Phytochemicals perturb membranes and promiscuously alter protein function

Helgi I. Ingólfsson, Pratima Thakur, Karl F. Herold, E. Ashley Hobart, Nicole B. Ramsey, Xavier Periole, Djurre H. De Jong, Martijn Zwama, Duygu Yilmaz, Katherine Hall, Thorsten Maretzky, Hugh C. Hemmings, Carl Blobel, Siewert J. Marrink, Armaǧan Koçer, Jon T Sack, Olaf S. Andersen

Research output: Contribution to journalArticle

122 Scopus citations

Abstract

A wide variety of phytochemicals are consumed for their perceived health benefits. Many of these phytochemicals have been found to alter numerous cell functions, but the mechanisms underlying their biological activity tend to be poorly understood. Phenolic phytochemicals are particularly promiscuous modifiers of membrane protein function, suggesting that some of their actions may be due to a common, membrane bilayer-mediated mechanism. To test whether bilayer perturbation may underlie this diversity of actions, we examined five bioactive phenols reported to have medicinal value: capsaicin from chili peppers, curcumin from turmeric, EGCG from green tea, genistein from soybeans, and resveratrol from grapes. We find that each of these widely consumed phytochemicals alters lipid bilayer properties and the function of diverse membrane proteins. Molecular dynamics simulations show that these phytochemicals modify bilayer properties by localizing to the bilayer/solution interface. Bilayer-modifying propensity was verified using a gramicidin-based assay, and indiscriminate modulation of membrane protein function was demonstrated using four proteins: membrane-anchored metalloproteases, mechanosensitive ion channels, and voltage-dependent potassium and sodium channels. Each protein exhibited similar responses to multiple phytochemicals, consistent with a common, bilayer-mediated mechanism. Our results suggest that many effects of amphiphilic phytochemicals are due to cell membrane perturbations, rather than specific protein binding.

Original languageEnglish (US)
Pages (from-to)1788-1798
Number of pages11
JournalACS Chemical Biology
Volume9
Issue number8
DOIs
StatePublished - Aug 15 2014

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Ingólfsson, H. I., Thakur, P., Herold, K. F., Hobart, E. A., Ramsey, N. B., Periole, X., De Jong, D. H., Zwama, M., Yilmaz, D., Hall, K., Maretzky, T., Hemmings, H. C., Blobel, C., Marrink, S. J., Koçer, A., Sack, J. T., & Andersen, O. S. (2014). Phytochemicals perturb membranes and promiscuously alter protein function. ACS Chemical Biology, 9(8), 1788-1798. https://doi.org/10.1021/cb500086e