The biosynthesis of tigliane and related diterpenoids; an intriguing problem

Schmidt, Richard J.

doi:10.1111/j.1095-8339.1987.tb01047.x

Cited by 32 publications

(17 citation statements)

References 48 publications

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“…The only presumed step is the first cyclization of tiglian by casbene synthase (CS), during which geranylgeranyl pyrophosphate is converted to a monocyclic diterpene, casbene. Macrocyclic diterpenoids, including tigliane, are thought to be biosynthesized from casbene, through several catalytic conversion or modification steps (Figure 1; Schmidt 1987). Casbene was isolated as the antifungal diterpene from castor bean (Ricinus communis), and stress-treated castor bean seedlings were found to exhibit high levels of CS activity (Moesta and West 1985).…”

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confidence: 99%

Characterization of the casbene synthase homolog from Jatropha (<i>Jatropha curcas</i> L.)

Nakano

Ohtani

Polsri

et al. 2012

Plant Biotechnology

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Abstracte high oil content of Jatropha (Jatropha curcas L.) seeds makes Jatropha an attractive resource for the production of sustainable bioenergy. However, the Jatropha seed kernels also contain antinutrients and various toxins that persist in the oil and seed cakes and pose a safety risk. Since phorbol esters (PEs) are the major contributor to toxicity, a better understanding of PE biosynthesis is expected to elucidate an e ective strategy for the utilization of Jatropha plants. In this study, a Jatropha curcas casbene synthase homolog (JcCSH) with high sequence similarity to casbene synthases (CSs) from Ricinus communis, Euphorbia esula, and Sapium sebiferum was cloned from Jatropha leaf tissue. CS has been hypothesized to catalyze the rst step of phorbol biosynthesis. JcCSH encodes a protein that contains a chloroplast transit peptide and a DDXXD motif that is conserved among known terpene cyclases. JcCSH was expressed in seedlings, mature leaves, and the esh of developing fruits, but not in developing seeds. Our results suggest that JcCSH is widely involved in casbene biosynthesis in various tissues other than seeds. Key words:Casbene synthase, Jatropha (Jatropha curcas L.), phorbol ester.Recently, Jatropha (Jatropha curcas L.) has attracted much attention as a potential resource for the production of sustainable bioenergy, following concerns about the depletion of fossil fuels and global warming. Jatropha, a perennial shrub that originated in Mexico and Central America and belongs to the Euphorbiaceae family, is widely distributed between the tropics of Cancer and Capricorn.e seed kernels are rich in oil (44-62%) and proteins (22-35%), making this plant a favorable feedstock not only for biodiesel but also for protein (Makkar et al. 1998). However, it is hard to utilize the Jatropha seed cakes for animal feed a er extracting the oil, because several antinutrients and various toxins, such as curcin, trypsin inhibitors, and phorbol esters (PEs), are contained in the seed kernels (Makkar et al. 1998). Among these harmful substances, the major contributor to toxicity is PEs (Makkar et al. 1998). PEs are tetracyclic diterpenoids that occur in the seeds, sap, and latex of plants of the ymelaeaceae and Euphobiaceae families. Six PE derivatives were identified from Jatropha oil and their structures were solved by nuclear magnetic resonance (NMR) analysis. They were all found to contain 12-hydroxy-16-deoxyphorbol (Adolf et al. 1984;Haas et al. 2002). Since a PE isolated from Jatropha is known to have tumor-promoting activity (Hirota et al. 1988), it is critical to eliminate the risk of PEs toxicity if Jatropha is to be used commercially. One e ective means of doing so is to shut down and/or modify the biosynthesis of PEs at the molecular level.PEs are composed of a tetracyclic diterpene, named tiglian, and two fatty acids, which are esterified to C13 and C16 of the tiglian skeleton (Haas et al. 2002). The biosynthetic pathway of PEs is currently poorly understood. The only presumed step is the first cyclization of...

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confidence: 99%

Characterization of the casbene synthase homolog from Jatropha (<i>Jatropha curcas</i> L.)

Nakano

Ohtani

Polsri

et al. 2012

Plant Biotechnology

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“…The daphnanes are related in chemical structure to the phorbol esters which are well known as tumour-promoting and irritant toxins (Hecker & Schmidt 1975). Daphnanes are found in similar plant species and have a range of biological activities in common with phorbol esters (Schmidt 1987). The best known derivative of the daphnane group is the second stage tumour-promoting agent mezerein (Slaga et al 1980).…”

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Properties of a Resiniferatoxin-stimulated, Calcium Inhibited but Phosphatidylserine-dependent Kinase, which is Distinct from Protein Kinase C Isotypes α, β1γ, δ, ε and η

