Cytochrome P450 and O-methyltransferase catalyze the final steps in the biosynthesis of the anti-addictive alkaloid ibogaine from Tabernanthe iboga
Monoterpenoid indole alkaloids are a large (∼3000 members) and structurally diverse class of metabolites restricted to a limited number of plant families in the order Gentianales. Tabernanthe iboga or iboga (Apocynaceae) is native to western equatorial Africa and has been used in traditional medicin...
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Published in | The Journal of biological chemistry Vol. 293; no. 36; pp. 13821 - 13833 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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United States
Elsevier Inc
07.09.2018
American Society for Biochemistry and Molecular Biology |
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Abstract | Monoterpenoid indole alkaloids are a large (∼3000 members) and structurally diverse class of metabolites restricted to a limited number of plant families in the order Gentianales. Tabernanthe iboga or iboga (Apocynaceae) is native to western equatorial Africa and has been used in traditional medicine for centuries. Howard Lotsof is credited with bringing iboga to the attention of Western medicine through his accidental discovery that iboga can alleviate opioid withdrawal symptoms. Since this observation, iboga has been investigated for its use in the general management of addiction. We were interested in elucidating ibogaine biosynthesis to understand the unique reaction steps en route to ibogaine. Furthermore, because ibogaine is currently sourced from plant material, these studies may help improve the ibogaine supply chain through synthetic biology approaches. Here, we used next-generation sequencing to generate the first iboga transcriptome and leveraged homology-guided gene discovery to identify the penultimate hydroxylase and final O-methyltransferase steps in ibogaine biosynthesis, herein named ibogamine 10-hydroxylase (I10H) and noribogaine-10-O-methyltransferase (N10OMT). Heterologous expression in Saccharomyces cerevisiae (I10H) or Escherichia coli (N10OMT) and incubation with putative precursors, along with HPLC–MS analysis, confirmed the predicted activities of both enzymes. Moreover, high expression levels of their transcripts were detected in ibogaine-accumulating plant tissues. These discoveries coupled with our publicly available iboga transcriptome will contribute to additional gene discovery efforts and could lead to the stabilization of the global ibogaine supply chain and to the development of ibogaine as a treatment for addiction. |
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AbstractList | Monoterpenoid indole alkaloids are a large (∼3000 members) and structurally diverse class of metabolites restricted to a limited number of plant families in the order Gentianales. Tabernanthe iboga or iboga (Apocynaceae) is native to western equatorial Africa and has been used in traditional medicine for centuries. Howard Lotsof is credited with bringing iboga to the attention of Western medicine through his accidental discovery that iboga can alleviate opioid withdrawal symptoms. Since this observation, iboga has been investigated for its use in the general management of addiction. We were interested in elucidating ibogaine biosynthesis to understand the unique reaction steps en route to ibogaine. Furthermore, because ibogaine is currently sourced from plant material, these studies may help improve the ibogaine supply chain through synthetic biology approaches. Here, we used next-generation sequencing to generate the first iboga transcriptome and leveraged homology-guided gene discovery to identify the penultimate hydroxylase and final O-methyltransferase steps in ibogaine biosynthesis, herein named ibogamine 10-hydroxylase (I10H) and noribogaine-10-O-methyltransferase (N10OMT). Heterologous expression in Saccharomyces cerevisiae (I10H) or Escherichia coli (N10OMT) and incubation with putative precursors, along with HPLC–MS analysis, confirmed the predicted activities of both enzymes. Moreover, high expression levels of their transcripts were detected in ibogaine-accumulating plant tissues. These discoveries coupled with our publicly available iboga transcriptome will contribute to additional gene discovery efforts and could lead to the stabilization of the global ibogaine supply chain and to the development of ibogaine as a treatment for addiction. Monoterpenoid indole alkaloids are a large (∼3000 members) and structurally diverse class of metabolites restricted to a limited number of plant families in the order Gentianales. Tabernanthe iboga or iboga (Apocynaceae) is native to western equatorial Africa and has been used in traditional medicine for centuries. Howard Lotsof is credited with bringing iboga to the attention of Western medicine through his accidental discovery that iboga can alleviate opioid withdrawal symptoms. Since this observation, iboga has been investigated for its use in the general management of addiction. We were interested in elucidating ibogaine biosynthesis to understand the unique reaction steps en route to ibogaine. Furthermore, because ibogaine is currently sourced from plant material, these studies may help improve the ibogaine supply