NMR of lipidsSlawomir Pikula,*a Joanna Bandorowicz-Pikulaa andPatrick Grovesb

DOI: 10.1039/9781849738125-00378

This chapter reviews articles on NMR and lipids published between June 2012 and May2013. The number of papers devoted to NMR utilization to investigate lipids, their struc-tures, behavior in native and artificial membranes, interactions with proteins and peptides,as well as with low molecular weight molecules, biomedical applications and newmethods is growing (over 1300 articles in Pub-Med) although we included here only aselection of those papers that were accessible and peer-reviewed. The reviewed materialhas been arranged in chapters devoted to the structure and function of lipids in mem-branes, their roles in membrane-related processes including lipid-mediated signaltransduction, interactions of lipids with membrane and soluble proteins, peptides andvarious low molecular weight compounds, lipid metabolomics, visualization of lipid re-lated processes in biomedicine, lipid-based diagnosis, and methodological approaches.

1 Introduction

This is our second review for RSC Specialist Periodical Reports in the fieldof NMR of lipids. We cover the same topic and areas as before in 2012.1

Previous reviews covering NMR of lipids were written from 1995 until 2009by Dr Elizabeth F. Hounsel. In 2010 and 2011 (volumes 41 and 42),Dr Elzbieta Swiezewska and Dr Jacek Wojcik2,3 covered a broader area,including carbohydrates. Our contribution reviews articles on NMR andlipids published between June 2012 and May 2013. The number of papersdevoted to NMR investigations of lipids, their structures, behavior in nativeand artificial membranes, interactions with proteins and peptides, as wellas with low molecular weight compounds, and biomedical applicationscontinues to grow (over 1300 in Pub-Med). We have covered a selection ofaccessible and peer-reviewed papers. As previously, the review has beendivided into several sections devoted to the structure and function of lipidsin membranes, their roles in membrane-related processes includingmembrane fusion and lipid-mediated signal transduction, interactions oflipids with membrane and soluble proteins, peptides and antibiotics, lipidmetabolomics, visualization of lipid related processes in biomedicine,diagnosis and therapy, and methodological approaches.

2 The structures and cellular functions of lipids

Important discoveries made over the last decade, using also NMR techni-ques (as reviewed in ref. 4–6 strongly suggest that lipid and lipid-derivedmolecules play pivotal roles in vital biological processes including cellular

aDepartment of Biochemistry, Nencki Institute of Experimental Biology,3 Pasteur St., 02-093 Warsaw, Poland. E-mail: s.pikula@nencki.gov.pl

bDepartment of Biological Chemistry, Instituto de Tecnologia Quimica e Biologica,Universidade Nova de Lisboa, Av. da Republica, 2780-157 Oeiras, Portugal

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�c The Royal Society of Chemistry 2014

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signalling, secretion, fertilization, cellular proliferation and death. This es-pecially takes into account the roles of certain lipids, such as cholesterol,sphingomyelin (SM), phosphatidylserine (PS), phosphatidylinositol (PI) andits derivatives: phosphatidylinositol (4,5)-bisphosphate (PtdIns(3,4)P2),phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2), and phosphatidy-linositol (3,4,5)-triphosphate (PtdIns(3,4,5)P3), and their protein partners,including lipid- and membrane-binding proteins (as for example annex-ins),7 in the formation, stabilization and sustenance of lipid membranemicrodomains of specific chemical composition.8,9 These roles rely onspecific interactions of lipids with proteins and low molecular weight mol-ecules (as reviewed in the Section 3). Moreover, it has been shown that uponcell stimulation, a membrane lipid degradation cascade is induced throughthe activation of several phospholipases, yielding various lipid metabolitessuch as diacylglycerols, free fatty acids, lysophospholipids and phosphatidicacid, playing a role in literally every biological process, including thephysiological and pathological mineralization.10

2.1 The structures of lipids and lipid-derived moleculesThe structure of semi-rough lipopolysaccharide from Plesiomonas shi-gelloides was solved with the aid of 1H- and 13C-NMR spectroscopy,matrix-assisted laser-desorption/ionization time-of-flight mass spec-troscopy and chemical methods by Kaszowska et al.11 It was found thatthe core oligosaccharide is a nonasaccharide.12 The carbohydrate back-bone structure of the lipopolysaccharide from Piscirickettsia salmonis wasestablished by a combination of monosaccharide and methylation ana-lyses of the lipopolysaccharide, by NMR and mass spectrometries.13 Perryet al.14 by using NMR spectroscopy, mass spectrometry and chemicalmethods studied the structures of capsular polysaccharide and lipooli-gosaccharide of Haemophilus parasuis. The structures of the four majorglycolipids from the cariogenic bacterium Streptococcus, namely monoand diglucosyldiacylglycerols, diglucosylmonoacylglycerol and glycero-phosphoryldiglucosyldiacylglycerol were analysed by Sallans et al.15

Brash et al.16 investigated the transformation of 9S-hydroperoxylinoleicacid with the allene oxide synthase CYP74C3, that results in production ofan allene oxide-derived cyclopentenone. The membrane forming prop-erties of trehalose 6,60-dimycolate, the major lipid in the outer membraneof Corynebacteria and Mycobacteria, was studied by Rath et al.17

