Isolation and Structure Elucidation of Parnafungins, Antifungal Natural Products that Inhibit mRNA Polyadenylation

Parish, Craig A.; Smith, Scott K.; Calati, Kathleen; Zink, Deborah L.; Wilson, Kenneth E.; Roemer, Terry; Jiang, Bo; Xu, Deming; Bills, Gerald F.; Platas, Gonzalo; Peláez, Fernando; Dı́ez, Maria Teresa; Tsou, Nancy N.; McKeown, Arlene E.; Ball, Richard G.; Powles, Mary Ann; Yeung, Lai; Liberator, Paul; Harris, Guy H.

doi:10.1021/ja711209p

Cited by 78 publications

(100 citation statements)

References 28 publications

(32 reference statements)

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“…Strains F-159,080, F-159,081 and F-155,597 were discovered from 12 mL fermentation agitated in 40 mL vials as described by Parish et al (2008). Antifungal activities caused by parnafungins in Fusarium strains F-242,915, F-253,264, F-257,517, Trichonectria rectipila (CBS 132.87) and Cl.…”

Section: Introductionmentioning

confidence: 99%

Discovery of the parnafungins, antifungal metabolites that inhibit mRNA polyadenylation, from theFusarium larvarumcomplex and other Hypocrealean fungi

Bills

Platas²,

Overy³

et al. 2009

Mycologia

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Evaluation of fungal fermentation extracts with whole cell Candida albicans activity resulted in the identification of a novel class of isoxazolidinone-containing metabolites named parnafungins. Chemical-genetic profiling with the C. albicans fitness test identified the biochemical target as inhibition of polyadenosine polymerase, a component of the mRNA cleavage and polyadenylation complex. Parnafungins were discovered from fermentation extracts of fungi resembling F. larvarum isolated from plants, plant litter and lichens. Furthermore authentic strains of F. larvarum var. larvarum and F. larvarum var. rubrum could be induced to produce parnafungins and their degradation products in low titers. Relationships among strains of the F. larvarum complex (FLC), including parnafungin-producing strains, were examined by cladistic analyses of rDNA, mitochondrial rDNA, and two protein-coding genes, comparisons of antifungal activity and antifungal metabolite profiles, and morphological phenotypes. Integrated analyses of these data led to the conclusion that the diversity within the FLC exceeded the one-to-one correspondence between F. larvarum and its teleomorph Cosmospora aurantiicola. Based on multiple gene sequence analyses, strains of the FLC formed a monophyletic clade inclusive of the parnafungin-producing strains. The FLC, including newly discovered parnafungin-producing strains, could be resolved into at least six different lineages, possibly representing cryptic' species, of which one was not fully resolved from F. larvarum var. rubrum. Fusarium larvarum var. rubrum represents a species distinct from var. larvarum. Finally we report that two other species from the Hypocreales, Trichonectria rectipila and Cladobotryum pinarense, are able to produce parnafungins and their open-ring forms.

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Section: Introductionmentioning

confidence: 99%

Discovery of the parnafungins, antifungal metabolites that inhibit mRNA polyadenylation, from theFusarium larvarumcomplex and other Hypocrealean fungi

Bills

Platas²,

Overy³

et al. 2009

Mycologia

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“…CP and the related phosphoamino acids phosphoserine and arginine phosphate are the only smallmolecule reagents known to have an activating effect on the in vitro cleavage reaction. No specific inhibitors of the cleavage reaction have been reported, though a natural product inhibitor of polyadenylation was recently discovered Parish et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Small molecule activators of pre-mRNA 3′ cleavage

Ryan

Khleborodova²,

Pan³

et al. 2009

RNA

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39 Cleavage and polyadenylation are obligatory steps in the biogenesis of most mammalian pre-mRNAs. In vitro reconstitution of the 39 cleavage reaction from human cleavage factors requires high concentrations of creatine phosphate (CP), though how CP activates cleavage is not known. Previously, we proposed that CP might work by competitively inhibiting a cleavagesuppressing serine/threonine (S/T) phosphatase. Here we show that fluoride/EDTA, a general S/T phosphatase inhibitor, activates in vitro cleavage in place of CP. Subsequent testing of inhibitors specific for different S/T phosphatases showed that inhibitors of the PPM family of S/T phosphatases, which includes PP2C, but not the PPP family, which includes PP1, PP2A, and PP2B, activated 39 cleavage in vitro. In particular, NCI 83633, an inhibitor of PP2C, activated extensive 39 cleavage at a concentration 50-fold below that required by fluoride or CP. The testing of structural analogs led to the identification of a more potent compound that activated 39 cleavage at 200 mM. While testing CP analogs to understand the origin of its cleavage activation effect, we found phosphocholine to be a more effective activator than CP. The minimal structural determinants of 39 cleavage activation by phosphocholine were identified. Our results describe a much improved small molecule activator of in vitro pre-mRNA cleavage, identify the molecular determinants of cleavage activation by phosphoamines such as phosphocholine, and suggest that a PPM family phosphatase is involved in the negative regulation of mammalian pre-mRNA 39 cleavage.

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“…[51][52][53][54] 11.4 Discovery of New Antibacterial Compounds 11.4.1 Antibacterial Compounds Derived from the Target-based Antisense-Sensitized S. aureus Screening…”

Section: Novel Approaches To Exploit Natural Products From Microbial mentioning

confidence: 99%

Chapter 11. Novel Approaches to Exploit Natural Products from Microbial Resources

Genilloud¹,

Vicente²

2012

Drug Discovery

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Isolation and Structure Elucidation of Parnafungins, Antifungal Natural Products that Inhibit mRNA Polyadenylation

Cited by 78 publications

References 28 publications

Discovery of the parnafungins, antifungal metabolites that inhibit mRNA polyadenylation, from theFusarium larvarumcomplex and other Hypocrealean fungi

Discovery of the parnafungins, antifungal metabolites that inhibit mRNA polyadenylation, from theFusarium larvarumcomplex and other Hypocrealean fungi

Small molecule activators of pre-mRNA 3′ cleavage

Chapter 11. Novel Approaches to Exploit Natural Products from Microbial Resources

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