Bioactive Structure of Membrane Lipids and Natural Products Elucidated by a Chemistry‐Based Approach

Murata, Michio; Sugiyama, Shigeru; Matsuoka, Shigeru; Matsumori, Nobuaki

doi:10.1002/tcr.201402097

Cited by 18 publications

(13 citation statements)

References 87 publications

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“…However, the domain formation at the nanometer scale, one of the major topics in this study, could not be visualized with the spatial resolution of these microscopic images. We thus became interested in FRET experiments because SM in the Lo phase is prone to form gel-like domains with nanometer size ( 7 , 23 , 24 , 25 , 28 , 33 ). Using this approach, we examined the possibility that SSM-SSM and ent- SSM- ent- SSM interactions caused the segregation of the SSM and ent -SSM nano-subdomains within the Lo domains of various membrane systems.…”

Section: Discussionmentioning

confidence: 99%

“…The results showed that the homophilic interactions between SSM and SSM through the amide (or hydroxy) group appeared to be a leading cause of the nanodomain formation of SSM (or ent -SSM). The ordering effect of Cho was comparable for SSM and ent -SSM, indicating that Cho does not strongly interact with the polar group of SMs bearing the chiral centers, instead largely interacting with the SM alkyl chains ( 11 , 28 , 33 ).…”

Section: Introductionmentioning

confidence: 97%

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Sphingomyelins and ent-Sphingomyelins Form Homophilic Nano-Subdomains within Liquid Ordered Domains

Yano

Hanashima

Tsuchikawa

et al. 2020

Biophysical Journal

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Sphingomyelin (SM), a major component of small domains (or lipid rafts) in mammalian cell membranes, forms a liquid-ordered phase in the presence of cholesterol (Cho). However, the nature of molecular interactions within the ordered SM/Cho phase remains elusive. We previously revealed that stearoyl-SM (SSM) and its enantiomer ( ent -SSM) separately form nano-subdomains within the liquid-ordered phase involving homophilic SSM-SSM and ent -SSM- ent -SSM interactions. In this study, the details of the subdomain formation by SSMs at the nanometer range were examined using Förster resonance energy transfer (FRET) measurements in lipid bilayers containing SSM and ent -SSM, dioleoyl-phosphatidylcholine and Cho. Although microscopy detected a stereochemical effect on partition coefficient favoring stereochemically homophilic interactions in the liquid-ordered state, it showed no significant difference in large-scale liquid-ordered domain formation by the two stereoisomers. In contrast to the uniform domains seen microscopy, FRET analysis using fluorescent donor- and acceptor-labeled SSM showed distinct differences in SM and ent- SM colocalization within nanoscale distances. Donor- and acceptor-labeled SSM showed significantly higher FRET efficiency than did donor-labeled SSM and acceptor-labeled ent -SSM in lipid vesicles composed of “racemic” (1:1) mixtures of SSM/ ent -SSM with dioleoylphosphatidylcholine and Cho. The difference in FRET efficiency indicated that SSM and ent -SSM assemble to form separate nano-subdomains. The average size of the subdomains decreased as temperature increased, and at physiological temperatures, the subdomains were found to have a single-digit nanometer radius. These results suggest that (even in the absence of ent- SM) SM-SM interactions play a crucial role in forming nano-subdomains within liquid-ordered domains and may be a key feature of lipid microdomains (or rafts) in biological membranes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Sphingomyelins and ent-Sphingomyelins Form Homophilic Nano-Subdomains within Liquid Ordered Domains

Yano

Hanashima

Tsuchikawa

et al. 2020

Biophysical Journal

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“…Lipid membranes comprising chiral lipids are expected to serve as a chiral environment for the transformation of asymmetric compounds by chemical and enzymatic reactions, which may occur in biological membranes. Organic synthesis for preparing stereoisomers of lipids and physicochemical methodologies for examining their interactions are indispensable to make the best use of chirality of lipids in chemistry‐ and biophysics‐based research of biological membranes.…”