The structure of resolvins and protectins, important anti-inflammatoryand pro-resolution compounds derived from the enzymatic oxidation ofomega-3 fatty acids all-cis-5,8,11,14,17-eicosapentaenoic acid and all-cis-4,7,10,13,16,19-docosahexaenoic acid was characterized by normal phaseHPLC, GC-MS, TOF-MS, UV-visible spectroscopy, and NMR spec-troscopy.18 The total non-acid glycosphingolipid fractions from twohuman embryonic stem cell lines (SA121 and SA181) originating fromleftover in vitro fertilized human embryos were studied by Barone et al.19

Thomas et al.20 characterized the regio- and stereo-chemistry of the allylicepoxyalcohols and their trihydroxy hydrolysis products generated from9R- and 9S-hydroperoxy-octadecenoic acid under non-enzymatic andenzymatic conditions, by a combination of 1H NMR and GC-MS analysis.

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An unusual a-(1,1)-galacturonic acid lipid A modification discovered insome Gram-negative bacteria was further elucidated by combination ofmatrix-assisted laser desorption/ionization time-of-flight mass spec-trometry analysis and NMR.21 Jin et al.22 studied, by using NMR techni-ques, structural features of leukotriene A4 and closely related allylicepoxides, intermediates in lipooxygenase pathways leading to bioactivelipid mediators such as leukotrienes, lipoxins, eoxins, resolvins, andprotectins. Ogawa et al.23 found that the 1H- and 13C-NMR analysis maybe useful for determining the stereochemical configuration at C-24 ofthis type of 24-alkyl oxysterols. Furthermore, Ottria et al.24 reported thecomplete 1H, 13C and 15N NMR signal assignments of some N- andO-acylethanolamines, important bioactive lipid mediators.

The major fatty acids of a novel species of Thermogemmatispora sp.were identified and structurally analyzed using 1H- and 13C-NMR, with1H–1H-COSY and 1H–13C-HSQC experiments, by Vyssotski et al.25 Struc-tural rearrangements of oxidized and enzymatically modified low-densitylipoproteins, playing a key role in early stages of atherogenesis, werecharacterized with the aid of 1H-NMR spectroscopy by Ramm Sander et al.26

2.2 Lipid molecules in membrane-related processes and artificialmembranesWallgren et al.27 studied the impact of oxidized phospholipid species onthe organization and biophysical properties of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) based lipid membranes by differential scan-ning calorimetry and solid state NMR spectroscopy. To characterize thestructure and dynamics of fluorescent cholesterol analogs in membranesNMR and EPR spectroscopies were employed by Milles et al.28

Shi et al.29 reported, on the basis of the results obtained with the aid of31P-NMR spectroscopy, that that Ca2þ can bind directly to anionicphospholipids in membranes and thus modulate membrane proteinfunction important for T-cell activation.

Omega-3 polyunsaturated fatty acids, as reported by Williams et al.,30

may serve to disrupt lipid raft domain organization of the membranesand therefore participate in remodeling membrane architecture. Freik-man et al.31 measured PS externalization and shedding by flow cytometryand the cholesterol/phospholipids by 1H-NMR, and found that the Ca2þ

flux and microtubule depolymerization of erythroid cells mediate PSexternalization and shedding, which in turn changes their membranecomposition. Wallgren et al.32 observed that the presence of oxidizedphospholipids in mitochondria-like liposomes increases the populationof membrane-associated proapoptotic protein, Bax, and facilitates theprotein’s insertion into the membrane by distorting the bilayer’s organ-ization, as revealed by solid-state high-resolution 1H and 31P magic anglespinning NMR spectroscopy.

The interactions between cholesterol and phospholipids in form ofbilayers composed of ternary complexes mimicking lipid rafts, e.g.,1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)–sphingomyelin (SM)–cholesterol and DOPC–1,2-dipalmitoyl-sn-glycero-3-phosphocholine(DPPC)–cholesterol, were studied using differential scanning calorimetry

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and 13C cross polarization magic angle spinning solid-state NMR byFritzsching et al.33 Similarly, Ciesielski et al.34 studied interactions oflipopolysaccharides from Brucella melitensis, Klebsiella pneumoniae andEscherichia coli with mixed lipid membranes, mimicking raft typemembrane microdomains. Lipid mixture phase behavior and morph-ology were characterized in bicellar dispersions of chain perdeuterated1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC-d54), 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-(10-rac-glycerol) (DMPG) using 2H-NMR spectroscopy.35

3 Interactions of lipids with proteins, peptides andsmall molecules

Many interesting reviews as well as experimental articles have been pub-lished between June 2012 and May 2013 discussing advantages of using theNMR methods to study protein structure in lipid environment, and protein–lipid and protein–peptides interactions in natural and artificial lipidmembranes.36–39 For example, solid-state NMR, the most suitable methodthat can be used for proteins in liquid crystalline lipid bilayers, has emergedas an important tool for structural biology and chemistry, capable of solvingatomic resolution structures for proteins in membrane-bound and aggre-gated states.40,41 This technique, as well as solution NMR, were found usefulalso in studying lipid membrane insertion and translocation of manymembrane-active peptides, such as cationic cell-penetrating peptides42 andantimicrobial peptides43 (see also Section 3.3). Since modern solid-stateNMR methods require rapid sample spinning and intense decoupling fieldsthat can heat and denature the protein being studied, a strategy to avoiddestroying the samples was proposed, suggesting creation of a ‘‘sacrificial’’sample that allows characterization of the heating conditions first.44

