Research Progress in Accurate Mass Spectrometry-Based Measurement Methods for Lipid Fine Structure
-
摘要: 脂质是细胞内的重要功能生物分子,其数量庞大,种类繁多,且具有结构多样性。近年来,许多学者致力于脂质精细结构的准确测量,以期发现新型脂质分子(群)作为疾病标志物或开展功能研究。脂质标准物质在脂质的定性定量中发挥着重要作用,但由于脂质精细结构的多样性,其制备和定值都不是一件易事。质谱具有强大的化合物结构精准测量能力,在脂质精细结构测量领域备受关注。脂质精细结构质谱分析方法在近年来取得迅速发展,为人们提供了脂质分子研究新视角,加深了人们对脂质结构多样性和脂质代谢网络的认识,也推动了潜在疾病标志物和代谢通路的发现。目前,基于质谱的脂质精细结构测量方法主要采用新型的离子活化裂解和特异性化学衍生两种策略,实现了多种脂质精细结构异构体有效区分和准确测量。对近年来基于上述原理的质谱测量方法进行了归纳及评述,并对未来脂质标准物质的研制进行了展望。Abstract: Lipids are essential functional biomolecules within cells, characterized by their abundant quantities, diverse species, and versatile structures. In recent years, numerous scholars have devoted efforts to developing advanced techniques for the accurate characterization of lipid fine structures, aiming to identify novel lipid molecules as disease biomarkers and for lipid functional research. Lipid reference materials play important roles in the qualitative and quantitative analysis of lipids, but due to the diversity of lipid fine structures, their preparation and quantification are challenging tasks. Mass spectrometry (MS), renowned for its robust capability in accurate compound structure measurement, has gained significant attention in the field of lipid fine structure characterization. MS-based analytical methods for lipid fine structure analysis have rapidly progressed, offering a novel perspective for lipid study, deepening our understanding of lipid structural diversity and the lipid metabolic network. Moreover, these methods have propelled the screening of potential disease biomarkers and the discovery of new metabolic pathways. Currently, MS-based analytical methods for accurate lipid fine structure measurement primarily employ two strategies: novel ion activation/dissociation methods and specific chemical derivatization. These approaches demonstrate excellent analytical performance for a variety of lipid fine structure isomers. This review summarizes the MS-based analytical methods for lipid fine structure and provides an outlook on their applications in the preparation of lipid reference materials.
-
Key words:
- metrology /
- lipids /
- reference materials /
- fine structure /
- mass spectrometry /
- accurate measurement methods
-
图 2 基于OzID的脂质C=C位置测量原理示意图[13]
Figure 2. Schematic diagram illustrating the principle of OzID for measuring lipid C=C location
图 3 脂质C=C位置异构体的HCD谱图和UVPD谱图对比[28]
Figure 3. Comparison of HCD and UVPD MS spectra of lipid C=C location isomers
图 4 PB光化学衍生用于脂质C=C位置异构体准确测量[40]
Figure 4. PB photochemical derivatization used for the accurate measurement of lipid C=C location isomers
图 5 环氧化反应用于脂质 C=C 位置异构体准确测量[50]
Figure 5. The epoxidation reaction used for the accurate measurement of lipid C=C location isomers
-
[1] MEIER U, GRESSNER A M. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin[J]. Clinical Chemistry, 2004, 50(9): 1511-1525. doi: 10.1373/clinchem.2004.032482 [2] LINGWOOD D, SIMONS K. Lipid rafts as a membrane-organizing principle[J]. Science, 2010, 327(5961): 46-50. doi: 10.1126/science.1174621 [3] WYMANN M P, SCHNEITER R. Lipid signalling in disease[J]. Nature Reviews Molecular Cell Biology, 2008, 9(2): 162-176. doi: 10.1038/nrm2335 [4] FAHY E, COTTER D, SUD M, et al. Lipid classification, structures and tools[J]. Biochimica Et Biophysica Acta, 2011, 1811(11): 637-647. doi: 10.1016/j.bbalip.2011.06.009 [5] LIEBISCH G, FAHY E, AOKI J, et al. Update on lipid maps classification, nomenclature, and shorthand notation for ms-derived lipid structures[J]. Journal of Lipid Research, 2020, 61(12): 1539-1555. doi: 10.1194/jlr.S120001025 [6] WENK M R. Lipidomics: new tools and applications[J]. Cell, 2010, 143(6): 888-895. doi: 10.1016/j.cell.2010.11.033 [7] ZHANG W, JIAN R, ZHAO J, et al. Deep-lipidotyping by mass spectrometry: recent technical advances and applications[J]. Journal of Lipid Research, 2022, 63(7): 100219. doi: 