Sarah o'connor

Sarah o'connor
Max Planck Institute for Chemical Ecology | ice · Department of Natural Product Biosynthesis

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202
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Publications

Publications (202)
Article
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Plants produce a wide variety of pharmacologically active molecules classified as natural products. Derivatization of these natural products can modulate or improve the bioactivity of the parent compound. Unfortunately, chemical derivatization of natural products is often difficult or impractical. Here we use the newly discovered biosynthetic genes...
Article
Monoterpene indole alkaloids (MIAs) comprise a large and diverse class of plant natural products, many of which exhibit potent biological activities such as anticancer, antimalarial, and antihypertensive. While the biosynthetic construction of these compounds has been a subject of intensive study for the past six decades, the identification of spec...
Article
Countless reports describe the isolation and structural characterization of natural products, yet this information remains disconnected and under-utilized. Using a cheminformatics approach, we leverage the reported observations of iridoid glucosides with the known phylogeny of a large iridoid producing plant family (Lamiaceae), to generate a set of...
Article
Many plant species from the Apocynaceae, Loganiaceae and Rubiaceae families evolved a specialized metabolism leading to the synthesis of a broad palette of monoterpene indole alkaloids (MIAs). These compounds are believed to constitute a cornerstone of the plant chemical arsenal but above all several MIAs display pharmacological properties that hav...
Preprint
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Monoterpene indole alkaloids (MIAs) are a diverse and important class of plant natural products that include a number of medicinally significant compounds, often present at low concentrations within their native plant species. The complex biosynthesis of MIAs requires the assembly of tryptamine with a secoiridoid to produce the central intermediate...
Article
Here we report the one-pot, cell-free enzymatic synthesis of the plant monoterpene nepetalactol starting from the readily available geraniol. A pair of orthogonal cofactor regeneration systems permitted NAD+-dependent geraniol oxidation followed by NADPH-dependent reductive cyclization without isolation of intermediates. The orthogonal cofactor reg...
Article
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Specialized metabolites are chemically complex small molecules with a myriad of biological functions. To investigate plant specialized metabolite biosynthesis more effectively, we developed an improved method for virus-induced gene silencing (VIGS). We designed a plasmid that incorporates fragments of both the target gene and knockdown marker gene...
Article
Microorganisms and plants represent major sources of natural compounds with a plethora of bioactive properties. Among these, plant natural products (PNPs) remain indispensable to human health. With few exceptions, PNP-based pharmaceuticals come from plant specialized metabolisms and display a structure far too complex for a profitable production by...
Article
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Mitragyna speciosa (kratom) produces numerous compounds with pharmaceutical properties including the production of bioactive monoterpene indole and oxindole alkaloids. Using a linked-read approach, a 1,122,519,462 bp draft assembly of M. speciosa ‘Rifat’ was generated with an N50 scaffold size of 1,020,971 bp and an N50 contig size of 70,448 bp tha...
Article
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The enzymatic basis for quinine 1 biosynthesis was investigated. Transcriptomic data from the producing plant led to the discovery of three enzymes involved in the early and late steps of the pathway. A medium-chain alcohol dehydrogenase (CpDCS) and an esterase (CpDCE) yielded the biosynthetic intermediate dihydrocorynantheal 2 from strictosidine a...
Article
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A nonribosomal peptide having a unique relationship with iron is used by ants to protect their fungal gardens.
Article
Deglycosylation is a key step in the activation of specialized metabolites involved in plant defense mechanisms. This reaction is notably catalyzed by β-glucosidases of the glycosyl hydrolase 1 (GH1) family such as strictosidine β-d-glucosidase (SGD) from Catharanthus roseus. SGD catalyzes the deglycosylation of strictosidine, forming a highly reac...
Article
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The lesser periwinkle Vinca minor accumulates numerous monoterpene indole alkaloids (MIAs) including the vasodilator vincamine. While the biosynthetic pathway of MIAs has been largely elucidated in other Apocynaceae such as Catharanthus roseus, the counterpart in V. minor remains mostly unknown, especially for reactions leading to MIAs specific to...