According to Maslennikov and Choe45 as well as Arora46 solution NMR is,aside from X-ray crystallography, the major tool in structural biology for de-termination of integral membrane protein structures in a native-like lipidenvironment. In addition, Alvares et al.47 pointed to importance of use ofanionic and zwitterionic detergents in proper folding of transmembranesegments of integral membrane proteins being prepared for NMRmeasurements.

Due to the structural complexity of membrane integral proteins in lipidenvironment, protein–lipid interactions and structures of protein–lipidcomplexes are frequently studied using recombinant peptides, repre-senting transmembrane domains of membrane integral proteins, andartificial lipids and/or detergents mimicking natural membranes. Moredetails about experiments aimed to study protein–lipid, peptide–lipidand small molecular weight compounds–lipids interactions and theirstructures are given in the Sections 3.1–3.3.

3.1 Interactions with membrane proteins3.1.1 Proteins involved in signal transduction. The structure of the

myristoylated cytosolic domain of the leukocyte specific integrin aXb2 inperdeuterated dodecylphosphocholine (DPC), solved by NMR spectroscopy,

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was reported by Chua et al.48 Sommer et al.49 characterized the interactionswith lipids and different membrane mimetics of the FATC domains (sharedby all members of the family of phosphatidylinositol-3 kinase-relatedkinases) of human proteins: DNA-PKcs, ATM, ATR, SMG-1, and TRRAP byNMR and CD spectroscopies. Goncalves et al.50 described in details the basicmethods used for magic angle spinning solid-state NMR measurements ofchemical shifts and dipolar couplings aimed to reveal structural infor-mation on G protein-coupled receptors (GPCRs), mediating a diversity ofcellular processes. Langelaan et al.,51 among various GPCRs, reported thehigh-resolution NMR spectroscopy-based structure of the NH2-terminusand first transmembrane segment of apelin receptor AR, while Vukoti et al.52

provided insights into differential effects of detergents, lipids and canna-binoid ligands on stability of another member of GCPR family of receptors,the recombinant cannabinoid receptor CB2.

Muhle-Goll et al.53 determined the structure of the transmembranesegment of the platelet-derived growth factor receptor b (member of thecell surface receptor tyrosine kinase family) in DPC micelles by liquid-state NMR and found that it forms a stable left-handed helical dimer.NMR methods have been used to analyze the GTPase domain of Rashomologue enriched in brain (Rheb), belonging to Ras superfamily ofproteins, tethered to nanodiscs, monodisperse protein-encapsulatedlipid bilayers with a diameter of 10 nm.54 Matsushita et al.,55 by usingsolid-state NMR and fluorescence spectroscopy, provided an evidence oftight interactions of juxtamembrane regions of rat ErbB2, the memberof ErbB family receptor tyrosine kinases, with negatively charged lipids,including PtdIns(3,4)P2. Furthermore, Bocharov et al.56 observed, usingsolution NMR, the dimerization of the ErbB4 transmembrane domain inmembrane-mimicking lipid bicelles made of DMPC/DHPC. They havefound that the ErbB4 membrane-spanning a-helices (651–678) form aright-handed parallel dimer through the N-terminal double GG4-likemotif A(655)GxxGG(660) in a fashion that probably permits proper kinasedomain activation. In addition, Park et al.57 described structural featuresimportant for intracellular G-protein activation and signal transductionof CXCR1, one of two high-affinity receptors for the CXC chemokineinterleukin-8, and member of GPCR family of receptors.

Using solution NMR structure of C-terminal PDZ recognition motif ofhuman transmembrane protein, Jagged-1, one of the ligands of Notchreceptors, was reported by Popovic et al.58 Zhou et al.59 analyzed synap-totagmin-1–SNARE complex interactions by monitoring the decrease inthe intensities of 1-D 13C-edited 1H-NMR spectra of 13C-labeled fragmentsof synaptotagmin-1 upon binding to unlabeled SNARE complex. Theyfound that there is a primary binding mode between synaptotagmin-1and the SNARE complex that involves a polybasic region in the C2B do-main of synaptotagmin-1.

3.1.2 Proteins involved in membrane transport of ions and othersolutes. Lee et al.,60 using NMR techniques, characterized the structuresof fragments of membrane domain of the Naþ/Hþ exchanger isoform1(NHE1) present in the plasma membrane of the mammalian myocardium.

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The molecular mechanism of signaling between the V-ATPase, cytohesin-2,and Arf GTP-binding proteins has been studied by Hosokawa et al.61

They have found that part of the NH2-terminal cytosolic tail of theV-ATPase a2-subunit, modulates the enzymatic GDP/GTP exchangeactivity of cytohesin-2. Using solution NMR, Yu et al.62 described structureof human voltage-dependent anion channel (VDAC) isoform 2 inlauryldimethylamine-oxide (LDAO) detergent micelles and DMPC lipidbilayer nanodiscs.

