A database-driven approach identifies additional diterpene synthase activities in the mint family (Lamiaceae)

Johnson, Sean R.; Bhat, Wajid Waheed; Bibik, Jacob; Turmo, Aiko; Hamberger, Britta; Consortium, Evolutionary Mint Genomics; Hamberger, Björn

doi:10.1074/jbc.ra118.006025

Cited by 63 publications

(77 citation statements)

References 96 publications

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“…Beyond Scrophulariaceae, there are hundreds of other diterpene backbones with unknown biosynthetic routes. In Lamiaceae alone there are at least 200 ( Johnson et al ., 2019a ), and in Salvia sclarea (Lamiaceae), two previously reported diterpenoids salviatriene A and B ( Laville et al ., 2012 ) resemble a cycloserrulatane and tricyclic viscidane, respectively. Given the independent emergence of cis -PTs which yield NNPP in different plant families, it may be that some of these unknown diterpenoid pathways involve NNPP as well.…”

Section: Discussionmentioning

confidence: 99%

“…Transient expression assays in N . benthamiana were carried out as described earlier ( Johnson et al ., 2019a ). N .…”

Section: Methodsmentioning

confidence: 99%

“…This wide variety of uses can be attributed to the incredible structural diversity of terpenoid compounds, resulting from sequential and combinatorial modifications of common starting molecules. Typically beginning with three common C10, C15, and C20 trans -prenyl diphosphate substrates, hundreds of mono-, sesqui-, and diterpene backbones are cyclized by terpene synthases (TPSs) ( Degenhardt et al ., 2009 ; Durairaj et al ., 2019 ; Johnson et al ., 2019a ). These backbones are further diversified to thousands of terpenoids ( Zeng et al ., 2019 ) through successive modification by enzymes such as cytochrome P450 mono-oxygenases, aldehyde dehydrogenases, and acetyl transferases ( Luo et al ., 2016 ; Pateraki et al ., 2017 ; Johnson et al ., 2019b ; Karunanithi and Zerbe, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…These backbones are further diversified to thousands of terpenoids ( Zeng et al ., 2019 ) through successive modification by enzymes such as cytochrome P450 mono-oxygenases, aldehyde dehydrogenases, and acetyl transferases ( Luo et al ., 2016 ; Pateraki et al ., 2017 ; Johnson et al ., 2019b ; Karunanithi and Zerbe, 2019 ). Diterpenoids (C20) make up more than 13 000 known plant terpenoids ( Johnson et al ., 2019a ), and the vast majority with known biosynthetic pathways are derived from all- trans ( E,E,E )-geranylgeranyl diphosphate (GGPP). A given diterpene backbone can be the source of anywhere from one to hundreds of diterpenoids following downstream modification ( Johnson et al ., 2019a ), and the biosynthetic routes for the majority of these backbones remain unknown ( Johnson et al ., 2019b ).…”

Section: Introductionmentioning

confidence: 99%

“…Diterpenoids (C20) make up more than 13 000 known plant terpenoids ( Johnson et al ., 2019a ), and the vast majority with known biosynthetic pathways are derived from all- trans ( E,E,E )-geranylgeranyl diphosphate (GGPP). A given diterpene backbone can be the source of anywhere from one to hundreds of diterpenoids following downstream modification ( Johnson et al ., 2019a ), and the biosynthetic routes for the majority of these backbones remain unknown ( Johnson et al ., 2019b ).…”

Section: Introductionmentioning

confidence: 99%

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The biosynthesis of the anti‐microbial diterpenoid leubethanol in Leucophyllum frutescens proceeds via an all‐cis prenyl intermediate

