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Review
. 2024 Mar 27;124(6):3284-3330.
doi: 10.1021/acs.chemrev.3c00608. Epub 2024 Mar 18.

The Chemical Reactivity of Membrane Lipids

Genevieve Duché  1 , John M Sanderson  2
Affiliations
Review

The Chemical Reactivity of Membrane Lipids

Genevieve Duché et al. Chem Rev. .

Abstract

It is well-known that aqueous dispersions of phospholipids spontaneously assemble into bilayer structures. These structures have numerous applications across chemistry and materials science and form the fundamental structural unit of the biological membrane. The particular environment of the lipid bilayer, with a water-poor low dielectric core surrounded by a more polar and better hydrated interfacial region, gives the membrane particular biophysical and physicochemical properties and presents a unique environment for chemical reactions to occur. Many different types of molecule spanning a range of sizes, from dissolved gases through small organics to proteins, are able to interact with membranes and promote chemical changes to lipids that subsequently affect the physicochemical properties of the bilayer. This Review describes the chemical reactivity exhibited by lipids in their membrane form, with an emphasis on conditions where the lipids are well hydrated in the form of bilayers. Key topics include the following: lytic reactions of glyceryl esters, including hydrolysis, aminolysis, and transesterification; oxidation reactions of alkenes in unsaturated fatty acids and sterols, including autoxidation and oxidation by singlet oxygen; reactivity of headgroups, particularly with reactive carbonyl species; and E/Z isomerization of alkenes. The consequences of reactivity for biological activity and biophysical properties are also discussed.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of phospholipids described in this review. Numbering corresponds to common nomenclature.
Figure 2
Figure 2
Glycerophospholipid bonds cleaved by phospholipases A–D.
Scheme 1
Scheme 1. Ester Hydrolysis Reactions of PCs
Scheme 2
Scheme 2. Hydrolysis of Plasmenyl Lipids
Scheme 3
Scheme 3. Aminolysis Reactions of Glycerophospholipids
Figure 3
Figure 3
Sequence and structure of melittin: top, sequence; middle, crystal structure (PDB code 2MLT) with the major acylation sites shown in bold and the minor sites in italics; and bottom, helical wheel representation with the major acylation sites shown as diamonds, the minor sites shown as pink, charged residues shown as blue, polar uncharged residues shown as green, and apolar residues shown as yellow.
Figure 4
Figure 4
LC-MS analysis of melittin/liposome mixtures. Reaction conditions unless otherwise stated: [melittin], 26 μM; [POPC], 0.26 mM (P/L, 1:10), [NaCl], 90 mM; NaHCO3, 10 mM; pH 7.4; 37 °C. Key: rt, retention time. (a) No NaHCO3, 72 h. (b) 20 °C, 150 mM NaCl, 72 h. (c) Water (no NaHCO3 or NaCl), 48 h. (d) POPC/SLPS (4:1), 72 h. (e) POPC/SLPG (4:1), 48 h. (f) POPC/SLPE (4:1), 72 h. (a) Total ion chromatograms (TICs; area normalized). The broken box indicates the region in (b). (b) Extracted ion chromatograms (EICs; area normalized) for palmitoyl–melittin (blue) and oleoyl–melittin (red). For (d–f), combined EICs for oleoyl/stearoyl/linoleoyl–melittin are shown in red. The peak indicated by an asterisk is from a polymeric impurity. Chromatographic peak identities are annotated using a roman numeral to indicate the main site of peptide modification responsible for the peak, with a subscript to identify the acyl group; i–v correspond to S18, K21, K7, K23, and the N-terminus, respectively. Reprinted with permission from ref (274). Copyright 2013 Elsevier.
Figure 5
Figure 5
Lipidation activity of exemplar low molecular weight organic molecules with neutral phospholipid membranes., The changes in lysolipid concentration are ≥24 h following the addition of the compounds to liposomes. Compounds with “no effect” yielded neither lipidated products nor changes in lysolipid levels relative to controls.
Scheme 4
Scheme 4. Overview of Processes Involved in the Autoxidation of Homoconjugated Dienes
The atom numbering of 18 corresponds to the carbon atom numbers of linoleic acid.
Figure 6
Figure 6
Secondary orbital interactions lead to a preferred geometry in the transition state structure for the reaction between pentadienyl radicals and molecular oxygen. From ref (368). Copyright 2011 American Chemical Society.
Scheme 5
Scheme 5. Reactions of Peroxyl Radicals with Neighboring Alkenes
Scheme 6
Scheme 6. Overview of Key Reactions Involved in Secondary Oxidation
Figure 7
Figure 7
Isoprostanes and isofurans formed by fragmentation of endoperoxides. R and R′ correspond respectively to the groups proximal to the carboxyl and methyl ends of the parent fatty acid.
Scheme 7
Scheme 7. Reactions of Isolated Alkenes
The numbering corresponds to the carbon atom numbering of oleic acid.
Scheme 8
Scheme 8. Products Formed by the Reaction of PE Lipids with 4-HNE
Figure 8
Figure 8
Amino-modified PE lipids isolated from HP-60 cells after exposure to acrolein.
Figure 9
Figure 9
Products formed by the reaction of PE with reactive oxygen carbonyl compounds derived from fatty acid oxidation.
Scheme 9
Scheme 9. Amadori Rearrangement Product Formed by the Reaction of Glucose with PE
Scheme 10
Scheme 10. Oxidation of Plasmalogens with a PUFA at the sn-2 Position
The double bond pattern shown here is that of arachidonic acid.
Figure 10
Figure 10
Products formed by the oxidation of sphingolipids.
Figure 11
Figure 11
Predominant products arising from the autoxidation of cholesterol.
Figure 12
Figure 12
Oxidation products arising from the autoxidation of cholesterol at the 7-position of the sterol ring.
Figure 13
Figure 13
Transition states for hydrogen abstraction by peroxyl radicals during the propagation stage of cholesterol autoxidation.,
Scheme 11
Scheme 11. Generation of 5,6-Epoxycholesterol (91)
Figure 14
Figure 14
Higher-order cholesterol oxidation products.
Scheme 12
Scheme 12. Products Arising from the Oxidation of Cholestadiene
Figure 15
Figure 15
Products arising from the oxidation of cholestadiene following hydrogen atom abstraction at C14.
Scheme 13
Scheme 13. Reaction of PC Lipids with Hypochlorous Acid
Scheme 14
Scheme 14. Ozonolysis Reactions of Fatty Acid Alkenes
Scheme 15
Scheme 15. Reactions of Singlet Oxygen with Alkenes
Figure 16
Figure 16
Dioxetane formed by the reaction of cholesterol with singlet oxygen.
Figure 17
Figure 17
Examples of oxidized PCs.,− All examples here have palmitoyl at the sn-1 position.
Figure 18
Figure 18
Bond cleavages, indicated by wavy lines, following γ-irradiation of DPPG (5.8 × 104 Gy).
Scheme 16
Scheme 16. Sterols Formed by Enzymatic Processing of 5,6-Epoxycholesterol
Scheme 17
Scheme 17. Alkene Isomerization Mediated by Electrophilic Radical Addition
Figure 19
Figure 19
Free energy landscapes of radical additions. Only the lowest barrier path is shown; the reaction sites of lowest barrier are shown in parentheses. From reference (557). Copyright 2014 American Chemical Society.
Scheme 18
Scheme 18. Generation of the Sulfhydryl Radical from Cys
Scheme 19
Scheme 19. Generation of Thiyl Radicals by Fe(III) Complexes of Bleomycin (BLM)
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