Diterpenoids from <i>Euphorbia peplus</i>

Hohmann, Judit; Evanics, Ferenc; Berta, László; Bartók, Tibor

doi:10.1055/s-2000-8568

Cited by 65 publications

(66 citation statements)

References 3 publications

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“…For example, in the case of prostratin production by H. nutans, the desired compound is produced mainly within the stem of this slow growing plant, at a concentration of 0.2 to 52.6 mg g 21 (Johnson et al, 2008). The amounts of ingenol mebutate present within E. peplus are also low, at around 1.1 mg of ingenol mebutate per kilogram of plant material (Hohmann et al, 2000). To circumvent supply problems of ingenol mebutate, two chemical approaches have been investigated.…”

Section: Introductionmentioning

confidence: 99%

“…J. curcas in particular is known to produce a wide variety of diterpenoids, including a number of diterpenoids within roots (Zhang et al, 2012) and phorbol esters within seeds (Haas et al, 2002;He et al, 2011). E. peplus also produces a range of diterpenoids, including the licensed pharmaceutical ingenol mebutate (Hohmann et al, 2000).…”

Section: Clustering Of Diterpenoid Biosynthetic Genes Is Common In Thmentioning

confidence: 99%

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Production of Bioactive Diterpenoids in the Euphorbiaceae Depends on Evolutionarily Conserved Gene Clusters

et al. 2014

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The Euphorbiaceae produce a diverse range of diterpenoids, many of which have pharmacological activities. These diterpenoids include ingenol mebutate, which is licensed for the treatment of a precancerous skin condition (actinic keratosis), and phorbol derivatives such as resiniferatoxin and prostratin, which are undergoing investigation for the treatment of severe pain and HIV, respectively. Despite the interest in these diterpenoids, their biosynthesis is poorly understood at present, with the only characterized step being the conversion of geranylgeranyl pyrophosphate into casbene. Here, we report a physical cluster of diterpenoid biosynthetic genes from castor (Ricinus communis), including casbene synthases and cytochrome P450s from the CYP726A subfamily. CYP726A14, CYP726A17, and CYP726A18 were able to catalyze 5-oxidation of casbene, a conserved oxidation step in the biosynthesis of this family of medicinally important diterpenoids. CYP726A16 catalyzed 7,8-epoxidation of 5-keto-casbene and CYP726A15 catalyzed 5-oxidation of neocembrene. Evidence of similar gene clustering was also found in two other Euphorbiaceae, including Euphorbia peplus, the source organism of ingenol mebutate. These results demonstrate conservation of gene clusters at the higher taxonomic level of the plant family and that this phenomenon could prove useful in further elucidating diterpenoid biosynthetic pathways.

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Section: Introductionmentioning

confidence: 99%

Section: Clustering Of Diterpenoid Biosynthetic Genes Is Common In Thmentioning

confidence: 99%

Production of Bioactive Diterpenoids in the Euphorbiaceae Depends on Evolutionarily Conserved Gene Clusters

et al. 2014

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“…In 2012, ingenol mebutate gel was approved for the treatment of actinic keratosis, a precondition of squamous cell carcinoma (6). The current supply of ingenol mebutate is limited to direct isolation from E. peplus, which yields only 1.1 mg/kg from the aerial tissue (7). Due to the increasing demand and low isolation yields of ingenol mebutate from the native plant, there is a strong need for the development of a more economical and efficient method for its production and for a robust supply chain.…”

mentioning

confidence: 99%

Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

Luo

Callari

Hamberger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The seed oil of Euphorbia lathyris L. contains a series of macrocyclic diterpenoids known as Euphorbia factors. They are the current industrial source of ingenol mebutate, which is approved for the treatment of actinic keratosis, a precancerous skin condition. Here, we report an alcohol dehydrogenase-mediated cyclization step in the biosynthetic pathway of Euphorbia factors, illustrating the origin of the intramolecular carbon-carbon bonds present in lathyrane and ingenane diterpenoids. This unconventional cyclization describes the ring closure of the macrocyclic diterpene casbene. Through transcriptomic analysis of E. lathyris L. mature seeds and in planta functional characterization, we identified three enzymes involved in the cyclization route from casbene to jolkinol C, a lathyrane diterpene. These enzymes include two cytochromes P450 from the CYP71 clan and an alcohol dehydrogenase (ADH). CYP71D445 and CYP726A27 catalyze regio-specific 9-oxidation and 5-oxidation of casbene, respectively. When coupled with these P450-catalyzed monooxygenations, E. lathyris ADH1 catalyzes dehydrogenation of the hydroxyl groups, leading to the subsequent rearrangement and cyclization. The discovery of this nonconventional cyclization may provide the key link to complete elucidation of the biosynthetic pathways of ingenol mebutate and other bioactive macrocyclic diterpenoids.terpenoid biosynthesis | transcriptomic analysis | regio-specific oxidation | nonconventional cyclization

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“…Ingenol mebutate Euphorbia peplus L. (Hohmann et al, 2000) Picato (2012) Actinic keratosis (inducer of cell death)…”

Section: Atanasov Et Al Page 74mentioning

confidence: 99%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

2015

Draw Science

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Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product- Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis.While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

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Diterpenoids from Euphorbia peplus

Cited by 65 publications

References 3 publications

Production of Bioactive Diterpenoids in the Euphorbiaceae Depends on Evolutionarily Conserved Gene Clusters

Production of Bioactive Diterpenoids in the Euphorbiaceae Depends on Evolutionarily Conserved Gene Clusters

Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.

Discovery and resupply of pharmacologically active plant-derived natural products: A review

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