporters that control the movement of these biosynthetic intermediates within cellular compartments have not been discovered. Here we present the discovery of a tonoplast localized nitrate/peptide family (NPF) transporter from Catharanthus roseus, CrNPF2.9, that exports strictosidine, the central intermediate of this pathway, into the cytosol from the vacuole. This discovery highlights the role that intracellular localization plays in specialized metabolism, and sets the stage for understanding and controlling the central branch point of this pharmacologically important group of compounds.

Published
2017

25. Integration of cell differentiation and initiation of monoterpenoid indole alkaloid metabolism in seed germination of Catharanthus roseus.

Author

Uzaki, Mai, Mori, Tetsuya, Sato, Mayuko, Wakazaki, Mayumi, Takeda‐Kamiya, Noriko, Yamamoto, Kotaro, Murakami, Akio, Guerrero, Delia Ayled Serna, Shichijo, Chizuko, Ohnishi, Miwa, Ishizaki, Kimitsune, Fukaki, Hidehiro, O'Connor, Sarah E., Toyooka, Kiminori, Mimura, Tetsuro, and Hirai, Masami Yokota

Subjects
INDOLE alkaloids, CATHARANTHUS roseus, GERMINATION, CELL differentiation, MONOTERPENOIDS, SEEDS
Abstract

Summary: In Catharanthus roseus, monoterpenoid indole alkaloids (MIAs) are produced through the cooperation of four cell types, with final products accumulating in specialized cells known as idioblasts and laticifers. To explore the relationship between cellular differentiation and cell type‐specific MIA metabolism, we analyzed the expression of MIA biosynthesis in germinating seeds.Embryos from immature and mature seeds were observed via stereomicroscopy, fluorescence microscopy, and electron microscopy. Time‐series MIA and iridoid quantification, along with transcriptome analysis, were conducted to determine the initiation of MIA biosynthesis. In addition, the localization of MIAs was examined using alkaloid staining and imaging mass spectrometry (IMS).Laticifers were present in embryos before seed maturation. MIA biosynthesis commenced 12 h after germination. MIAs accumulated in laticifers of embryos following seed germination, and MIA metabolism is induced after germination in a tissue‐specific manner.These findings suggest that cellular morphological differentiation precedes metabolic differentiation. Considering the well‐known toxicity and defense role of MIAs in matured plants, MIAs may be an important defense strategy already in the delicate developmental phase of seed germination, and biosynthesis and accumulation of MIAs may require the tissue and cellular differentiation. [ABSTRACT FROM AUTHOR]

Published
2024
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29. Two Tabersonine 6,7-Epoxidases Initiate Lochnericine-Derived Alkaloid Biosynthesis in Catharanthus roseus

Author

Carqueijeiro, Inês, Brown, Stephanie, Chung, Khoa, Dang, Thu-Thuy, Walia, Manish, Besseau, Sébastien, de Bernonville, Thomas Dugé, Oudin, Audrey, Lanoue, Arnaud, Billet, Kevin, Munsch, Thibaut, Koudounas, Konstantinos, Melin, Céline, Godon, Charlotte, Razafimandimby, Bienvenue, de Craene, Johan-Owen, Glévarec, Gaëlle, Marc, Jillian, Giglioli-Guivarc'h, Nathalie, Clastre, Marc, St-Pierre, Benoit, Papon, Nicolas, Andrade, Rodrigo B., O'Connor, Sarah E., and Courdavault, Vincent

Published
2018

37. Metabolite and Molecular Characterization of Mitragyna speciosa Identifies Developmental and Genotypic Effects on Monoterpene Indole and Oxindole Alkaloid Composition

Author

Laforest, Larissa C., primary, Kuntz, Michelle A., additional, Kanumuri, Siva Rama Raju, additional, Mukhopadhyay, Sushobhan, additional, Sharma, Abhisheak, additional, O’Connor, Sarah E., additional, McCurdy, Christopher R., additional, and Nadakuduti, Satya Swathi, additional

Published
2023
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38. Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast

Author

Bradley, Samuel A., Lehka, Beata J., Hansson, Frederik G., Adhikari, Khem B., Rago, Daniela, Rubaszka, Paulina, Haidar, Ahmad K., Chen, Ling, Hansen, Lea G., Gudich, Olga, Giannakou, Konstantina, Lengger, Bettina, Gill, Ryan T., Nakamura, Yoko, de Bernonville, Thomas Dugé, Koudounas, Konstantinos, Romero-Suarez, David, Ding, Ling, Qiao, Yijun, Frimurer, Thomas M., Petersen, Anja A., Besseau, Sébastien, Kumar, Sandeep, Gautron, Nicolas, Melin, Celine, Marc, Jillian, Jeanneau, Remi, O’Connor, Sarah E., Courdavault, Vincent, Keasling, Jay D., Zhang, Jie, Jensen, Michael K., Bradley, Samuel A., Lehka, Beata J., Hansson, Frederik G., Adhikari, Khem B., Rago, Daniela, Rubaszka, Paulina, Haidar, Ahmad K., Chen, Ling, Hansen, Lea G., Gudich, Olga, Giannakou, Konstantina, Lengger, Bettina, Gill, Ryan T., Nakamura, Yoko, de Bernonville, Thomas Dugé, Koudounas, Konstantinos, Romero-Suarez, David, Ding, Ling, Qiao, Yijun, Frimurer, Thomas M., Petersen, Anja A., Besseau, Sébastien, Kumar, Sandeep, Gautron, Nicolas, Melin, Celine, Marc, Jillian, Jeanneau, Remi, O’Connor, Sarah E., Courdavault, Vincent, Keasling, Jay D., Zhang, Jie, and Jensen, Michael K.

Abstract

Monoterpenoid indole alkaloids (MIAs) represent a large class of plant natural products with marketed pharmaceutical activities against a wide range of indications, including cancer, malaria and hypertension. Halogenated MIAs have shown improved pharmaceutical properties; however, synthesis of new-to-nature halogenated MIAs remains a challenge. Here we demonstrate a platform for de novo biosynthesis of two MIAs, serpentine and alstonine, in baker’s yeast Saccharomyces cerevisiae and deploy it to systematically explore the biocatalytic potential of refactored MIA pathways for the production of halogenated MIAs. From this, we demonstrate conversion of individual haloindole derivatives to a total of 19 different new-to-nature haloserpentine and haloalstonine analogs. Furthermore, by process optimization and heterologous expression of a modified halogenase in the microbial MIA platform, we document de novo halogenation and biosynthesis of chloroalstonine. Together, this study highlights a microbial platform for enzymatic exploration and production of complex natural and new-to-nature MIAs with therapeutic potential.

Published
2023

39. Class II Cytochrome P450 Reductase Governs the Biosynthesis of Alkaloids

Author

Parage, Claire, Foureau, Emilien, Kellner, Franziska, Burlat, Vincent, Mahroug, Samira, Lanoue, Arnaud, de Bernonville, Thomas Dugé, Londono, Monica Arias, Carqueijeiro, Inês, Oudin, Audrey, Besseau, Sébastien, Papon, Nicolas, Glévarec, Gaëlle, Atehortùa, Lucia, Giglioli-Guivarc'h, Nathalie, St-Pierre, Benoit, Clastre, Marc, O'Connor, Sarah E., and Courdavault, Vincent

Published
2016

40. Vacuole-Targeted Proteins: Ins and Outs of Subcellular Localization Studies

Author

Carqueijeiro, Inês, primary, Sepúlveda, Liuda J., additional, Mosquera, Angela, additional, Payne, Richard, additional, Corbin, Cyrielle, additional, Papon, Nicolas, additional, de Bernonville, Thomas Dugé, additional, Besseau, Sébastien, additional, Lanoue, Arnaud, additional, Glévarec, Gaëlle, additional, Clastre, Marc, additional, St-Pierre, Benoit, additional, Atehortùa, Lucia, additional, Giglioli-Guivarc’h, Nathalie, additional, O’Connor, Sarah E., additional, Oudin, Audrey, additional, and Courdavault, Vincent, additional

Published
2018
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42. Directed Biosynthesis of Mitragynine Stereoisomers

Author

Schotte, Carsten, primary, Jiang, Yindi, additional, Grzech, Dagny, additional, Dang, Thu-Thuy T., additional, Laforest, Larissa C., additional, León, Francisco, additional, Mottinelli, Marco, additional, Nadakuduti, Satya Swathi, additional, McCurdy, Christopher R., additional, and O’Connor, Sarah E., additional

Published
2023
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43. Directed Biosynthesis of Mitragynine Stereoisomers

Author

Schotte, Carsten, primary, Jiang, Yindi, additional, Grzech, Dagny, additional, Dang, Thu-Thuy T., additional, Laforest, Larissa, additional, León, Francisco, additional, Mottinelli, Marco, additional, Nadakuduti, Satya S., additional, McCurdy, Christopher R., additional, and O’Connor, Sarah E., additional

Published
2022
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50. Biosynthesis of iridoid sex pheromones in aphids

Author

Köllner, Tobias G., primary, David, Anja, additional, Luck, Katrin, additional, Beran, Franziska, additional, Kunert, Grit, additional, Zhou, Jing-Jiang, additional, Caputi, Lorenzo, additional, and O’Connor, Sarah E., additional

Published
2022
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