Alkaloid chemodiversity in Mandragora spp. is associated with loss-of-functionality of MoH6H, a hyoscyamine 6β-hydroxylase gene

Daniel Schlesinger, Rachel Davidovich Rikanati, Sergei Volis, Adi Faigenboim, Vera Vendramin, Federica Cattonaro, Matthew Hooper, Elad Oren, Mark Taylor, Yaron Sitrit, Moshe Inbar, Efraim Lewinsohn*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Mandrakes (Mandragora spp., Solanaceae) are known to contain tropane alkaloids and have been used since antiquity in traditional medicine. Tropane alkaloids such as scopolamine and hyoscyamine are used in modern medicine to treat pain, motion sickness, as eye pupil dilators and antidotes against organo-phosphate poisoning. Hyoscyamine is converted to 6β-hydroxyhyoscyamine (anisodamine) and scopolamine by hyoscyamine 6β-hydroxylase (H6H), a 2-oxoglutarate dependent dioxygenase. We describe here a marked chemo-diversity in the tropane alkaloid content in Mandragora spp. M. officinarum and M. turcomanica lack anisodamine and scopolamine but display up to 10 fold higher hyoscyamine levels as compared with M. autumnalis. Transcriptomic analyses revealed that H6H is highly conserved among scopolamine-producing Solanaceae. MoH6H present in M. officinarum differs in several amino acid residues including a homozygotic mutation in the substrate binding region of the protein and its prevalence among accessions was confirmed by Cleaved-Amplified-Polymorphic-Sequence analyses. Functional expression revealed that MaH6H, a gene isolated from M. autumnalis encodes an active H6H enzyme while the MoH6H sequence isolated from M. officinarum was functionally inactive. A single G to T mutation in nucleotide 663 of MoH6H is associated with the lack of anisodamine and scopolamine in M. officinalis.
Original languageEnglish
Pages (from-to)301-310
Number of pages10
JournalPlant Science
Volume283
Early online date20 Mar 2019
DOIs
Publication statusPublished - Jun 2019
Externally publishedYes

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Mandragora
Hyoscyamine
atropine
scopolamine
Mixed Function Oxygenases
Scopolamine Hydrobromide
Alkaloids
alkaloids
Tropanes
tropane alkaloids
Solanaceae
Genes
genes
Motion Sickness
antidotes
mutation
Dioxygenases
Antidotes
Modern 1601-history
Mutation

Cite this

Schlesinger, D., Rikanati, R. D., Volis, S., Faigenboim, A., Vendramin, V., Cattonaro, F., ... Lewinsohn, E. (2019). Alkaloid chemodiversity in Mandragora spp. is associated with loss-of-functionality of MoH6H, a hyoscyamine 6β-hydroxylase gene. Plant Science, 283, 301-310. https://doi.org/10.1016/j.plantsci.2019.03.013
Schlesinger, Daniel ; Rikanati, Rachel Davidovich ; Volis, Sergei ; Faigenboim, Adi ; Vendramin, Vera ; Cattonaro, Federica ; Hooper, Matthew ; Oren, Elad ; Taylor, Mark ; Sitrit, Yaron ; Inbar, Moshe ; Lewinsohn, Efraim. / Alkaloid chemodiversity in Mandragora spp. is associated with loss-of-functionality of MoH6H, a hyoscyamine 6β-hydroxylase gene. In: Plant Science. 2019 ; Vol. 283. pp. 301-310.
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abstract = "Mandrakes (Mandragora spp., Solanaceae) are known to contain tropane alkaloids and have been used since antiquity in traditional medicine. Tropane alkaloids such as scopolamine and hyoscyamine are used in modern medicine to treat pain, motion sickness, as eye pupil dilators and antidotes against organo-phosphate poisoning. Hyoscyamine is converted to 6β-hydroxyhyoscyamine (anisodamine) and scopolamine by hyoscyamine 6β-hydroxylase (H6H), a 2-oxoglutarate dependent dioxygenase. We describe here a marked chemo-diversity in the tropane alkaloid content in Mandragora spp. M. officinarum and M. turcomanica lack anisodamine and scopolamine but display up to 10 fold higher hyoscyamine levels as compared with M. autumnalis. Transcriptomic analyses revealed that H6H is highly conserved among scopolamine-producing Solanaceae. MoH6H present in M. officinarum differs in several amino acid residues including a homozygotic mutation in the substrate binding region of the protein and its prevalence among accessions was confirmed by Cleaved-Amplified-Polymorphic-Sequence analyses. Functional expression revealed that MaH6H, a gene isolated from M. autumnalis encodes an active H6H enzyme while the MoH6H sequence isolated from M. officinarum was functionally inactive. A single G to T mutation in nucleotide 663 of MoH6H is associated with the lack of anisodamine and scopolamine in M. officinalis.",
author = "Daniel Schlesinger and Rikanati, {Rachel Davidovich} and Sergei Volis and Adi Faigenboim and Vera Vendramin and Federica Cattonaro and Matthew Hooper and Elad Oren and Mark Taylor and Yaron Sitrit and Moshe Inbar and Efraim Lewinsohn",
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Schlesinger, D, Rikanati, RD, Volis, S, Faigenboim, A, Vendramin, V, Cattonaro, F, Hooper, M, Oren, E, Taylor, M, Sitrit, Y, Inbar, M & Lewinsohn, E 2019, 'Alkaloid chemodiversity in Mandragora spp. is associated with loss-of-functionality of MoH6H, a hyoscyamine 6β-hydroxylase gene', Plant Science, vol. 283, pp. 301-310. https://doi.org/10.1016/j.plantsci.2019.03.013