10.1016/j.jlr.2022.100219 [8] MA X, ZHANG W, LI Z, et al. Enabling high structural specificity to lipidomics by coupling photochemical derivatization with tandem mass spectrometry[J]. Accounts of Chemical Research, 2021, 54(20): 3873-3882. doi: 10.1021/acs.accounts.1c00419 [9] SCHWUDKE D, SCHUHMANN K, HERZOG R, et al. Shotgun lipidomics on high resolution mass spectrometers[J]. Cold Spring Harbor Perspectives in Biology, 2011, 3(9): a004614. [10] BRÜGGER B. Lipidomics: analysis of the lipid composition of cells and subcellular organelles by electrospray ionization mass spectrometry[J]. Annual Review of Biochemistry, 2014, 83: 79-98. doi: 10.1146/annurev-biochem-060713-035324 [11] BRÜGGER B, ERBEN G, SANDHOFF R, et al. Quantitative analysis of biological membrane lipids at the low picomole level by nano-electrospray ionization tandem mass spectrometry[J]. Proceedings of the National Academy of Sciences of the United States of America, 1997, 94(6): 2339-2344. [12] PULFER M, MURPHY R C. Electrospray mass spectrometry of phospholipids[J]. Mass Spectrometry Reviews, 2003, 22(5): 332-364. doi: 10.1002/mas.10061 [13] THOMAS M C, MITCHELL T W, HARMAN D G, et al. Ozone-induced dissociation: elucidation of double bond position within mass-selected lipid ions[J]. Analytical Chemistry, 2008, 80(1): 303-311. doi: 10.1021/ac7017684 [14] THOMAS M C, MITCHELL T W, HARMAN D G, et al. Elucidation of double bond position in unsaturated lipids by ozone electrospray ionization mass spectrometry[J]. Analytical Chemistry, 2007, 79(13): 5013-5022. doi: 10.1021/ac0702185 [15] THOMAS M C, MITCHELL T W, BLANKSBY S J. Ozonolysis of phospholipid double bonds during electrospray ionization: a new tool for structure determination[J]. Journal of the American Chemical Society, 2006, 128(1): 58-59. doi: 10.1021/ja056797h [16] HARRIS R A, MAY J C, STINSON C A, et al. Determining double bond position in lipids using online ozonolysis coupled to liquid chromatography and ion mobility-mass spectrometry[J]. Analytical Chemistry, 2018, 90(3): 1915-1924. doi: 10.1021/acs.analchem.7b04007 [17] STINSON C A, ZHANG W, XIA Y. UV lamp as a facile ozone source for structural analysis of unsaturated lipids via electrospray ionization-mass spectrometry[J]. Journal of the American Society for Mass Spectrometry, 2018, 29(3): 481-489. doi: 10.1007/s13361-017-1861-2 [18] ZHANG J I, TAO W A, COOKS R G. Facile determination of double bond position in unsaturated fatty acids and esters by low temperature plasma ionization mass spectrometry[J]. Analytical Chemistry, 2011, 83(12): 4738-4744. doi: 10.1021/ac1030946 [19] POAD B L J, PHAM H T, THOMAS M C, et al. Ozone-induced dissociation on a modified tandem linear ion-trap: observations of different reactivity for isomeric lipids[J]. Journal of the American Society for Mass Spectrometry, 2010, 21(12): 1989-1999. doi: 10.1016/j.jasms.2010.08.011 [20] YOUNG R S E, CLAES B S R, BOWMAN A P, et al. Isomer-resolved imaging of prostate cancer tissues reveals specific lipid unsaturation profiles associated with lymphocytes and abnormal prostate epithelia[J]. Frontiers in Endocrinology, 2021, 12: 689600. doi: 10.3389/fendo.2021.689600 [21] YOUNG R S E, BOWMAN A P, WILLIAMS E D, et al. Apocryphal fads2 activity promotes fatty acid diversification in cancer[J]. Cell Reports, 2021, 34(6): 108738. doi: 10.1016/j.celrep.2021.108738 [22] POAD B L J, MARSHALL D L, HARAZIM E, et al. Combining charge-switch derivatization with ozone-induced dissociation for fatty acid analysis[J]. Journal of the American Society for Mass Spectrometry, 2019, 30(10): 2135-2143. doi: 10.1007/s13361-019-02285-5 [23] LIU X, JIAO B, CAO W, et al. Development of a miniature mass spectrometry system for point-of-care analysis of lipid isomers based on ozone-induced dissociation[J]. Analytical Chemistry, 2022, 94(40): 13944-13950. doi: 10.1021/acs.analchem.2c03112 [24] BRODBELT J