A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate

Tatsis, Evangelos C.; Carqueijeiro, Inês; Bernonville, Thomas Dugé de; Franke, Jakob; Dang, Thu-Thuy T.; Oudin, Audrey; Lanoue, Arnaud; Lafontaine, Florent; Stavrinides, Anna; Clastre, Marc; Courdavault, Vincent; O’Connor, Sarah E.

doi:10.1038/s41467-017-00154-x

Cited by 116 publications

(100 citation statements)

References 39 publications

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“…The extensive chemical diversity of the MIAs is largely derived from the reactivity of the strictosidine aglycone substrate. Two previously reported dehydrogenases that use strictosidine aglycone as a substrate turn over specific strictosidine aglycone isomers—pro‐heteroyohimbine or dehydrogeissoschizine—to generate highly divergent structures (Scheme ). Although the experiments reported here do not unequivocally demonstrate that strictosidine aglycone is the physiological substrate, the in vitro reactivity of VAS clearly shows that a third isomer of strictosidine aglycone can be reductively trapped.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a Short‐Chain Dehydrogenase from Catharanthus roseus that Produces a New Monoterpene Indole Alkaloid

et al. 2018

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Plant monoterpene indole alkaloids, a large class of 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 plant producers of monoterpene indole alkaloids (Catharanthus roseus and Rauvolfia serpentina) that reduce strictosidine aglycone and produce an alkaloid that does not correspond to any previously reported compound. Here we report the structural characterization of this product, which we have named vitrosamine, as well as the crystal structure of the SDR. This discovery highlights the structural versatility of the strictosidine aglycone biosynthetic intermediate and expands the range of enzymatic reactions that SDRs can catalyse. This discovery further highlights how a sequence‐based gene mining discovery approach in plants can reveal cryptic chemistry that would not be uncovered by classical natural product chemistry approaches.

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Section: Resultsmentioning

confidence: 99%

Discovery of a Short‐Chain Dehydrogenase from Catharanthus roseus that Produces a New Monoterpene Indole Alkaloid

et al. 2018

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“…Reactive non-isolable substrates appear elsewhere in plant specialised metabolism, including monoterpene indole alkaloid 32 and lignan biosynthesis 33,34 . NEPS are reminiscent of dirigent proteins, proteins in lignan biosynthesis that control the stereoselective cyclisation of a reactive intermediate that is generated by a separate enzyme 33,34 .…”

Section: Discussionmentioning

confidence: 99%

Uncoupled activation and cyclisation in catmint reductive terpenoid biosynthesis

Lichman

Kamileen

Tichman

et al. 2018

Preprint

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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, catalyses the activation of its substrate 8-oxogeranial into a reactive enol intermediate but does not catalyse the subsequent cyclisation into nepetalactol. This discovery led us to identify a class of nepetalactol-related short-chain dehydrogenase enzymes (NEPS) from catmint (Nepeta mussinii) which catalyse the stereoselective cyclisation of the enol intermediate into nepetalactol isomers. Subsequent oxidation of nepetalactols by NEPS1 provides nepetalactones, metabolites that are well known for both insect-repellent activity and euphoric effect in cats. Structural characterisation of the NEPS3 cyclase reveals it binds to NAD + yet does not utilise it chemically for a nonoxidoreductive formal [4+2] cyclisation. These discoveries will complement metabolic reconstructions of iridoid and monoterpene indole alkaloid biosynthesis. Main paperNepetalactones 1 are volatile natural products produced by plants of the genus Nepeta, notably catmint (Nepeta mussinii syn racemosa) and catnip (N. cataria) (Fig. 1a) 1,2 . These compounds are responsible for the stimulatory effects these plants have on cats [3][4][5] . Moreover, certain insects use nepetalactones as sex pheromones, so production of these compounds by the plant also impacts interactions with insects 6 . Notably, the bridgehead stereocentres (carbons 4a and 7a) vary between 2 and within 2,4,7 Nepeta species. N. mussinii individuals, for example, produce different ratios of cis-trans 1a, cis-cis 1b and trans-cis-nepetalactone 1c 7 . Variation in stereoisomer ratio may influence the repellence of insect herbivores 8,9 . While the ratio of stereoisomers may be responsible for important biological effects, the mechanism of stereocontrol in nepetalactone biosynthesis is not known.Nepetalactones are iridoids, non-canonical monoterpenoids containing a cyclopentanopyran ring. Canonical cyclic terpenoids (e.g. (-)-limonene) are biosynthesised from linear precursors by terpene synthases (Fig. 1b) 10 . These enzymes activate linear precursors either by loss of pyrophosphate or protonation [10][11][12] . The resulting carbocations generated cyclise rapidly to form an array of cyclic products 13 . Therefore, in canonical terpenoid biosynthesis, activation and cyclisation of precursors are coupled and occur in the same enzyme active site.In plant iridoid biosynthesis, geranyl pyrophosphate is hydrolysed and oxidised into 8-oxogeranial 2 14 . This precursor then undergoes a two-step activation-cyclisation process, analogous to canonical terpene synthesis (Fig. 1c) 15 . Unlike canonical terpene synthesis, however, activation is achieved by reduction, and the intermediate is not a carbocation, but the enol or enolate species 3. Cyclisation of this intermediate yields cis-trans-nepetalactol 4a along with iridodial side products 5 (Fig. 1c).

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“…Our understanding of the biocatalytic cascade or multistep reactions made by enzymes in different cellular compartment remains limited, and yet deciphering new biocatalytic systems in nature for future bioinspired synthetic strategies represents a stimulating interdisciplinary field for chemists and biologists. In this context, two recent studies on plant alkaloids and plant terpenoids report rare examples of tandem biocatalysis, which is an exciting and emerging field in chemical biology …”

Section: Methodsmentioning

confidence: 99%

Tandem Biocatalysis Unlocks the Challenging de Novo Production of Plant Natural Products

Duplais

Estevez

2017

ChemBioChem

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Intimate partnership: Knowledge of the biocatalytic cascades in different cellular compartments is limited, but deciphering these systems in nature can be used to inspire synthetic strategies. Two studies report new insights into the biosynthesis of alkaloids and sesterterpenoids in plants. This highlight presents these novel biotransformations to illustrate how tandem biocatalysis can impact the future of natural product production.

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A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate

Cited by 116 publications

References 39 publications

Discovery of a Short‐Chain Dehydrogenase from Catharanthus roseus that Produces a New Monoterpene Indole Alkaloid

Discovery of a Short‐Chain Dehydrogenase from Catharanthus roseus that Produces a New Monoterpene Indole Alkaloid

Uncoupled activation and cyclisation in catmint reductive terpenoid biosynthesis

Tandem Biocatalysis Unlocks the Challenging de Novo Production of Plant Natural Products

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