The gating mechanism of the VDAC channels was further studied bysolid-state NMR spectroscopy. The obtained data suggest that the NH2-terminal helix controls entry into elliptic b-barrel states which underlieVDAC closure.63 The solid-state NMR spectroscopy has been also used toinvestigate structural interactions of lipids and water with S1–S4 voltage-sensing domains of voltage-activated ion channels and revealed extensiveinteractions of these domains with lipids and that these domains areheavily hydrated when embedded in a membrane.64

Perdih et al.65 by using multidimensional NMR spectroscopy, de-scribed a high-resolution 3-D structure of an 18 amino acid residueslong peptide corresponding to the third transmembrane part of bili-translocase TCDB 2.A.65 in detergent micelle mimicking the biologicalmembrane. The structure of the S4–S5 linker and COOH-terminus of S6of the Drosophila Shaw2 Kv channel interacting with 1-alkanols andinhaled anesthetics was determined by Zhang et al.66 Imai et al.67 re-vealed, by NMR and single-channel recording analyses, that transportactivity of KcsA, Kþ channel from Streptomyces lividans, is stronglymodulated by the membrane environment. 31P-NMR data enabled in-vestigators to conclude that the activity of tafazzin, mitochondrialphospholipid-lysophospholipid transacylase, is highly sensitive to thelipid phase.68

3.1.3 Other membrane proteins. Li et al.69 described variance be-tween already published solution NMR structure of diacylglycerol kinasethat catalyses the ATP-dependent phosphorylation of diacylglycerol tophosphatidic acid and crystal structures for three functional forms of theenzyme. Tieu et al.70 studied the ability of rat CYP24A1 to metabolize andinactivate 1,25-dihydroxyvitamin D3. Estrada et al.71 investigated theinteractions between the soluble domain of microsomal membraneheme protein cytochrome b5 and the catalytic domain of the bifunctionalsteroidogenic cytochrome P450 17A1 (CYP17A1). NMR chemical shiftmapping of b5 titrations with CYP17A1 allowed identification of chargedsurface residues involved in the protein–protein interactions.

Merozoite surface protein 2 (MSP2) of the Plasmodium falciparumparasite is considered as a target for the development of an effectivemalaria vaccine. MacRaild et al.72 solved the MSP2 structure in DPCmicelles. The dynamics of the transmembrane domain of Klebsiella pneu-moniae OmpA (KpOmpA) in a lipid bilayer were investigated, using magicangle spinning solid-state NMR.73 With the aid of [1H,15N]-transfer relax-ation optimization NMR spectroscopy Lim et al.74 studied ligand bindingmechanisms for human lipocalin prostaglandin D synthase (L-PGDS).

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3.2 Interactions with soluble and viral proteins3.2.1 Soluble and membrane-binding proteins. Palleboina et al.,75

using 1H and 31P-NMR, determined the effect of N-terminal (SP-B8–25) andC-terminal (SP-B63–78) helices of the hydrophobic lung surfactant protein,SP-B, on phospholipid chain orientation order, and headgroup orien-tation in artificial membranes. Structure and dynamics of human liverfatty acid binding protein (L-FABP) with and without bound ligands bymeans of heteronuclear NMR were reported by Cai et al.76 2-D NMRspectroscopy was used to examine the ability of human serum albumin(HSA) to bind fatty acids in multiple sites,77 while solid-state NMR toinvestigate membrane partitioning properties of NH2-terminal domain ofhuntingtin (Htt17), located immediately upstream of the decisive poly-glutamine tract, involved in the development of Huntington’s disease.78

Letourneau et al.79 by 1H–15N heteronuclear single-quantum coherence(HSQC) NMR approach investigated the binding of sterols to STARD5, amember of steroidogenic acute regulatory-related lipid transfer (START)domain protein family. Xiao et al.80 identified and structurally charac-terized a minimal region in Disabled-2 (Dab2) that modulates platelethomotypic interactions during the aggregation process. Sugiki et al.81

using solution NMR determined the 3-D structure of the ceramide traf-ficking protein (CERT) pleckstrin homology (PH) domain that specificallyrecognizes phosphatidylinositol 4-monophosphate (PtdIns(4)P). Sameapproach was used to characterize structures and backbone 15Ndynamics of the specialized acyl carrier protein (ACP), RpAcpXL, fromRhodopseudomonas palustris, in both the apo form and holo form,modified by covalent attachment of 40-phosphopantetheine at S37.82

CD spectroscopy and solid-state magic-angle spinning NMR spec-troscopy were employed to study the structure and dynamics of the three-repeat domain of the microtubule-associated protein, tau when bound tomembranes consisting of a PC–PS mixture or PS alone.83 Haupt et al.,84

by heteronuclear NMR spectroscopy, characterized the contact regionsbetween the prosurvival protein Bcl-2 and the catalytic domain of itsregulatory protein FKBP38. Yates et al.85 reported that focal adhesionprotein kindling-3 specifically recognizes the membrane-distal tail NPXYmotif in both the b(1A) and b(1D) isoforms of b-integrin. Leftin et al.86

used 2-D 13C separated local-field NMR to study interaction of the wild-type a-synuclein (in Lewy body plaques this disordered protein is acharacteristic marker of late-stage Parkinson’s disease) or its N-terminalamino acid sequence with a cholesterol-enriched ternary membranesystem.

