Sesterterpenoids with Anticancer Activity

Evidente, Antonio; Kornienko, Alexander; Lefranc, Florence; Cimmino, Alessio; Dasari, Ramesh; Evidente, Marco M; Mathieu, Véronique; Kiss, Róbert

doi:10.2174/0929867322666150821101047

Cited by 55 publications

(36 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…OphA is a phytotoxin produced by the fungal pathogen Drechslera gigantea and other Bipolaris spp (11,12). The sesterterpene-type compound (C25) is one of a group of over 25 Ophiobolin analogues (13), which are characterized by the unique 5-8-5 carbotricyclic skeleton (Fig.…”

Section: Introductionmentioning

confidence: 99%

Ophiobolin A, a sesterpenoid fungal phytotoxin, displays different mechanisms of cell death in mammalian cells depending upon the cancer cell origin

Morrison

Lodge

Evidente

et al. 2017

International Journal of Oncology

Self Cite

View full text Add to dashboard Cite

Herein we have undertaken a systematic analysis of the effects of the fungal derivative ophiobolin A (OphA) on eight cancer cell lines from different tissue types. The LD50 for each cell line was determined and the change in cell size determined. Flow cytometric analysis and western blotting were used to assess the cell death markers for early apoptosis, late apoptosis and necrosis, and the involvement of the caspase signalling pathway. Alterations in calcium levels and reactive oxygen species were assessed due to their integral involvement in intracellular signalling. Subsequently, the endoplasmic reticulum (ER) and mitochondrial responses were investigated more closely. The extent of ER swelling, and the upregulation of proteins involved in the unfolded protein responses (UPR) were seen to vary according to cell line. The mitochondria were also shown to behave differently in response to the OphA in the different cell lines in terms of the change in membrane potential, the total area of mitochondria in the cell and the number of mitochondrial bifurcations. The data obtained in the present study indicate that the cancer cell lines tested are unable to successfully activate the ER stress/UPR responses, and that the mitochondria appear to be a central player in OphA-induced cancer cell death.

show abstract

Section: Introductionmentioning

confidence: 99%

Ophiobolin A, a sesterpenoid fungal phytotoxin, displays different mechanisms of cell death in mammalian cells depending upon the cancer cell origin

Morrison

Lodge

Evidente

et al. 2017

International Journal of Oncology

Self Cite

View full text Add to dashboard Cite

show abstract

“…These compounds are structurally diverse and have a wide spectrum of biological activities, ranging from antiinflammatory, anticancer, cytotoxic, and antimicrobial bioactivities to phytotoxicity and plant defense (1). Recent work on sesterterpenoids has suggested that this terpene class could be an important new source of anticancer drugs (2,3). The majority of sesterterpenoids characterized to date are from marine sponges and terrestrial fungi, with only ∼60-70 being of plant origin.…”

mentioning

confidence: 99%

Unearthing a sesterterpene biosynthetic repertoire in the Brassicaceae through genome mining reveals convergent evolution

