The structure of new lathyrane diterpenes, jolkinols a, b, c, and d, from Euphorbia jolkini boiss.

Uemura, Daisuke; Nobuhara, Kazunori; Nakayama, Yutaka; Shizuri, Yoshikazu; Hiratå, Yoshimasa

doi:10.1016/s0040-4039(00)93940-6

Cited by 36 publications

(36 citation statements)

References 9 publications

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“…NMR analysis (Supporting Information) indicated that one of LC peaks ( 4, 5 ) corresponded to a mixture of epimers with the lathyrane skeleton, the most abundant of which (ca. 80 %) has previously been described in the literature as jolkinol C ( 4 ) . We have therefore called the other epi‐ jolkinol C ( 5 ).…”

Section: Methodsmentioning

confidence: 99%

A Cytochrome P450‐Mediated Intramolecular Carbon–Carbon Ring Closure in the Biosynthesis of Multidrug‐Resistance‐Reversing Lathyrane Diterpenoids

et al. 2016

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The Euphorbiaceae produce a wide variety of bioactive diterpenoids. These include the lathyranes, which have received much interest due to their ability to inhibit the ABC transporters responsible for the loss of efficacy of many chemotherapy drugs. The lathyranes are also intermediates in the biosynthesis of range of other bioactive diterpenoids with potential applications in the treatment of pain, HIV and cancer. We report here a gene cluster from Jatropha curcas that contains the genes required to convert geranylgeranyl pyrophosphate into a number of diterpenoids, including the lathyranes jolkinol C and epi‐jolkinol C. The conversion of casbene to the lathyranes involves an intramolecular carbon–carbon ring closure. This requires the activity of two cytochrome P450s that we propose form a 6‐hydroxy‐5,9‐diketocasbene intermediate, which then undergoes an aldol reaction. The discovery of the P450 genes required to convert casbene to lathyranes will allow the scalable heterologous production of these potential anticancer drugs, which can often only be sourced in limited quantities from their native plant.

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Section: Methodsmentioning

confidence: 99%

A Cytochrome P450‐Mediated Intramolecular Carbon–Carbon Ring Closure in the Biosynthesis of Multidrug‐Resistance‐Reversing Lathyrane Diterpenoids

et al. 2016

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“…Structure elucidation by NMR analysis established 5 as jolkinol C (SI Appendix, Fig. S5 and Table S2B), a lathyrane type diterpene naturally found in Euphorbia jolkini Boiss (25).…”

Section: Ms (Lc-hrms)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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Section: Resultsmentioning

confidence: 99%

“…Although compound 1 and other seven lathyranes of the Δ 6(7), 12 type were synthesized [9,10], the stereochemistry of lathyranes of the Δ 6(7), 12 type was tangled. According to Uemura et al [9], 1 was figured as 5α-OH-6E,12E-diene. While E. Hecker considered 1 and seven others as 5α-H-6,12E-diene with the unestablished conformation of Δ 6(7) , and named one basic structure of the seven compounds as isolathyrol [10].…”

Section: Resultsmentioning

confidence: 99%

Two new diterpenes from Euphorbia kansuensis

et al. 2008

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The structure of new lathyrane diterpenes, jolkinols a, b, c, and d, from Euphorbia jolkini boiss.

Cited by 36 publications

References 9 publications

A Cytochrome P450‐Mediated Intramolecular Carbon–Carbon Ring Closure in the Biosynthesis of Multidrug‐Resistance‐Reversing Lathyrane Diterpenoids

A Cytochrome P450‐Mediated Intramolecular Carbon–Carbon Ring Closure in the Biosynthesis of Multidrug‐Resistance‐Reversing Lathyrane Diterpenoids

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

Two new diterpenes from Euphorbia kansuensis

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