3.2.2 Viral proteins. Prchal et al.87 determined the solution structureof myristoylated Mason-Pfizer monkey virus matrix protein by NMRspectroscopy. By solution NMR and attenuated total reflection-Fouriertransform infrared spectroscopy the structure of the small hydrophobic(SH) protein encoded by the human respiratory syncytial virus was solvedin detergent micelles.88 Using saturation transfer difference (STD) NMRthe receptor binding properties of the influenza A the envelope proteinhemagglutinin (HA) were studied.89

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3.3 Interactions with peptidesThe spatial structure of an active fragment of ß-amyloid Ab(1–40) peptidein aqueous buffer solution and in complex with detergent micelles wasinvestigated by 1H NMR spectroscopy and two-dimensional NMR (TOCSY,Heteronuclear Couplings from ASSCI-domain experiments with E.COSY-type crosspeaks, and NOESY) spectroscopy.90 The main objective of Desaiet al.91 was to investigate penetration of cell penetrating peptides (CPPs:TAT, R8, R11, and YKA) through skin intercellular lipids using 31P magicangle spinning solid-state NMR. Zhao J. et al.,92 by combination of NMR-derived structures and molecular modeling, characterized interactions ofhuman islet amyloid polypeptide (hIAPP) with the cell membrane. On theother hand, the interactions of the antimicrobial peptides aurein 1.2 andcaerin 1.1 with the lipid membranes made of DMPC or DMPC/DMPG wereobserved by 31P and 2H solid-state NMR as well as circular dichroismspectroscopy.93 Similar experimental approach was used by Ulmschneideret al.94 to study interactions of antimicrobial peptide PGLa from Xenopuslaevis with membrane surfaces. The solution structure of obestatin, a pu-tative hormone that is potentially produced in the cells lining the stomachand small intestine of several mammals including humans, was deter-mined by Alen et al.95 High-resolution 13C/15N NMR analysis in detergentmicelles revealed a helical stretch in the PhoD signal peptide from Bacillussubtilis between positions 5 and 15 in suitable membrane-mimickingenvironments.96 The membrane alignment of the amphiphilic alpha-hel-ical model peptide MSI-103 (sequence [KIAGKIA]3-NH2) was examined bysolid state 2H-NMR in different lipid systems by systematically varying thelength and degree of saturation of acyl chain, the lipid head group type, andthe peptide-to-lipid molar ratio.97

Da Costa et al.98 solved the NMR structure of neurotensin, a tridecapep-tide, playing a role of hormone in the periphery and neurotransmitter in thebrain. The paramagnetic relaxation effect due to the presence of Mn2þon 13Cmagic angle spinning NMR was used to measure the insertion depth of thenew class of penetrating peptides that can target the mitochondria with highspecificity.99 Oriented-sample 31P solid-state NMR spectroscopy was used toprobe the membrane perturbations and disruption by caused by alamethi-cin and novicidin, two antimicrobial peptides.100

Further readings in the field of membrane integral and surface pro-teins as well as soluble lipid-binding proteins, and peptides are sum-marized in Table 1.101–127

3.4 Interactions of lipids with low molecular weight molecules andsolutesPawlikowska-Pawlega et al.128 probed the effects of genistein, a phy-toestrogen that belongs to the category of isoflavones, on the liposomesformed with DMPC with Fourier-transform infrared spectroscopy, 1HNMR and electron paramagnetic resonance techniques. With the aidof FTIR spectroscopy, 1H NMR and EPR techniques the interactionsof apigenin (5,7,4 0-trihydroxyflavone), cancer chemopreventive agentand a member of the family of plant flavonoids, with liposomes madeof DPPC was investigated.129 The membrane location of the local

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Table 1 Structure of proteins and peptides interacting with lipids determined by the NMRspectroscopy techniques.

Protein/peptide Lipid/membrane/organism Ref.

Membrane proteinsPotassium channel KcsA Cooperative binding of anionic

nonannular lipids101

Cytochrome b5 complex with its redoxpartner, cytochrome P4502B4

Rabbit microsomes 102

Homotetrameric Kþ channel KcsA DMPG, DMPC Streptomyces lividans 103TatA, the protein-translocating element

of the twin-arginine translocasesystem

Escherichia coli 104

Bacteriorhodopsin DMPG, DMPC Exiguobacteriumsibiricum

103

Bacteriorhodopsin In detergent micelles, amphipolsand nanodiscs

105

DsbA/DsbB, a 41 kDa membraneprotein complex

The disulfide bond generationsystem in Escherichia coli

106, 107

TBsmr, a secondary active multidrugtransporter

Mycobacterium tuberculosis 108

The HIV type-1 (HIV-1) Gag protein PE, PC, PS and PtdIns(4,5)P2 inplasma membrane

