The squalestatings, novel inhibitors of squalene synthase produced by a species of Phoma. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.

Dawson, Michael J.; Farthing, John E.; Marshall, Peter S.; Middleton, Robert F.; O’Neill, Melanie J.; SHUTTLEWORTH, ALAN; Harri.Stylli, C.; Tait, R. M.; TAYLOR, PAM M.; Wildman, Howard G.; Buss, Antony D.; Langley, D.B.; Hayes, Michael

doi:10.7164/antibiotics.45.639

Cited by 180 publications

(33 citation statements)

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“…C2932, 123 is a close homolog of LovF in which its polyketide product has been identified. 35 It has the exact domain architecture as LovF but exhibits a higher level of programming complexity in that it catalyzes two more iterations of extension, during which the tailoring domains are selectively used.…”

Section: Highly-reducing Polyketide Synthasesmentioning

confidence: 99%

Navigating the Fungal Polyketide Chemical Space: From Genes to Molecules

2012

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The iterative type I polyketide synthases (IPKSs) are central to the biosynthesis of an enormously diverse array of natural products in fungi. These natural products, known as polyketides, exhibit a wide range of biological activities and include clinically important drugs as well as undesirable toxins. The PKSs synthesize these structurally diverse polyketides via a series of decarboxylative condensations of malonyl-CoA extender units and β-keto modifications in a highly programmed manner. Significant progress has been made over the past few years in understanding the biosynthetic mechanism and programming of fungal PKSs. The continuously expanding fungal genome sequence data have sparked genome-directed discoveries of new fungal PKSs and associated products. The increasing number of fungal PKSs that have been linked to their products along with in-depth biochemical and structural characterizations of these large enzymes have remarkably improved our knowledge on the molecular basis for polyketide structural diversity in fungi. This perspective highlights the recent advances and examines how the newly expanded paradigm has contributed to our ability to link fungal PKS genes to chemical structures and vice versa. The knowledge will help us navigate through the logarithmically expanding seas of genomic information for polyketide compound discovery and provided opportunities to reprogram these megasynthases to generate new chemical entities.

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Section: Highly-reducing Polyketide Synthasesmentioning

confidence: 99%

Navigating the Fungal Polyketide Chemical Space: From Genes to Molecules

2012

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“…The compound zaragozic acid, also known as squalestatin, is a carboxylic acid, with the molecular structure C 35 H 43 O 14 Na 3 (2,8-dioxabicyclo-[3.2.1]-octan-3 core acid, 4,5-tricarboxylic), that was discovered by screening metabolites of filamentous fungi for inhibitors of squalene synthase, the enzyme responsible for the first step of sterol biosynthesis (18)(19)(20)(21). Detailed analysis disclosed that it acts as a competitive inhibitor of squalene synthase by mimicking the farnesyl-PP substrate or the stable intermediate pres-qualene-PP with its bicyclic, highly acidic core (22).…”

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confidence: 99%

Squalestatin Is an Inhibitor of Carotenoid Biosynthesis in Plasmodium falciparum

Gabriel

Silva

Kimura

et al. 2015

Antimicrob Agents Chemother

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The increasing resistance of malaria parasites to almost all available drugs calls for the characterization of novel targets and the identification of new compounds. Carotenoids are polyisoprenoids from plants, algae, and some bacteria, and they are biosynthesized by Plasmodium falciparum but not by mammalian cells. Biochemical and reverse genetics approaches were applied to demonstrate that phytoene synthase (PSY) is a key enzyme for carotenoid biosynthesis in P. falciparum and is essential for intraerythrocytic growth. The known PSY inhibitor squalestatin reduces biosynthesis of phytoene and kills parasites during the intraerythrocytic cycle. PSY-overexpressing parasites showed increased biosynthesis of phytoene and its derived product phytofluene and presented a squalestatin-resistant phenotype, suggesting that this enzyme is the primary target of action of this drug in the parasite.

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“…AcylCoA:cholesterol acyltransferase (ACAT) inhibition assay was performed by radio isotope 14 detection with [1-C]oleoyl-coenzyme A (Amersham, CFA634) as substrate. Squalene synthase (SQS) inhibition was assayed for the 50% ethanol extract with rat liver microsome as the enzyme source and [l(n)-3H]farnesyl pyrophosphate trisodium salt (Amersham TRK917) as the substrate (Dawson et al, 1992). Chitin synthase II (CS-II) inhibition was assayed with crude enzyme from Saccaromyces cerevisiae strain ECY38-3A(pAs6) (Choi et al, 1994) and UDP-14C-N-acetyI-D-glucosamine (Choi and Cabib, 1994).…”

Section: Methodsmentioning

confidence: 99%

Amplification of farnesyl protein transferase inhibitory activity from Aspergillus fumigatus F93 by Plackett-Burman design

et al. 1996

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Fermentation optimization for the fungus Aspergillus fumigatus F93 was performed to amplify the most promising biological activity. Twelve active variables were analysed and optimized by the Plackett-Burman design, consisting of 16 experiments. Farnesyl protein transferase inhibitory activity showed the best response for the design, and selected parameters were confirmed by separate experiments in the optimized fermentation condition.

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The squalestatings, novel inhibitors of squalene synthase produced by a species of Phoma. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.

Cited by 180 publications

References 0 publications

Navigating the Fungal Polyketide Chemical Space: From Genes to Molecules

Navigating the Fungal Polyketide Chemical Space: From Genes to Molecules

Squalestatin Is an Inhibitor of Carotenoid Biosynthesis in Plasmodium falciparum

Amplification of farnesyl protein transferase inhibitory activity from Aspergillus fumigatus F93 by Plackett-Burman design

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