Alkaloid chemodiversity in Mandragora spp. is associated with loss-of-functionality of MoH6H, a hyoscyamine 6β-hydroxylase gene. / Schlesinger, Daniel; Rikanati, Rachel Davidovich; Volis, Sergei; Faigenboim, Adi; Vendramin, Vera; Cattonaro, Federica; Hooper, Matthew; Oren, Elad; Taylor, Mark; Sitrit, Yaron; Inbar, Moshe; Lewinsohn, Efraim.

In: Plant Science, Vol. 283, 06.2019, p. 301-310.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Alkaloid chemodiversity in Mandragora spp. is associated with loss-of-functionality of MoH6H, a hyoscyamine 6β-hydroxylase gene

AU - Schlesinger, Daniel

AU - Rikanati, Rachel Davidovich

AU - Volis, Sergei

AU - Faigenboim, Adi

AU - Vendramin, Vera

AU - Cattonaro, Federica

AU - Hooper, Matthew

AU - Oren, Elad

AU - Taylor, Mark

AU - Sitrit, Yaron

AU - Inbar, Moshe

AU - Lewinsohn, Efraim

PY - 2019/6

Y1 - 2019/6

N2 - Mandrakes (Mandragora spp., Solanaceae) are known to contain tropane alkaloids and have been used since antiquity in traditional medicine. Tropane alkaloids such as scopolamine and hyoscyamine are used in modern medicine to treat pain, motion sickness, as eye pupil dilators and antidotes against organo-phosphate poisoning. Hyoscyamine is converted to 6β-hydroxyhyoscyamine (anisodamine) and scopolamine by hyoscyamine 6β-hydroxylase (H6H), a 2-oxoglutarate dependent dioxygenase. We describe here a marked chemo-diversity in the tropane alkaloid content in Mandragora spp. M. officinarum and M. turcomanica lack anisodamine and scopolamine but display up to 10 fold higher hyoscyamine levels as compared with M. autumnalis. Transcriptomic analyses revealed that H6H is highly conserved among scopolamine-producing Solanaceae. MoH6H present in M. officinarum differs in several amino acid residues including a homozygotic mutation in the substrate binding region of the protein and its prevalence among accessions was confirmed by Cleaved-Amplified-Polymorphic-Sequence analyses. Functional expression revealed that MaH6H, a gene isolated from M. autumnalis encodes an active H6H enzyme while the MoH6H sequence isolated from M. officinarum was functionally inactive. A single G to T mutation in nucleotide 663 of MoH6H is associated with the lack of anisodamine and scopolamine in M. officinalis.

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DO - 10.1016/j.plantsci.2019.03.013

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