et al. 2020

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SUMMARY Serrulatane diterpenoids are natural products found in plants from a subset of genera within the figwort family (Scrophulariaceae). Many of these compounds have been characterized as having anti-microbial properties and share a common diterpene backbone. One example, leubethanol from Texas sage ( Leucophyllum frutescens ) has demonstrated activity against multi-drug-resistant tuberculosis. Leubethanol is the only serrulatane diterpenoid identified from this genus; however, a range of such compounds have been found throughout the closely related Eremophila genus. Despite their potential therapeutic relevance, the biosynthesis of serrulatane diterpenoids has not been previously reported. Here we leverage the simple product profile and high accumulation of leubethanol in the roots of L . frutescens and compare tissue-specific transcriptomes with existing data from Eremophila serrulata to decipher the biosynthesis of leubethanol. A short-chain cis -prenyl transferase ( Lf CPT1) first produces the rare diterpene precursor nerylneryl diphosphate, which is cyclized by an unusual plastidial terpene synthase ( Lf TPS1) into the characteristic serrulatane diterpene backbone. Final conversion to leubethanol is catalyzed by a cytochrome P450 (CYP71D616) of the CYP71 clan. This pathway documents the presence of a short-chain cis -prenyl diphosphate synthase, previously only found in Solanaceae, which is likely involved in the biosynthesis of other known diterpene backbones in Eremophila . Lf TPS1 represents neofunctionalization of a compartment-switching terpene synthase accepting a novel substrate in the plastid. Biosynthetic access to leubethanol will enable pathway discovery to more complex serrulatane diterpenoids which share this common starting structure and provide a platform for the production and diversification of this class of promising anti-microbial therapeutics in heterologous systems.

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Section: Discussionmentioning

confidence: 99%

“…Transient expression assays in N . benthamiana were carried out as described earlier ( Johnson et al ., 2019a ). N .…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The biosynthesis of the anti‐microbial diterpenoid leubethanol in Leucophyllum frutescens proceeds via an all‐cis prenyl intermediate

et al. 2020

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Recent progress and new perspectives for diterpenoid biosynthesis in medicinal plants

Liu

Tian

et al. 2021

Medicinal Research Reviews

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Diterpenoids, including more than 18,000 compounds, represent an important class of metabolites that encompass both phytohormones and some industrially relevant compounds. These molecules with complex, diverse structures and physiological activities, have high value in the pharmaceutical industry. Most medicinal diterpenoids are extracted from plants. Major advances in understanding the biosynthetic pathways of these active compounds are providing unprecedented opportunities for the industrial production of diterpenoids by metabolic engineering and synthetic biology. Here, we summarize recent developments in the field of diterpenoid biosynthesis from medicinal herbs. An overview of the pathways and known biosynthetic enzymes is presented. In particular, we look at the main findings from the past decade and review recent progress in the biosynthesis of different groups of ringed compounds. We also discuss diterpenoid production using synthetic biology and metabolic engineering strategies, and draw on new technologies and discoveries to bring together many components into a useful framework for diterpenoid production.

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Engineering Nannochloropsis oceanica for the production of diterpenoid compounds

Du,

Bhat,

Poliner

et al. 2023

mLife

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Photosynthetic microalgae like Nannochloropsis hold enormous potential as sustainable, light‐driven biofactories for the production of high‐value natural products such as terpenoids. Nannochloropsis oceanica is distinguished as a particularly robust host with extensive genomic and transgenic resources available. Its capacity to grow in wastewater, brackish, and sea waters, coupled with advances in microalgal metabolic engineering, genome editing, and synthetic biology, provides an excellent opportunity. In the present work, we demonstrate how N. oceanica can be engineered to produce the diterpene casbene—an important intermediate in the biosynthesis of pharmacologically relevant macrocyclic diterpenoids. Casbene accumulated after stably expressing and targeting the casbene synthase from Daphne genkwa (DgTPS1) to the algal chloroplast. The engineered strains yielded production titers of up to 0.12 mg g−1 total dry cell weight (DCW) casbene. Heterologous overexpression and chloroplast targeting of two upstream rate‐limiting enzymes in the 2‐C‐methyl‐ d‐erythritol 4‐phosphate pathway, Coleus forskohlii 1‐deoxy‐ d‐xylulose‐5‐phosphate synthase and geranylgeranyl diphosphate synthase genes, further enhanced the yield of casbene to a titer up to 1.80 mg g−1 DCW. The results presented here form a basis for further development and production of complex plant diterpenoids in microalgae.

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A database-driven approach identifies additional diterpene synthase activities in the mint family (Lamiaceae)

Cited by 63 publications

References 96 publications

The biosynthesis of the anti‐microbial diterpenoid leubethanol in Leucophyllum frutescens proceeds via an all‐cis prenyl intermediate

The biosynthesis of the anti‐microbial diterpenoid leubethanol in Leucophyllum frutescens proceeds via an all‐cis prenyl intermediate

Recent progress and new perspectives for diterpenoid biosynthesis in medicinal plants

Engineering Nannochloropsis oceanica for the production of diterpenoid compounds

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