109

Flavivirus nonstructural protein 2A(NS2A), a component of the viralreplication complex

Host cell endoplasmic reticulummembranes

110

Soluble proteinsLiver fatty acid-binding protein

(LFABP; FABP1)Mouse cytosolic protein with two

monooleins bound111

MFG-E8 (lactadherin), a secretedglycoprotein

PS, role in apoptosis 112

a-Synuclein (aS), the major componentof Lewy bodies

Negatively charged lipid membranes 113, 114

Malaria parasite protein, UIS3 Plasmodium species 115

PeptidesHuman islet amyloid polypeptide

protein (hIAPP)Human ß-cells, Ca2þ 116, 117

Lactoferrampin (LFampinB) Bovine antimicrobial peptide 118Cathelicidin-PY, an antimicrobial

peptideFrom the skin of the frog

Paa yunnanensis119

PGLa and magainin 2 (MAG2) Amphiphilic antimicrobial peptidesfrom frog skin

120

Maculatin 1.1 and its analogs Antimicrobial peptides interactingwith DMPC/DMPG bilayers

121

Theonellamide A (TNM A) Antifungal and cytotoxicdodecapeptide from the marinesponge Theonella sp., POPC and3ß-hydroxysterols

122

Fluorinated glycopeptides Staphylococcus aureus 123WALP peptides DLPC, DMPC and DOPC 124RW9 and RL9, cell penetrating peptides POPC and POPG 125Fusion peptide derived from gp41

(an integral membrane protein)HIV 126

Fusion peptide derived from F protein The paramyxovirus, parainfluenzavirus 5 (PIV5)

127

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anesthetics: lidocaine, dibucaine, tetracaine, and procaine hydrochlorideand their effects on phospholipid bilayers were studied by 31P and 1Hmagic-angle spinning NMR spectroscopy.130

The location, orientation, and dynamics of hydrophobic small mol-ecules (1-naphthol and 1-methylnaphthalene) in lipid membranes werestudied through combined use of solution-state 1H-NMR and moleculardynamics simulations. The nuclear Overhauser effect (NOE) measure-ments were performed for large unilamellar vesicles composed ofDMPC.131 Tokarska-Schlattner et al.132 provided evidence for interactionof phosphocreatine and phosphocyclocreatine with different zwitterionicphospholipids by applying four independent, complementary bio-chemical and biophysical assays: chemical binding assay, surface plas-mon resonance spectroscopy, solid-state 31P-NMR, and differentialscanning calorimetry.

4 Lipid markers in biomedicine

A growing number of diseases, accompanied by defects in metabolism andstorage of lipids or lipid-derived molecules, with problematic or difficultdiagnostics, call for the development of reliable methods of assessment ofchanges in lipid metabolism and content. These diseases include wholespectrum of adipose tissue diseases ranging from obesity to lipodystrophy,and is accompanied by insulin resistance syndrome, which promotes theoccurrence of type 2 diabetes, dyslipidemia and cardiovascular compli-cations. Lipodystrophy refers to a group of rare diseases characterized bythe generalized or partial absence of adipose tissue.133 Other type of dis-eases are peroxisomal disorders, an important group of neurometabolicdiseases and cardiovascular disease, which accounts for the highest mor-bidity and mortality in USA and EU countries. Their clinical presentation isvaried in terms of age of onset, severity, and different neurological symp-toms. The role of MRI findings in the clinical approach of listed abovedisorders received recently broad appreciation.134–136

4.1 Diagnostic approachesNMR techniques including in vivo proton magnetic resonance spec-troscopy (MRS) and magnetic resonance imaging are frequently used fordiagnostic purposes related to the abnormal metabolism of lipids andtheir derivatives. For example in patients with genetically proven Fabrydisease 1H MRS of the hart was acquired and no significant effects onmyocardial triglyceride deposition was observed.137

MRI (magnetic resonance imaging) and MRS were performed in 60 pa-tients with histologically verified brain tumors and were proven useful indiscriminating between high-grade and low-grade gliomas as well as couldbe allowed even in those patients who cannot undergo biopsy.138 Bothtechniques were also very powerful in diagnosing patients with myocardialsteatosis and diabetic cardiomyopathy,139 with Alzheimer disease and in-creased risk for developing dementia,140 with obesity,141,142 with athero-sclerosis,143 with cerebral X-linked adrenoleukodystrophy,144 withmetabolic syndrome,145 with primary chronic insomnia,146 with b-cell

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lipotoxicity,147 with cervical cancer,148 with brain metastatic tumors,149,150

with long-chain mitochondrial b-oxidation disorders,151 as well as withneutral lipid storage disease with myopathy.152 Similar conclusions werereached on the basis of experiments performed on animals.153,154

Another strategy in diagnosing patients suffering from lipid-related dis-eases is so-called focused metabolic profiling designed for the determin-ation of biomarkers. It includes global proton 1H NMR-based metabolomicapproach coupled with ultra high performance liquid chromatography-based focused metabolomic approach, and metabolic challenge proto-cols.155–157 By using such or similar experimental approach monitoring ofprogression of HIV infection to full-blown acquired immune deficiencysyndrome (AIDS),158 cardiovascular disease as the leading cause of death inHIV infected patients,159 diet-induced hyperlipidemia in humans,160 pre-eclampsia,161 human colorectal cancer,162,163 and other types of cancer,164

obesity and fatty liver,165,166 cirrhotic livers,167 ulcerative colitis,168 andhepatic steatosis as a hallmark of chemotherapy169 was performed.