Article
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Plant secondary metabolites have applications for the food, biofuel, and pharmaceutical industries. Recent advances in pathway elucidation and host expression systems now allow metabolic engineering of plant metabolic pathways to produce "new-to-nature" derivatives with novel biological activities, thereby amplifying the range of industrial uses fo...
Article
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Olive (Olea europaea) is an important crop in Europe, with high cultural, economic and nutritional significance. Olive oil flavor and quality depend on phenolic secoiridoids, but the biosynthetic pathway of these iridoids remains largely uncharacterized. We discovered two bifunctional cytochrome P450 enzymes, catalyzing the rare oxidative C‐C bond...
Preprint
Full-text available
Olive ( Olea europaea ) is an important crop in Europe, with high cultural, economic, and nutritional significance. Olive oil flavor and quality depend on phenolic secoiridoids, but the biosynthetic pathway of these iridoids remains largely uncharacterized. We discovered two novel, bi-functional cytochrome P450 enzymes, catalysing the rare oxidativ...
Article
Full-text available
Catharanthus roseus produces a wide spectrum of monoterpene indole alkaloids (MIAs). MIA biosynthesis requires a tightly coordinated pathway involving more than 30 enzymatic steps that are spatio-temporally and environmentally regulated so that some MIAs specifically accumulate in restricted plant parts. The first regulatory layer involves a comple...
Article
Efficiency is a key organizing principle in modern natural product synthesis. Practical criteria include time, cost, and effort expended to synthesize the target, which tracks with step-count and scale. The execution of a natural product synthesis, that is, the sum and identity of each reaction employed therein, falls along a continuum of chemical...
Article
During the last years halogenated compounds have drawn a lot of attention. Metabolites with one or more halogen atoms are often more active than their non-halogenated derivatives like indole-3-acetic acid (IAA) and 4-Cl-IAA. Within this work, bacterial flavin-dependent tryptophan halogenase genes were inserted into Brassica rapa ssp. pekinensis (Ch...
Chapter
Virus-induced gene silencing (VIGS) is a versatile tool for genetic studies that has been applied to a variety of plant species. With the advent of more accessible genomic and transcriptomic technology applied to an increasing range of plants, tools such as VIGS are being adapted to more non-model plants to explore genes relevant to agriculture and...
Article
Full-text available
Nepenthes is a genus of carnivorous plants that evolved a pitfall trap, the pitcher, to catch and digest insect prey to obtain additional nutrients. Each pitcher is part of the whole leaf, together with a leaf blade. These two completely different parts of the same organ were studied separately in a non-targeted metabolomics approach in Nepenthes x...
Article
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Iridoids are plant-derived terpenoids with a rich array of bioactivities. The key step in iridoid skeleton formation is the reduction of 8-oxogeranial by certain members of the progesterone 5β-reductase/iridoid synthase (PRISE) family of short chain alcohol dehydrogenases. Other members of the PRISE family have previously been implicated in the bio...
Article
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Catnip or catmint ( Nepeta spp.) is a flowering plant in the mint family (Lamiaceae) famed for its ability to attract cats. This phenomenon is caused by the compound nepetalactone, a volatile iridoid that also repels insects. Iridoids are present in many Lamiaceae species but were lost in the ancestor of the Nepetoideae, the subfamily containing Ne...
Article
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Plant hormones have various functions in plants and play crucial roles in all developmental and differentiation stages. Auxins constitute one of the most important groups with the major representative indole-3-acetic acid (IAA). A halogenated derivate of IAA, 4-chloro-indole-3-acetic acid (4-Cl-IAA), has previously been identified in Pisum sativum...
Article
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Cycloaddition reactions generate chemical complexity in a single step. Here we report the crystal structures of three homologous plant-derived cyclases involved in the biosynthesis of iboga and aspidosperma alkaloids. These enzymes act on the same substrate, named angryline, to generate three distinct scaffolds. Mutational analysis reveals how thes...
Article
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Many of the plant-derived compounds used in chemotherapies are currently produced by semisynthesis, which results in limited supplies at exorbitant market prices. However, the synthetic biology era, which began ca 15 years ago, has progressively yielded encouraging advances by using engineered microbes for the practical production of cheaper plant...