Sharma

Ryves

Gordge

et al. 1995

Journal of Pharmacy and Pharmacology

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We have separated a resiniferatoxin-stimulated histone-kinase activity from human neutrophils, elicited mouse macrophages and murine alveolar macrophages by hydroxyapatite chromatography. The assay conditions for resiniferatoxin kinase were optimized as part of this study and in the presence of phosphatidylserine but absence of Ca2+ the Ka for histone IIIs phosphorylation by resiniferatoxin was calculated as 16 nM. Using a phosphate gradient of 20-500 mM, peaks of protein kinase C activity could be washed from the hydroxyapatite column in 300 nM phosphate and resiniferatoxin kinase recovered in 500 mM phosphate. At the optimum concentration of 160 nM, the ability of resiniferatoxin to induce enzyme activity was compared with a range of phorbol esters all at the same concentration. These related compounds failed to activate resiniferatoxin kinase although they have previously been shown to activate protein kinase C isotypes. Similarly sn-1,2,-dioleoylglycerol and the potent irritant capsaicin at 30 microM failed to activate the kinase. A Scatchard analysis of [3H] phorbol dibutyrate binding produced a linear plot (Kd 41.6 nM; Bmax 11.6 fmol unit-1) and binding was inhibited by resiniferatoxin and 12-O-tetradecanoylphorbol-13-acetate (TPA), with resiniferatoxin 700 times more potent than TPA in this respect. A radiolabelled resiniferatoxin binding assay was also used to demonstrate specific binding of [3H]resiniferatoxin which could be inhibited by unlabelled compound. Resiniferatoxin kinase activity was shown to be distinct from the protein kinase C isotypes alpha, beta 1, gamma, delta and epsilon by means of immunological analysis and from the eta isotype, because that isotype was not stimulated by resiniferatoxin but was stimulated by TPA when a pseudosubstrate was used. In addition the resiniferatoxin-stimulated activity was inhibited in-vitro by the addition of Ca2+ (Ki 0.1-0.5 nM free Ca2+). Further purification of resiniferatoxin kinase by Superose chromatography indicated a major activity fraction of about 70-90 kDa. Thus resiniferatoxin kinase, isolated from human and mouse inflammatory cells is distinct from the known isotypes of protein kinase C and is a major resiniferatoxin receptor.

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“…Biosynthesis of ingenanes, tiglanes and jatrophanes has been proposed in the literature to involve a lathyrane intermediate (Evans and Taylor, 1983 ; Schmidt, 1987 ). It is noteworthy that while lathyranes such as jolkinol C contain a C12‐C13 double bond, this position is reduced in these other classes (Durán‐Peña et al ., 2014 ; Evans and Taylor, 1983 ).…”

Section: Resultsmentioning

confidence: 99%

Developing a Nicotiana benthamiana transgenic platform for high‐value diterpene production and candidate gene evaluation

Forestier

Czechowski

Cording

et al. 2021

Plant Biotechnology Journal

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To engineer Nicotiana benthamiana to produce novel diterpenoids, we first aimed to increase production of the diterpenoid precursor geranylgeranyl pyrophosphate (GGPP) by up-regulation of key genes of the non-mevalonate (MEP) pathway sourced from Arabidopsis thaliana. We used transient expression to evaluate combinations of the eight MEP pathway genes plus GGPP synthase and a Jatropha curcas casbene synthase (JcCAS) to identify an optimal combination for production of casbene from GGPP. AtDXS and AtHDR together with AtGGPPS and JcCAS gave a 410% increase in casbene production compared to transient expression of JcCAS alone. This combination was cloned into a single construct using the MoClo toolkit, and stably integrated into the N. benthamiana genome. We also created multigene constructs for stable transformation of two J. curcas cytochrome P450 genes, JcCYP726A20 and JcCYP71D495 that produce the more complex diterpenoid jolkinol C from casbene when expressed transiently with JcCAS in N. benthamiana. Stable transformation of JcCYP726A20, JcCYP71D495 and JcCAS did not produce any detectable jolkinol C until these genes were co-transformed with the optimal set of precursor-pathway genes. One such stable homozygous line was used to evaluate by transient expression the involvement of an 'alkenal reductase'-like family of four genes in the further conversion of jolkinol C, leading to the demonstration that one of these performs reduction of the 12,13-double bond in jolkinol C. This work highlights the need to optimize precursor supply for production of complex diterpenoids in stable transformants and the value of such lines for novel gene discovery.

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The biosynthesis of tigliane and related diterpenoids; an intriguing problem

Cited by 32 publications

References 48 publications

Characterization of the casbene synthase homolog from Jatropha (<i>Jatropha curcas</i> L.)

Characterization of the casbene synthase homolog from Jatropha (<i>Jatropha curcas</i> L.)

Properties of a Resiniferatoxin-stimulated, Calcium Inhibited but Phosphatidylserine-dependent Kinase, which is Distinct from Protein Kinase C Isotypes α, β1γ, δ, ε and η

Developing a Nicotiana benthamiana transgenic platform for high‐value diterpene production and candidate gene evaluation

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