Huang

Kautsar

Hong

et al. 2017

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

116

123

View full text Add to dashboard Cite

Sesterterpenoids are a rare terpene class harboring untapped chemodiversity and bioactivities. Their structural diversity originates primarily from the scaffold-generating sesterterpene synthases (STSs). In fungi, all six known STSs are bifunctional, containing C-terminal trans-prenyltransferase (PT) and N-terminal terpene synthase (TPS) domains. In plants, two colocalized PT and TPS gene pairs from Arabidopsis thaliana were recently reported to synthesize sesterterpenes. However, the landscape of PT and TPS genes in plant genomes is unclear. Here, using a customized algorithm for systematically searching plant genomes, we reveal a suite of physically colocalized pairs of PT and TPS genes for the biosynthesis of a large sesterterpene repertoire in the wider Brassicaceae. Transient expression of seven TPSs from A. thaliana, Capsella rubella, and Brassica oleracea in Nicotiana benthamiana yielded fungal-type sesterterpenes with tri-, tetra-, and pentacyclic scaffolds, and notably (−)-ent-quiannulatene, an enantiomer of the fungal metabolite (+)-quiannulatene. Protein and structural modeling analysis identified an amino acid site implicated in structural diversification. Mutation of this site in one STS (AtTPS19) resulted in premature termination of carbocation intermediates and accumulation of bi-, tri-, and tetracyclic sesterterpenes, revealing the cyclization path for the pentacyclic sesterterpene (−)-retigeranin B. These structural and mechanistic insights, together with phylogenetic analysis, suggest convergent evolution of plant and fungal STSs, and also indicate that the colocalized PT-TPS gene pairs in the Brassicaceae may have originated from a common ancestral gene pair present before speciation. Our findings further provide opportunities for rapid discovery and production of sesterterpenes through metabolic and protein engineering.sesterterpene biosynthesis | plant natural products | cyclization mechanism | convergent evolution | Brassicaceae S esterterpenoids are a largely unexplored class of terpenes with only around 1,000 members isolated from nature so far, representing a mere <2% of the reported terpene family members (>70,000). These compounds are structurally diverse and have a wide spectrum of biological activities, ranging from antiinflammatory, anticancer, cytotoxic, and antimicrobial bioactivities to phytotoxicity and plant defense (1). Recent work on sesterterpenoids has suggested that this terpene class could be an important new source of anticancer drugs (2, 3). The majority of sesterterpenoids characterized to date are from marine sponges and terrestrial fungi, with only ∼60-70 being of plant origin. Many of these plant sesterterpenes were isolated from the mint family (Lamiaceae) and have been implicated in plant defense (4-7). Although large transcriptome datasets for the mint family have been generated (8), very limited genome sequences for the Lamiaceae are currently available (9, 10).Like other classes of terpenes, the structural diversity of sesterterpenes largely originates from the...

show abstract

“…C 25 GFPP is a precursor of sesterterpenoids, which are compounds with multiple bioactive properties and thus promising pharmacological potential [55]. They were occasionally reported in plants, but their origin had not been addressed until recently.…”

Section: Trans-prenyltransferasesmentioning

confidence: 99%

Functional Gene Network of Prenyltransferases in Arabidopsis thaliana

Kopcsayová

Vranová

2019

Molecules

View full text Add to dashboard Cite

Prenyltransferases (PTs) are enzymes that catalyze prenyl chain elongation. Some are highly similar to each other at the amino acid level. Therefore, it is difficult to assign their function based solely on their sequence homology to functional orthologs. Other experiments, such as in vitro enzymatic assay, mutant analysis, and mutant complementation are necessary to assign their precise function. Moreover, subcellular localization can also influence the functionality of the enzymes within the pathway network, because different isoprenoid end products are synthesized in the cytosol, mitochondria, or plastids from prenyl diphosphate (prenyl-PP) substrates. In addition to in vivo functional experiments, in silico approaches, such as co-expression analysis, can provide information about the topology of PTs within the isoprenoid pathway network. There has been huge progress in the last few years in the characterization of individual Arabidopsis PTs, resulting in better understanding of their function and their topology within the isoprenoid pathway. Here, we summarize these findings and present the updated topological model of PTs in the Arabidopsis thaliana isoprenoid pathway.

show abstract

Sesterterpenoids with Anticancer Activity

Cited by 55 publications

References 89 publications

Ophiobolin A, a sesterpenoid fungal phytotoxin, displays different mechanisms of cell death in mammalian cells depending upon the cancer cell origin

Ophiobolin A, a sesterpenoid fungal phytotoxin, displays different mechanisms of cell death in mammalian cells depending upon the cancer cell origin

Unearthing a sesterterpene biosynthetic repertoire in the Brassicaceae through genome mining reveals convergent evolution

Functional Gene Network of Prenyltransferases in Arabidopsis thaliana

Contact Info

Product

Resources

About