Article
Elucidating plant-specialized biosynthetic pathways has always constituted a laborious task, notably for natural products with high pharmaceutical values. Here, we discuss emerging omics-based strategies that facilitate the identification of genes from these complex metabolic pathways, paving the way to engineered supplies of these compounds throug...
Article
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The discovery and supply of plant-derived anti-cancer compounds remain challenging given their low bioavailability and structural complexity. Reconstituting the pathways of these compounds in heterologous hosts is a promising solution; however, requires the complete elucidation of the biosynthetic genes involved and extensive metabolic engineering...
Article
Catharanthus roseus is a medicinal plant well known for producing bioactive compounds such as vinblastine and vincristine, which are classified as terpenoid indole alkaloids (TIAs). Although the leaves of this plant are the main source of these antitumor drugs, much remains unknown about how TIAs are biosynthesized from a central precursor, stricto...
Article
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(–)-Ibogaine and (–)-voacangine are plant derived psychoac-tives that show promise as effective treatments for opioid addiction. However, these compounds are produced by hard to source plants, making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (–)-voacangine, and de-esterified voacangine, which is conv...
Preprint
Full-text available
(−)-Ibogaine and (−)-voacangine are plant derived psychoactives that show promise as effective treatments for opioid addiction. However, these compounds are produced by hard to source plants making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (−)-voacangine, and de-esterified voacangine, which is conver...
Article
Biocatalysis and synthetic organic chemistry play by the same physicochemical rules, but their strong suits are fundamentally different. A case in point are cycloaddition reactions: their wide use in synthetic organic chemistry contrasts with their scarcity in biological systems. In their Minireview on page 6864 ff., H. Kries et al. discuss and des...
Article
Long sought after [4+2] cyclases have sprouted up in numerous biosynthetic pathways in recent years, raising hopes for biocatalytic solutions to cycloaddition catalysis, an important problem in chemical synthesis. In a few cases, detailed pictures of the inner workings of these catalysts have emerged, but intense efforts to gain deeper understandin...
Article
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Terpene synthases typically form complex molecular scaffolds by concerted activation and cyclization of linear starting materials in a single enzyme active site. Here we show that iridoid synthase, an atypical reductive terpene synthase, catalyzes the activation of its substrate 8-oxogeranial into a reactive enol intermediate, but does not catalyze...
Article
Genome mining is a routine technique in microbes to discover biosynthetic pathways. In plants, however, genomic information to identify novel biosynthesis genes is not commonly used. Here, we present the genome of the medicinal plant and oxindole monoterpene indole alkaloid (MIA) producer Gelsemium sempervirens (Gelsemiaceae). A gene cluster from C...
Preprint
Full-text available
Terpene synthases typically form complex molecular scaffolds by concerted activation and cyclization of linear starting materials in a single enzyme active site. Here we show that iridoid synthase, an atypical reductive terpene synthase, catalyses the activation of its substrate 8-oxogeranial into a reactive enol intermediate but does not catalyse...
Article
Full-text available
Cyclization reactions that create complex polycyclic scaffolds are hallmarks of alkaloid biosynthetic pathways. We present the discovery of three homologous cytochrome P450s from three monoterpene indole alkaloid-producing plants (Rauwolfia serpentina, Gelsemium sempervirens and Catharanthus roseus) that provide entry into two distinct alkaloid cla...
Article
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Monoterpenoid indole alkaloids are a large (ca. 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...
Article
Lochnericine is a major monoterpene indole alkaloid (MIA) in the roots of Madagascar periwinkle (Catharanthus roseus). Lochnericine is derived from stereoselective C6, C7 epoxidation of tabersonine and can be further metabolized to generate other complex MIAs. While the enzymes responsible for its downstream modifications have been characterized, t...
Chapter
Accurate and efficient demonstrations of protein localizations to the vacuole or tonoplast remain strict prerequisites to decipher the role of vacuoles in the whole plant cell biology and notably in defence processes. In this chapter, we describe a reliable procedure of protein subcellular localization study through transient transformations of Cat...