S, MORRISON L J, SANTOS I. Ultraviolet photodissociation mass spectrometry for analysis of biological molecules[J]. Chemical Reviews, 2020, 120(7): 3328-3380. doi: 10.1021/acs.chemrev.9b00440 [25] PHAM H T, JULIAN R R. Mass shifting and radical delivery with crown ether attachment for separation and analysis of phosphatidylethanolamine lipids[J]. Analytical Chemistry, 2014, 86(6): 3020-3027. doi: 10.1021/ac403754j [26] PHAM H T, LY T, TREVITT A J, et al. Differentiation of complex lipid isomers by radical-directed dissociation mass spectrometry[J]. Analytical Chemistry, 2012, 84(17): 7525-7532. doi: 10.1021/ac301652a [27] PHAM H T, TREVITT A J, MITCHELL T W, et al. Rapid differentiation of isomeric lipids by photodissociation mass spectrometry of fatty acid derivatives: photodissociation of derivatized fatty acids[J]. Rapid Communications in Mass Spectrometry, 2013, 27(7): 805-815. doi: 10.1002/rcm.6503 [28] KLEIN D R, BRODBELT J S. Structural characterization of phosphatidylcholines using 193 nm ultraviolet photodissociation mass spectrometry[J]. Analytical Chemistry, 2017, 89(3): 1516-1522. doi: 10.1021/acs.analchem.6b03353 [29] MACIAS L A, FEIDER C L, EBERLIN L S, et al. Hybrid 193 nm ultraviolet photodissociation mass spectrometry localizes cardiolipin unsaturations[J]. Analytical Chemistry, 2019, 91(19): 12509-12516. doi: 10.1021/acs.analchem.9b03278 [30] WILLIAMS P E, KLEIN D R, GREER S M, et al. Pinpointing double bond and sn -positions in glycerophospholipids via hybrid 193 nm ultraviolet photodissociation (uvpd) mass spectrometry[J]. Journal of the American Chemical Society, 2017, 139(44): 15681-15690. doi: 10.1021/jacs.7b06416 [31] KLEIN D R, FEIDER C L, GARZA K Y, et al. Desorption electrospray ionization coupled with ultraviolet photodissociation for characterization of phospholipid isomers in tissue sections[J]. Analytical Chemistry, 2018, 90(17): 10100-10104. doi: 10.1021/acs.analchem.8b03026 [32] FANG M, RUSTAM Y, PALMIERI M, et al. Evaluation of ultraviolet photodissociation tandem mass spectrometry for the structural assignment of unsaturated fatty acid double bond positional isomers[J]. Analytical and Bioanalytical Chemistry, 2020, 412(10): 2339-2351. doi: 10.1007/s00216-020-02446-6 [33] CODY R B, FREISER B S. Electron impact excitation of ions from organics: an alternative to collision induced dissociation[J]. Analytical Chemistry, 1979, 51(4): 547-551. doi: 10.1021/ac50040a022 [34] CODY R B, FREISER B S. Electron impact excitation of ions in fourier transform mass spectrometry[J]. Analytical Chemistry, 1987, 59(7): 1054-1056. doi: 10.1021/ac00134a026 [35] CHEN X, WANG Z, WONG Y-L E, et al. Electron-ion reaction-based dissociation: a powerful ion activation method for the elucidation of natural product structures[J]. Mass Spectrometry Reviews, 2018, 37(6): 793-810. doi: 10.1002/mas.21563 [36] JONES J W, THOMPSON C J, CARTER C L, et al. Electron-induced dissociation (eid) for structure characterization of glycerophosphatidylcholine: determination of double-bond positions and localization of acyl chains[J]. Journal of Mass Spectrometry, 2015, 50(12): 1327-1339. doi: 10.1002/jms.3698 [37] CAMPBELL J L, BABA T. Near-complete structural characterization of phosphatidylcholines using electron impact excitation of ions from organics[J]. Analytical Chemistry, 2015, 87(11): 5837-5845. doi: 10.1021/acs.analchem.5b01460 [38] BÜCHI G, INMAN C G, LIPINSKY E S. Light-catalyzed organic reactions. i. the reaction of carbonyl compounds with 2-methyl-2-butene in the presence of ultraviolet light[J]. Journal of the American Chemical Society, 1954, 76(17): 4327-4331. doi: 10.1021/ja01646a024 [39] MA X, XIA Y. Pinpointing double bonds in lipids by paternò-büchi reactions and mass spectrometry[J]. Angewandte Chemie International Edition, 2014, 53(10): 2592-2596. doi: 10.1002/anie.201310699 [40] MA X, CHONG L, TIAN R, et al. Identification