Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.

@article{CastroFalcn2018NeolymphostinAI,
  title={Neolymphostin A Is a Covalent Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitor That Employs an Unusual Electrophilic Vinylogous Ester.},
  author={Gabriel Castro-Falc{\'o}n and Grant S Seiler and {\"O}zlem Demir and Manoj K. Rathinaswamy and David J. Hamelin and Reece M Hoffmann and Stefanie L Makowski and Anne-Catrin Letzel and Seth J. Field and John E. Burke and Rommie E. Amaro and Chambers C Hughes},
  journal={Journal of medicinal chemistry},
  year={2018},
  volume={61 23},
  pages={
          10463-10472
        }
}
Using a novel chemistry-based assay for identifying electrophilic natural products in unprocessed extracts, we identified the PI3-kinase/mTOR dual inhibitor neolymphostin A from Salinispora arenicola CNY-486. The method further showed that the vinylogous ester substituent on the neolymphostin core was the exact site for enzyme conjugation. Tandem MS/MS experiments on PI3Kα treated with the inhibitor revealed that neolymphostin covalently modified Lys802 with a shift in mass of +306 amu… Expand
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Dynamic structural biology at the protein membrane interface
  • J. Burke
  • Computer Science, Medicine
  • The Journal of Biological Chemistry
  • 2019
TLDR
This article will discuss my continued enthusiasm in using a synergistic application of hydrogen–deuterium exchange MS (HDX–MS) with other structural biology techniques to probe the mechanistic basis for how membrane-localized signaling enzymes are regulated and how these approaches can be used to understand how they are misregulated in disease. Expand
Development of a solid-supported cysteinyl probe for the isolation of electrophiles from plant pollen extracts.
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A solid-supported cysteinyl probe was developed in order to selectively extract physiologically relevant electrophiles from pollen extracts, and to enable their subsequent characterization by on-line and off-line spectroscopic analysis. Expand
Bioactive natural products from the genus Salinospora: a review.
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This review arranged Salinispora derived secondary metabolites according to the three species that comprise the genus and described muta- and semi-synthesis analogs derived from salinosporamide. Expand

References

Dynamic structural biology at the protein membrane interface
  • J. Burke
  • Computer Science, Medicine
  • The Journal of Biological Chemistry
  • 2019
TLDR
This article will discuss my continued enthusiasm in using a synergistic application of hydrogen–deuterium exchange MS (HDX–MS) with other structural biology techniques to probe the mechanistic basis for how membrane-localized signaling enzymes are regulated and how these approaches can be used to understand how they are misregulated in disease. Expand