Metabolic profiling was also used to study the biological processes oflongevity,170 changes in adipose tissue distribution and ectopic fat stor-age in liver and skeletal muscles,171 as well as to monitor healthy preg-nancies on the basis of urine analyses.172

Recent achievements in this field are summarized in Table 2.173–192

4.2 PathomechanismsBlumenthal et al.193 followed the process of HIV entry that involvesbinding of the trimeric viral envelope glycoprotein (Env) gp120/gp41 tocell surface receptors, which triggers conformational changes in Env, andresults in the membrane fusion reaction, by using biophysical meas-urements, electron tomography, X-rays, and NMR. Ho et al.,194 by usingsimilar approach as above, studied the association of long-chain fattyacids to a partially unfolded, extracellular protein, human a-lactalbumin,formation of a tumoricidal complex HAMLET and its cellular effects.

Gravel et al.,195 by using combination of solution and solid-state NMR,characterized the structure and function of the human ether-a-go-go-related gene (hERG) voltage-gated Kþ channel’s L(622)-K(638) segmentlocated in heart cell membranes holding a unique selectivity filter aminoacid sequence (SVGFG) in development of the acquired long QT syn-drome (ALQTS). Abnormal accumulation of lipids was detected withcerebral magnetic resonance spectroscopy that accompanied complexhereditary spastic paraplegia (HSP) due to recessive mutations inDDHD2, encoding one of the three mammalian intracellular phospho-lipases A1.196 Another type of disease the neutral lipid storage diseasewith myopathy (NLSDM) was accompanied by massive triglyceride stor-age in peripheral blood leukocytes and in muscles.197

4.3 Lipid nanoparticles and therapy responsesRecently the production of lipoprotein biomimetic particles loaded withdiagnostically active nanocrystals in their core was reported. Inclusion ofthese nanocrystals enables the utilization of lipoproteins as probes for avariety of imaging modalities such as computed tomography, magnetic

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resonance imaging, fluorescence while preserving their biological activ-ity.198 Eltayeb et al.199 developed transferrin-modified-artemether (anantimalaria and anticancer drug) lipid nanospheres as targeted nonexpensive anticancer drug delivery system. Moreover, since some of de-signed systems can elicit unwanted effects, the toxicological effects of

Table 2 Biomedical investigations related to changes of lipidome under normal andpathological states, performed with the aid of NMR metabolomic platforms and MRI and MRS.

Target investigated Pathology and organism Ref.

Fatty acid synthase (FASN),lipid metabolome

Abnormal fatty acid synthesis, humannon-small cell lung carcinoma cells

173

Lipid metabolome Alcoholic liver disease (ALD), hepaticalcohol dehydrogenase (ADH)-deficient(ADH�) versus hepatic ADH-normal(ADHþ) deer mice

174

Lipid content and composition Hepatic lipid accumulation associatedwith non-alcoholic fatty liver disease,leptin-deficient ob/ob mice

175

Biopsies, lipidome Human hepatitis C-related liver disease 176Lipoproteins Familial hypercholesterolaemia and

familial combined hyperlipidaemia177

Heart perfusates Cardiac hypertrophy, cardiac specificMyc-inducible C57/BL6 male mice

178

Lipoproteins Human psoriasis associated withincreased risk of cardiovasculardisease (CVD)

179

Atherosclerotic plaques Vascular calcification; humanatherosclerotic intimal plaques;human, equine, and bovine medialvascular calcifications; and humanand equine bone

180

Carotid plaques Human carotid atherosclerosis, humanpatients with carotid stenosis

181

Serum lipid profile Oxidation susceptibility of humanserum lipids

182

Metabolome including analysisof lipoproteins

Mice cerebral and non cerebralmalaria caused by Plasmodium berghei

183

Blood plasma metabolomicsprofiles

Human contracting high-altitudepulmonary edema

184

Lung tumor development in themice assessed by MRI

Squamous cell carcinoma (SCC) orvitamin D-resistant variant SCC-DR cells

185

Metabolome including lipidome Human head and neck squamous cellcarcinoma (HNSCC) cells

186

Metabolic signatures in plasmaand urine

Human esophageal cancer 187

Urine metabolomic profile Dog bladder cancer 188Altered choline phospholipid

metabolismHuman breast cancer cells 189

Lipid composition Rat BT4C glioma cells 190Lipid saturation profiles Sensitive (HeLa) and resistant

(C33A; Me180) cervical cancer cell lines191

Transport of gemcitabine, anucleoside analog against awide variety of tumors

MCF-7 and MDA-MB-231 cell lines 192

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single-walled carbon nanotubes were investigated after intratracheal in-stillation in male Wistar rats over a 15-day period using metabolomicanalysis of 1H NMR spectra of blood plasma and liver tissue extracts.200

