Chemistry and biology of resorcylic acid lactones

Winssinger, Nicolas; Barluenga, Sofía

doi:10.1039/b610344h

Cited by 254 publications

(165 citation statements)

References 56 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).…”

mentioning

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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“…1A) represent a unique family of fungal polyketides (8). These mycotoxins possess a wide array of potent biological activities, including radicicol (Hsp90 inhibitor) (9), LL-Z1640-2 (TAK1 inhibitor) (10), hypothemycin (MAP kinase inhibitor) (11), and zearalenone 1 (estrogen receptor agonist) (12).…”

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confidence: 99%

A polyketide macrolactone synthase from the filamentous fungus Gibberella zeae

Zhou

Zhan

Watanabe

et al. 2008

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

103

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Resorcylic acid lactones represent a unique class of fungal polyketides and display a wide range of biological activities, such as nanomolar inhibitors of Hsp90 and MAP kinase. The biosynthesis of these compounds is proposed to involve two fungal polyketide synthases (PKS) that function collaboratively to yield a 14-membered macrolactone with a resorcylate core. We report here the reconstitution of Gibberella zeae PKS13, which is the nonreducing PKS associated with zearalenone biosynthesis. Using a small molecule mimic of the natural hexaketide starter unit, we reconstituted the entire repertoire of PKS13 activities in vitro, including starter-unit selection, iterative condensation, regioselective C2-C7 cyclization, and macrolactone formation. PKS13 synthesized both natural 14-membered and previously uncharacterized 16-membered resorcylic acid lactones, indicating relaxed control in both iterative elongation and macrocyclization. PKS13 exhibited broad starter-unit specificities toward fatty acyl-CoAs ranging in sizes between C6 and C16 and displayed the highest activity toward decanoyl-CoA. PKS13 was shown to be active in Escherichia coli and synthesized numerous alkyl pyrones and alkyl resorcylic esters without exogenously supplied precursors. We demonstrated that PKS13 can interact with E. coli fatty acid biosynthetic machinery and can be primed with fatty-acyl ACPp at low-micromolar concentrations. PKS13 synthesized new polyketides in E. coli when the culture was supplemented with synthetic precursors, showcasing its utility in precursor-directed biosynthesis. PKS13 is therefore a highly versatile polyketide macrolactone synthase that is useful in the engineered biosynthesis of polyketides, including resorcylic acid lactones that are not found in nature.ketosynthase ͉ resorcylic acid ͉ starter unit ͉ Hsp90 ͉ thioesterase

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“…As an important extension of kinase inhibitor chemical space, the resorcylic lactone (RL)-based fungal metabolites hypothemycin, LL-Z1640-2, and L-783277 have recently been recognized as a new and structurally unique group of kinase inhibitors. 6,7 The suppression of kinase activity by these natural products involves 1,4-addition of a protein thiol to the cis-enone moiety in the macrocycle, as has been demonstrated in biochemical 8 as well as structural studies. 9,10 The inhibition of protein kinases by cis-enone-containing RL, thus, is largely confined to kinases incorporating a properly located Cys residue in their ATP binding pocket, corresponding to Cys166 in ERK2, 8 which provides a "built-in" selectivity advantage over other inhibitor classes.…”

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confidence: 94%

Kinase Inhibition by Deoxy Analogues of the Resorcylic Lactone L-783277

Liniger

Neuhaus

Hofmann

et al. 2010

ACS Med. Chem. Lett.

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The natural product L-783277 is a resorcylic lactone type covalent kinase inhibitor. We have prepared the 5 0 -deoxy analogue of L-783277 (1) in a stereoselective fashion. Remarkably, this analogue retains almost the full kinase inhibitory potential of natural L-783277, with low nanomolar IC 50 values against the most sensitive kinases, and it exhibits essentially the same selectivity profile (within the panel of 39 kinases investigated). In contrast, removal of both the 4 0 -and the 5 0 -hydroxyl groups leads to a more significant reduction in kinase inhibitory activity and so does a change in the geometry of the C7 0 -C8 0 double bond in 1 from Z to E. These findings offer new perspectives for the design of second generation resorcylic lactone-based kinase inhibitors.

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Chemistry and biology of resorcylic acid lactones

Cited by 254 publications

References 56 publications

Rational reprogramming of fungal polyketide first-ring cyclization

Rational reprogramming of fungal polyketide first-ring cyclization

A polyketide macrolactone synthase from the filamentous fungus Gibberella zeae

Kinase Inhibition by Deoxy Analogues of the Resorcylic Lactone L-783277

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