Article
The evolution of chemical complexity has been a major driver of plant diversification, with novel compounds serving as key innovations. The species-rich mint family (Lamiaceae) produces an enormous variety of compounds that act as attractants and defense molecules in nature and are used widely by humans as flavor additives, fragrances, and anti-her...
Article
Vinblastine, a potent anticancer drug, is produced by Madagascar periwinkle in small quantities: heterologous reconstitution of vinblastine biosynthesis could provide an additional source of this drug. The chemistry underlying vinblastine synthesis makes identification of the biosynthetic genes challenging. Here we identify the two missing steps of...
Article
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Centralized facilities for genetic engineering, or “biofoundries,” offer the potential to design organisms to address emerging needs in medicine, agriculture, industry, and defense. The field has seen rapid advances in technology, but it is difficult to gauge current capabilities or identify gaps across projects. To this end, our foundry was assess...
Article
While the characterization of the biosynthetic pathway of monoterpene indole alkaloids (MIAs) in leaves of Catharanthus roseus is now reaching completion, only two enzymes from the root counterpart dedicated to tabersonine metabolism have been identified to date, namely tabersonine 19-hydroxylase (T19H) and minovincine 19-O-acetyltransferase (MAT)....
Article
Full-text available
Monoterpene indole alkaloids, a large class of plant natural products, derive from the biosynthetic intermediate strictosidine aglycone. Strictosidine aglycone, which can exist as a variety of isomers, can be reduced to form numerous different structures. We have discovered a short chain alcohol dehydrogenase (SDR) from monoterpene indole alkaloid...
Article
Full-text available
Monoterpene indole alkaloids comprise a diverse family of over 2000 plant-produced natural products. This pathway provides an outstanding example of how nature creates chemical diversity from a single precursor, in this case from the intermediate strictosidine. The enzymes that elicit these seemingly disparate products from strictosidine have hithe...
Article
Tryptophan and indole derivatives are common precursors in many natural biosynthetic pathways. In recent years it has been shown that the substrate specificity of tryptophan halogenases is much more relaxed than previously thought. Using the tryptophan 7-halogenase PrnA, the tryptophan 6-halogenase ThdH, and the tryptophan 5-halogenase PyrH we achi...
Article
Phosphinothricin resistance is a widely used trait in plant science research and agriculture. The BAR resistance gene that inactivates phosphinothricin has now been shown to produce two non-specific metabolites in planta. An engineered BAR resistance gene with no detectable off-target activity is developed to address this issue.
Article
Full-text available
Nepetalactones are iridoid monoterpenes with a broad range of biological activities produced by plants in the Nepeta genus. However, none of the genes for nepetalactone biosynthesis have been discovered. Here we report the transcriptomes of two Nepeta species, each with distinctive profiles of nepetalactone stereoisomers. As a starting point for in...
Article
Monoterpenoid indole alkaloids (MIAs) are plant defense compounds and high-value pharmaceuticals. Biosynthesis of the universal MIA precursor, secologanin, is organized between internal phloem-associated parenchyma (IPAP) and epidermis cells. Transporters for intercellular transport of proposed mobile pathway intermediates have remained elusive. Sc...
Article
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Iridoid synthase from Nepeta cateria (catnip) and Nepeta mussinii , have been cloned and characterized. Abstract Nepetalactones are iridoid monoterpenes with a broad range of biological activities produced by plants in the Nepeta genus. However, none of the genes for nepetalactone biosynthesis have been discovered. Here we report the transcriptome...
Article
Full-text available
The natural product class of iridoids, found in various species of flowering plants, harbors astonishing chemical complexity. The discovery of iridoid biosynthetic genes in the medicinal plant Catharanthus roseus has provided insight into the biosynthetic origins of this class of natural product. However, not all iridoids share the exact 5-6 bicycl...
Article
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Plants create tremendous chemical diversity from a single biosynthetic intermediate. In plant-derived ajmalan alkaloid pathways, the biosynthetic intermediate vomilenine can be transformed into the anti-arrhythmic compound ajmaline, or alternatively, can isomerize to form perakine, an alkaloid with a structurally distinct scaffold. Here we report t...