Modular biomanufacturing for a sustainable production of terpenoid-based insect deterrents

Mischko, Wolfgang; Hirte, Max; Roehrer, Simon; Engelhardt, Hannes; Mehlmer, Norbert; Minceva, Mirjana; Brück, Thomas

doi:10.1039/c8gc00434j

Cited by 36 publications

(40 citation statements)

References 81 publications

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“…The cembrene-type diterpenes display diverse bioactivities, including cytotoxic, insect deterrent and antimicrobial. Relevant work on insecticidal cembrenes has recently been reported 43 . Similarly, the single mutation of W288G alters to product to (1 R ,3 E ,7 E ,11 S ,12 S )−3,7,18-dolabellatriene.…”

Section: Discussionmentioning

confidence: 99%

Towards a comprehensive understanding of the structural dynamics of a bacterial diterpene synthase during catalysis

et al. 2018

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Terpenes constitute the largest and structurally most diverse natural product family. Most terpenoids exhibit a stereochemically complex macrocyclic core, which is generated by C–C bond forming of aliphatic oligo-prenyl precursors. This reaction is catalysed by terpene synthases (TPSs), which are capable of chaperoning highly reactive carbocation intermediates through an enzyme-specific reaction. Due to the instability of carbocation intermediates, the proteins’ structural dynamics and enzyme:substrate interactions during TPS catalysis remain elusive. Here, we present the structure of the diterpene synthase CotB2, in complex with an in crystallo cyclised abrupt reaction product and a substrate-derived diphosphate. We captured additional snapshots of the reaction to gain an overview of CotB2’s catalytic mechanism. To enhance insights into catalysis, structural information is augmented with multiscale molecular dynamic simulations. Our data represent fundamental TPS structure dynamics during catalysis, which ultimately enable rational engineering towards tailored terpene macrocycles that are inaccessible by conventional chemical synthesis.

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Section: Discussionmentioning

confidence: 99%

Towards a comprehensive understanding of the structural dynamics of a bacterial diterpene synthase during catalysis

et al. 2018

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“…Besides, the external loop of the ERC allowed the semi-continuous product recovery, reaching (+)-zizaene titers of 93.4 mg L −1 . Such improvements have also been obtained by the use of ERC in other terpenes studies, such as monoterpene carvone (225 mg L −1 ) [37] and diterpene cembratriene-ol (78.9 mg L −1 ) [50].…”

Section: Discussionmentioning

confidence: 99%

Improved Production and In Situ Recovery of Sesquiterpene (+)-Zizaene from Metabolically-Engineered E. coli

2019

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The sesquiterpene (+)-zizaene is the direct precursor of khusimol, the main fragrant compound of the vetiver essential oil from Chrysopogon zizanioides and used in nearly 20% of men’s fine perfumery. The biotechnological production of such fragrant sesquiterpenes is a promising alternative towards sustainability; nevertheless, product recovery from fermentation is one of the main constraints. In an effort to improve the (+)-zizaene recovery from a metabolically-engineered Escherichia coli, we developed an integrated bioprocess by coupling fermentation and (+)-zizaene recovery using adsorber extractants. Initially, (+)-zizaene volatilization was confirmed from cultivations with no extractants but application of liquid–liquid phase partitioning cultivation (LLPPC) improved (+)-zizaene recovery nearly 4-fold. Furthermore, solid–liquid phase partitioning cultivation (SLPPC) was evaluated by screening polymeric adsorbers, where Diaion HP20 reached the highest recovery. Bioprocess was scaled up to 2 L bioreactors and in situ recovery configurations integrated to fermentation were evaluated. External recovery configuration was performed with an expanded bed adsorption column and improved (+)-zizaene titers 2.5-fold higher than LLPPC. Moreover, internal recovery configuration (IRC) further enhanced the (+)-zizaene titers 2.2-fold, whereas adsorption velocity was determined as critical parameter for recovery efficiency. Consequently, IRC improved the (+)-zizaene titer 8.4-fold and productivity 3-fold from our last report, achieving a (+)-zizaene titer of 211.13 mg L−1 and productivity of 3.2 mg L−1 h−1. This study provides further knowledge for integration of terpene bioprocesses by in situ product recovery, which could be applied for many terpene studies towards the industrialization of fragrant molecules.

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“…Furthermore, overexpression of cembratrien-ol synthase gene using either trichome-specific CYP450 or Cauliflower mosaic virus 35S promoters greatly increased aphid resistance by promoting the accumulation of CBT-diols in tobacco plants [23]. Recent studies show that the recombinant Escherichia coli can be used to generate 78.9 ± 2.4 mg·L −1 CBT-ol in a 50 L bioreactor, and in vivo and in vitro bioactivity studies confirmed the insecticidal characteristics [24]. Therefore, tobacco cembranoid diterpenes can be researched for the development of insecticides due to their insecticidal activity [22,23,24].…”

Section: Bioactivities Of Tobacco Cembranoid Diterpenesmentioning

confidence: 99%

“…Recent studies show that the recombinant Escherichia coli can be used to generate 78.9 ± 2.4 mg·L −1 CBT-ol in a 50 L bioreactor, and in vivo and in vitro bioactivity studies confirmed the insecticidal characteristics [24]. Therefore, tobacco cembranoid diterpenes can be researched for the development of insecticides due to their insecticidal activity [22,23,24].…”

Section: Bioactivities Of Tobacco Cembranoid Diterpenesmentioning

confidence: 99%

A Review on Bioactivities of Tobacco Cembranoid Diterpenes

Ning

Liu

et al. 2019

Biomolecules

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Cembranoids are carbocyclic diterpenes comprising four isoprene units and are natural products with a parent skeleton consisting of a 14-membered ring. They have gained wide interest in recent years and are a major hotspot in the research of natural product chemistry. Since 1962, various tobacco cembranoid diterpenes have been identified. This review systematically discusses and summarises the excellent antimicrobial, insecticidal, cytotoxic and neuroprotective activities of tobacco cembranoid diterpenes. These compounds show potential to be developed as botanical fungicides, cytotoxic drugs and drugs for the treatment of human immunodeficiency virus, Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases. However, there are relatively few studies on the structure–activity relationship (SAR) of tobacco cembranoid diterpenes. Therefore, future studies should focus on their structural modification, SAR and biogenic relationships.

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Modular biomanufacturing for a sustainable production of terpenoid-based insect deterrents

Abstract: A sustainable production process of a new terpenoid-based insect deterrent which might serve as a future alternative to synthetic solutions.

Cited by 36 publications

References 81 publications

Towards a comprehensive understanding of the structural dynamics of a bacterial diterpene synthase during catalysis

Towards a comprehensive understanding of the structural dynamics of a bacterial diterpene synthase during catalysis

Improved Production and In Situ Recovery of Sesquiterpene (+)-Zizaene from Metabolically-Engineered E. coli

A Review on Bioactivities of Tobacco Cembranoid Diterpenes

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