and quantitation of lipid c=c location isomers: a shotgun lipidomics approach enabled by photochemical reaction[J]. Proceedings of the National Academy of Sciences, 2016, 113(10): 2573-2578. doi: 10.1073/pnas.1523356113 [41] MA X, ZHAO X, LI J, et al. Photochemical tagging for quantitation of unsaturated fatty acids by mass spectrometry[J]. Analytical Chemistry, 2016, 88(18): 8931-8935. doi: 10.1021/acs.analchem.6b02834 [42] ZHANG W, ZHANG D, CHEN Q, et al. Online photochemical derivatization enables comprehensive mass spectrometric analysis of unsaturated phospholipid isomers[J]. Nature Communications, 2019, 10(1): 79. doi: 10.1038/s41467-018-07963-8 [43] ZHAO J, XIE X, LIN Q, et al. Next-generation paternò-büchi reagents for lipid analysis by mass spectrometry[J]. Analytical Chemistry, 2020, 92(19): 13470-13477. doi: 10.1021/acs.analchem.0c02896 [44] WÄLDCHEN F, BECHER S, ESCH P, et al. Selective phosphatidylcholine double bond fragmentation and localisation using paternò–büchi reactions and ultraviolet photodissociation[J]. The Analyst, 2017, 142(24): 4744-4755. doi: 10.1039/C7AN01158J [45] WÄLDCHEN F, MOHR F, WAGNER A H, et al. Multifunctional reactive maldi matrix enabling high-lateral resolution dual polarity ms imaging and lipid c=c position-resolved ms 2 imaging[J]. Analytical Chemistry, 2020, 92(20): 14130-14138. doi: 10.1021/acs.analchem.0c03150 [46] ESCH P, HEILES S. Charging and charge switching of unsaturated lipids and apolar compounds using paternò-büchi reactions[J]. Journal of the American Society for Mass Spectrometry, 2018, 29(10): 1971-1980. doi: 10.1007/s13361-018-2023-x [47] LI H-F, CAO W, MA X, et al. Visible-light-driven [2 + 2] photocycloadditions between benzophenone and c═c bonds in unsaturated lipids[J]. Journal of the American Chemical Society, 2020, 142(7): 3499-3505. doi: 10.1021/jacs.9b12120 [48] FENG G, HAO Y, WU L, et al. A visible-light activated [2 + 2] cycloaddition reaction enables pinpointing carbon-carbon double bonds in lipids[J]. Chemical Science, 2020, 11(27): 7244-7251. doi: 10.1039/D0SC01149E [49] BEDNAŘÍK A, BÖLSKER S, SOLTWISCH J, et al. An on-tissue paternò-büchi reaction for localization of carbon-carbon double bonds in phospholipids and glycolipids by matrix-assisted laser-desorption-ionization mass-spectrometry imaging[J]. Angewandte Chemie International Edition, 2018, 57(37): 12092-12096. doi: 10.1002/anie.201806635 [50] GUO X, CAO W, FAN X, et al. Tandem mass spectrometry imaging enables high definition for mapping lipids in tissues[J]. Angewandte Chemie International Edition, 2023, 62(9): e202214804. doi: 10.1002/anie.202214804 [51] ZHAO Y, ZHAO H, ZHAO X, et al. Identification and quantitation of c═c location isomers of unsaturated fatty acids by epoxidation reaction and tandem mass spectrometry[J]. Analytical Chemistry, 2017, 89(19): 10270-10278. doi: 10.1021/acs.analchem.7b01870 [52] CAO W, MA X, LI Z, et al. Locating carbon–carbon double bonds in unsaturated phospholipids by epoxidation reaction and tandem mass spectrometry[J]. Analytical Chemistry, 2018, 90(17): 10286-10292. doi: 10.1021/acs.analchem.8b02021 [53] ZHAO X, ZHAO Y, ZHANG L, et al. Rapid analysis of unsaturated fatty acids on paper-based analytical devices via online epoxidation and ambient mass spectrometry[J]. Analytical Chemistry, 2018, 90(3): 2070-2078. doi: 10.1021/acs.analchem.7b04312 [54] FENG Y, CHEN B, YU Q, et al. Identification of double bond position isomers in unsaturated lipids by m-cpba epoxidation and mass spectrometry fragmentation[J]. Analytical Chemistry, 2019, 91(3): 1791-1795. doi: 10.1021/acs.analchem.8b04905 [55] KUO T-H, CHUNG H-H, CHANG H-Y, et al. Deep lipidomics and molecular imaging of unsaturated lipid isomers: a universal strategy initiated by mcpba epoxidation[J]. Analytical Chemistry, 2019, 91(18): 11905-11915. doi: 10.1021/acs.analchem.9b02667 [56] SONG C, GAO D, LI S, et al. