Hsp90 Inhibition with Resorcylic Acid Lactones (RALs)

Winssinger, Nicolas; Fontaine, Jean-Gonzague; Barluenga, Sofía

doi:10.2174/156802609789895665

Cited by 50 publications

(36 citation statements)

References 91 publications

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“…Fungal RALs are rich pharmacophores with estrogen agonist (zearalenone), mitogen-activated protein kinase inhibitory (hypothemycin), and heat shock response modulatory activities [radicicol and monocillin II (1)] ( Fig. 1) (18,19). For these RALs, the hrPKS produces a reduced linear polyketide chain that is directly transferred to the nrPKS (9).…”

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confidence: 99%

Rational reprogramming of fungal polyketide first-ring cyclization

Zhou

et al. 2013

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

115

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Resorcylic acid lactones and dihydroxyphenylacetic acid lactones represent important pharmacophores with heat shock response and immune system modulatory activities. The biosynthesis of these fungal polyketides involves a pair of collaborating iterative polyketide synthases (iPKSs): a highly reducing iPKS with product that is further elaborated by a nonreducing iPKS (nrPKS) to yield a 1,3-benzenediol moiety bridged by a macrolactone. Biosynthesis of unreduced polyketides requires the sequestration and programmed cyclization of highly reactive poly-β-ketoacyl intermediates to channel these uncommitted, pluripotent substrates to defined subsets of the polyketide structural space. Catalyzed by product template (PT) domains of the fungal nrPKSs and discrete aromatase/cyclase enzymes in bacteria, regiospecific first-ring aldol cyclizations result in characteristically different polyketide folding modes. However, a few fungal polyketides, including the dihydroxyphenylacetic acid lactone dehydrocurvularin, derive from a folding event that is analogous to the bacterial folding mode. The structural basis of such a drastic difference in the way a PT domain acts has not been investigated until now. We report here that the fungal vs. bacterial folding mode difference is portable on creating hybrid enzymes, and we structurally characterize the resulting unnatural products. Using structure-guided active site engineering, we unravel structural contributions to regiospecific aldol condensations and show that reshaping the cyclization chamber of a PT domain by only three selected point mutations is sufficient to reprogram the dehydrocurvularin nrPKS to produce polyketides with a fungal fold. Such rational control of first-ring cyclizations will facilitate efforts to the engineered biosynthesis of novel chemical diversity from natural unreduced polyketides.

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confidence: 99%

Rational reprogramming of fungal polyketide first-ring cyclization

Zhou

et al. 2013

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

115

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“…They are defined by a 1,3-benzenediol moiety bridged by a macrocyclic lactone ring (9). Among BDLs, resorcylic acid lactones (RALs) display a C2-C7 connectivity, whereas dihydroxyphenylacetic acid lactones (DALs) feature a C3-C8 bond.…”

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confidence: 99%

“…Monocillin II (1; Fig. 1) and their congeners (radicicol and the pochonins) are RALs with 14-membered rings (RAL 14 ) that are specific inhibitors of heat shock protein 90 (Hsp90) (9,10). Inhibition of Hsp90 promotes the degradation of oncogenic client proteins and leads to the combinatorial blockade of multiple cancer-causing pathways.…”

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confidence: 99%

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Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases

Zhou

Zhang

et al. 2014

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

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Combinatorial biosynthesis aspires to exploit the promiscuity of microbial anabolic pathways to engineer the synthesis of new chemical entities. Fungal benzenediol lactone (BDL) polyketides are important pharmacophores with wide-ranging bioactivities, including heat shock response and immune system modulatory effects. Their biosynthesis on a pair of sequentially acting iterative polyketide synthases (iPKSs) offers a test case for the modularization of secondary metabolic pathways into "build-couple-pair" combinatorial synthetic schemes. Expression of random pairs of iPKS subunits from four BDL model systems in a yeast heterologous host created a diverse library of BDL congeners, including a polyketide with an unnatural skeleton and heat shock response-inducing activity. Pairwise heterocombinations of the iPKS subunits also helped to illuminate the innate, idiosyncratic programming of these enzymes. Even in combinatorial contexts, these biosynthetic programs remained largely unchanged, so that the iPKSs built their cognate biosynthons, coupled these building blocks into chimeric polyketide intermediates, and catalyzed intramolecular pairing to release macrocycles or α-pyrones. However, some heterocombinations also provoked stuttering, i.e., the relaxation of iPKSs chain length control to assemble larger homologous products. The success of such a plug and play approach to biosynthesize novel chemical diversity bodes well for bioprospecting unnatural polyketides for drug discovery.secondary metabolites | fungal genetics

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“…Over the years, these molecules have emerged as common targets for total synthesis and have led medicinal chemists to design analog programmes leading to a number of clinical trials. [12][13][14][15] Chen et al have recently isolated six new resorcylic acid lactones, namely paecilomycin A-F [16][17][18] ( Figure 1) along with other known RALs from the mycelial solid culture of Paecilomyces fungus SC0924. Interestingly, when these compounds were subjected to screening for plasmodicidal activity, paecilomycin F was found to display antiplasmodial activity against Plasmodium falciparum line 3D7 with an IC 50 value of 20.0 nM and moderate activity against P. falciparum line Dd2.…”

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confidence: 99%