Cellular and/or organism responses to treatment with various drugswas also examined using NMR techniques. For example 1H-NMR spec-troscopy-based metabolomics was applied to get novel insight into re-sponses of MCF7 and MDA-MB-231 breast cancer cells to curcumin anddocetaxel.201 By using physiological/pharmacological MRI the nutrientactivated central nervous system mechanisms controlling energy intakeand expenditure were studied in healthy people upon a ghrelin bolus(0.3 nmol kg�1, intravenous). It is worth stating the ghrelin is secretedfrom the stomach and stimulates food intake and gastric emptying, butthe relevant mechanisms are poorly understood.202

5 NMR-based methodology

In this chapter we refer to recent reports describing the successful de-velopment and application of NMR-based techniques to study lipids,lipid-binding proteins and peptides or to validate other methods on thebasis of NMR parameters.

Yoshii et al.203 published new method to separate lateral diffusion of lipidsin spherical large unilamellar vesicles from the rotational and the transla-tional diffusion of the vesicle as a whole. According to the authors the methodprovides a potential for quantifying the lateral diffusion of lipids and proteinsin fluid bilayer vesicles. Amphiphilic cyclodextrins, with a cholesterol anchoror an aspartic acid moiety esterified by two lauryl acyl chains were designed tostudy lateral phase separation in lipid artificial membranes. Furthermore,Macdonald et al.204 summarized advantages and limitations of using 1H PFGNMR measurements in magnetically aligned bicelles and 31P CODEX (Cen-treband-Only-Detection-of-Exchange) measurements in spherical phospho-lipid vesicles to determine lateral diffusion in membranes.205 Graber andKooijman206 proposed solid-state 31P-NMR procedure allowing gaining de-tailed knowledge on the degree of ionization of lipid titratable groups, im-portant for the evaluation of protein–lipid and lipid–lipid interactions. Inaddition the method of determination of relaxivities for both the longitudinaland transverse relaxations of two types of liposomes loaded with ultra smallsuper paramagnetic iron oxide nanoparticles was described.207 Solid-stateNMR was also suggested as a useful tool to probe the organization anddynamics of phospholipids in bilayers.208 In addition, a new type of pH-sensitive liposomes (fliposomes) was designed based on the amphiphilesthat are able to perform a pH-triggered conformational flip (flipids). This flipdisrupts the liposome membrane and causes rapid release of the liposomecargo, specifically in response to lowered pH.209

To determine the structures of integral membrane proteins using so-lution NMR spectroscopy, detergent-resistant DNA nanotubes that can beassembled into dilute liquid crystals for application as weak-alignmentmedia in NMR structure determination of membrane proteins in de-tergent micelles were synthesized and characterized.210 Wang et al.211

provided arguments for the use of the rigid-solid HETCOR experiment,

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with an additional spin diffusion period, over other NMR methods thatcan be used to determine the depth of proteins in gel-phase lipidmembranes. Banigan et al.212 shown that magic-angle-spinning solid-state NMR spectroscopy is a viable method to characterize membraneprotein structure and dynamics and is widely applicable to study mem-brane proteins in functional lipid bilayer environments.

Residue-specific location of peptides in the hydrophobic core ofmembranes was validated using 13C–2H REDOR and samples in whichthe lipids were selectively deuterated.213

A sample preparation method for reconstitution of membrane proteinswhich uses porous anodic aluminum oxide filters with 200 nm-widepores of high density was developed and shown to permit formation oftubular, single membranes that line the inner surface of pores.214

Phospholipid nanodiscs were proposed to overcome the intrinsic prob-lems of detergent-containing environments in studying lipid–proteininteractions in membranes using NMR applications.215–217

Finally, gadolinium (Gd)-containing liposomal MRI contrast agents havebeen developed for molecular and cellular imaging of disease-specificmarkers and for image-guided drug delivery. MRI-guided drug delivery usingsuch liposomes seems to allow the visualization and quantification of localdrug delivery.218

Abbreviations

DHPC 1,2-Dihexanoyl-sn-glycero-3-phosphocholineDLPC 1,2-Dilauroyl-sn-glycero-3-phosphocholineDMPC 1,2-Dimyristoyl-sn-glycero-3-phosphocholineDMPG 1,2-Dimyristoyl-sn-3-phosphoglycerolDOPC 1,2-Dioleoyl-sn-glycero-3-phosphocholineDPC DodecylphosphocholineDPPC 1,2-Dipalmitoyl-sn-glycero-3-phosphocholineLDAO Lauryldimethylamine-oxidePC PhosphatidylcholinePE PhosphatidylethanolaminePI PhosphatidylinositolPOPC 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholinePOPG 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerolPOPS 1-Palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serinePS PhosphatidylserinePtdIns(3,4,5)P3 Phosphatidylinositol (3,4,5)-triphosphatePtdIns(3,4)P2 Phosphatidylinositol (4,5)-bisphosphatePtdIns(4,5)P2 Phosphatidylinositol (4,5)-bisphosphatePtdIns(4)P Phosphatidylinositol 4-monophosphateSM Sphingomyelin

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