Section: Resultsmentioning

confidence: 99%

Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

2020

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Most phospholipids constituting biological membranes are chiral molecules with a hydrophilic head group and hydrophobic alkyl chains, rendering biphasic property characteristic of membrane lipids. Some lipids assemble into small domains via chirality‐dependent homophilic and heterophilic interactions, the latter of which sometimes include cholesterol to form lipid rafts and other microdomains. On the other hand, lipid mediators and hormones derived from chiral lipids are recognized by specific membrane or nuclear receptors to induce downstream signaling. It is crucial to clarify the physicochemical properties of the lipid self‐assembly for the study of the functions and behavior of biological membranes, which often become elusive due to effects of membrane proteins and other biological events. Three major lipids with different skeletal structures were discussed: sphingolipids including ceramides, phosphoglycerolipids, and cholesterol. The physicochemical properties of membranes and physiological functions of lipid enantiomers and diastereomers were described in comparison to natural lipids. When each enantiomer formed a self‐assembly or interacted with achiral lipids, both lipid enantiomers exhibited identical membrane physicochemical properties, while when the enantiomer interacted with chiral lipids or with the opposite enantiomer, mixed membranes exhibited different properties. For example, racemic membranes comprising native sphingomyelin and its antipode exhibited phase segregation due to their strong homophilic interactions. Therefore, lipid enantiomers and diastereomers can be good probes to investigate stereospecific lipid‐lipid and lipid‐protein interactions occurring in biological membranes.

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“…12 More recently, confocal fluorescence microscopy has disclosed that TNM-A permeabilizes the membrane by altering the membrane morphology; this effect significantly occurs only in Chol-containing liposomes. 18 However, it remains unclear how the interaction of TNM-A with membranes leads to the uneven membrane curvature, and what role…”

Section: Membrane Penetration Of Tnm-a Examined By 1 H Nmr Paramagnetmentioning

confidence: 99%

Sterol-dependent membrane association of the marine sponge-derived bicyclic peptide Theonellamide A as examined by 1H NMR

Cornelio

Espiritu

Todokoro

et al. 2016

Bioorganic & Medicinal Chemistry

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Theonellamide A (TNM-A) is an antifungal bicyclic dodecapeptide isolated from a marine sponge Theonella sp. Previous studies have shown that TNM-A preferentially binds to 3β-hydroxysterol-containing membranes and disrupts membrane integrity. In this study, several H NMR-based experiments were performed to investigate the interaction mode of TNM-A with model membranes. First, the aggregation propensities of TNM-A were examined using diffusion ordered spectroscopy; the results indicate that TNM-A tends to form oligomeric aggregates of 2-9 molecules (depending on peptide concentration) in an aqueous environment, and this aggregation potentially influences the membrane-disrupting activity of the peptide. Subsequently, we measured theH NMR spectra of TNM-A with sodium dodecyl sulfate-d (SDS-d) micelles and small dimyristoylphosphatidylcholine (DMPC)-d/dihexanoylphosphatidylcholine (DHPC)-d bicelles in the presence of a paramagnetic quencher Mn. These spectra indicate that TNM-A poorly binds to these membrane mimics without sterol and mostly remains in the aqueous media. In contrast, broader H signals of TNM-A were observed in 10mol% cholesterol-containing bicelles, indicating that the peptide efficiently binds to sterol-containing bilayers. The addition of Mn to these bicelles also led to a decrease in the relative intensity and further line-broadening of TNM-A signals, indicating that the peptide stays near the surface of the bilayers. A comparison of the relative signal intensities with those of phospholipids showed that TNM-A resides in the lipid-water interface (close to the C2' portion of the phospholipid acyl chain). This shallow penetration of TNM-A to lipid bilayers induces an uneven membrane curvature and eventually disrupts membrane integrity. These results shed light on the atomistic mechanism accounting for the membrane-disrupting activity of TNM-A and the important role of cholesterol in its mechanism of action.

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Bioactive Structure of Membrane Lipids and Natural Products Elucidated by a Chemistry‐Based Approach

Cited by 18 publications

References 87 publications

Sphingomyelins and ent-Sphingomyelins Form Homophilic Nano-Subdomains within Liquid Ordered Domains

Sphingomyelins and ent-Sphingomyelins Form Homophilic Nano-Subdomains within Liquid Ordered Domains

Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

Sterol-dependent membrane association of the marine sponge-derived bicyclic peptide Theonellamide A as examined by 1H NMR

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