title: Phytochemicals perturb membranes and promiscuously alter protein function.
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.
authors.affiliation: Zernike Institute for Advanced Materials, ‡Groningen Biomolecular Science and Biotechnology Institute, University of Groningen , Groningen, The Netherlands.
authors.forename: Helgi I
authors.initials: HI
authors.lastname: Ingólfsson
authors.forename: Pratima
authors.initials: P
authors.lastname: Thakur
authors.forename: Karl F
authors.initials: KF
authors.lastname: Herold
authors.forename: E Ashley
authors.initials: EA
authors.lastname: Hobart
authors.forename: Nicole B
authors.initials: NB
authors.lastname: Ramsey
authors.forename: Xavier
authors.initials: X
authors.lastname: Periole
authors.forename: Djurre H
authors.initials: DH
authors.lastname: de Jong
authors.forename: Martijn
authors.initials: M
authors.lastname: Zwama
authors.forename: Duygu
authors.initials: D
authors.lastname: Yilmaz
authors.forename: Katherine
authors.initials: K
authors.lastname: Hall
authors.forename: Thorsten
authors.initials: T
authors.lastname: Maretzky
authors.forename: Hugh C
authors.initials: HC
authors.lastname: Hemmings
authors.forename: Carl
authors.initials: C
authors.lastname: Blobel
authors.forename: Siewert J
authors.initials: SJ
authors.lastname: Marrink
authors.forename: Armağan
authors.initials: A
authors.lastname: Koçer
authors.forename: Jon T
authors.initials: JT
authors.lastname: Sack
authors.forename: Olaf S
authors.initials: OS
authors.lastname: Andersen
mesh_terms: D002462:Cell Membrane / Q000187:drug effects*; D008565:Membrane Proteins / Q000187:drug effects* / Q000502:physiology; D056004:Molecular Dynamics Simulation; D064209:Phytochemicals / Q000494:pharmacology*
chemical_list: D008565:Membrane Proteins; D064209:Phytochemicals