chain through synthetic biology approaches. Here, we used next-generation sequencing to generate the first iboga transcriptome and leveraged homology-guided gene discovery to identify the penultimate hydroxylase and final O -methyltransferase steps in ibogaine biosynthesis, herein named ibogamine 10-hydroxylase (I10H) and noribogaine-10- O -methyltransferase (N10OMT). Heterologous expression in Saccharomyces cerevisiae (I10H) or Escherichia coli (N10OMT) and incubation with putative precursors, along with HPLC–MS analysis, confirmed the predicted activities of both enzymes. Moreover, high expression levels of their transcripts were detected in ibogaine-accumulating plant tissues. These discoveries coupled with our publicly available iboga transcriptome will contribute to additional gene discovery efforts and could lead to the stabilization of the global ibogaine supply chain and to the development of ibogaine as a treatment for addiction. Monoterpenoid indole alkaloids are a large (∼3000 members) and structurally diverse class of metabolites restricted to a limited number of plant families in the order Gentianales. or iboga (Apocynaceae) is native to western equatorial Africa and has been used in traditional medicine for centuries. Howard Lotsof is credited with bringing iboga to the attention of Western medicine through his accidental discovery that iboga can alleviate opioid withdrawal symptoms. Since this observation, iboga has been investigated for its use in the general management of addiction. We were interested in elucidating ibogaine biosynthesis to understand the unique reaction steps en route to ibogaine. Furthermore, because ibogaine is currently sourced from plant material, these studies may help improve the ibogaine supply chain through synthetic biology approaches. Here, we used next-generation sequencing to generate the first iboga transcriptome and leveraged homology-guided gene discovery to identify the penultimate hydroxylase and final -methyltransferase steps in ibogaine biosynthesis, herein named ibogamine 10-hydroxylase (I10H) and noribogaine-10- -methyltransferase (N10OMT). Heterologous expression in (I10H) or (N10OMT) and incubation with putative precursors, along with HPLC-MS analysis, confirmed the predicted activities of both enzymes. Moreover, high expression levels of their transcripts were detected in ibogaine-accumulating plant tissues. These discoveries coupled with our publicly available iboga transcriptome will contribute to additional gene discovery efforts and could lead to the stabilization of the global ibogaine supply chain and to the development of ibogaine as a treatment for addiction. |
Author | Ameyaw, Belinda Farrow, Scott C. Meades, Jessica Xiao, Youli Kamileen, Mohamed O. O'Connor, Sarah E. |
Author_xml | – sequence: 1 givenname: Scott C. surname: Farrow fullname: Farrow, Scott C. organization: From the Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, United Kingdom – sequence: 2 givenname: Mohamed O. surname: Kamileen fullname: Kamileen, Mohamed O. organization: From the Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, United Kingdom – sequence: 3 givenname: Jessica surname: Meades fullname: Meades, Jessica organization: From the Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, United Kingdom – sequence: 4 givenname: Belinda surname: Ameyaw fullname: Ameyaw, Belinda organization: From the Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, United Kingdom – sequence: 5 givenname: Youli surname: Xiao fullname: Xiao, Youli organization: Chinese Academy of Sciences (CAS) Centre for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Shanghai 200000, China – sequence: 6 givenname: Sarah E. surname: O'Connor fullname: O'Connor, Sarah E. email: sarah.oconnor@jic.ac.uk organization: From the Department of Biological Chemistry, John Innes Centre, Norwich NR4 7UH, United Kingdom |
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Copyright | 2018 © 2018 Farrow et al. 2018 Farrow et al. 2018 Farrow et al. 2018 Farrow et al. |
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Keywords | Tabernanthe iboga natural product biosynthesis ibogaine monoterpene indole alkaloid plant biochemistry secondary metabolism O-methyltransferase transcriptomics cytochrome P450 Illumina sequencing |
Language | English |
License | This is an open access article under the CC BY license. 2018 Farrow et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license. |
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Notes | Supported by the CAS-BBSRC alliance. Supported by European Molecular Biology Organization (EMBO) Long-term Fellowship ALTF 846-2016. Edited by F. Peter Guengerich |
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SubjectTerms | Alkaloids Catalysis Cytochrome P-450 Enzyme System - metabolism High-Throughput Nucleotide Sequencing Ibogaine - biosynthesis Opioid-Related Disorders - drug therapy Plant Biology Protein O-Methyltransferase - metabolism Tabernaemontana - chemistry Tabernaemontana - enzymology Tabernaemontana - metabolism Transcriptome - genetics |
Title | Cytochrome P450 and O-methyltransferase catalyze the final steps in the biosynthesis of the anti-addictive alkaloid ibogaine from Tabernanthe iboga |
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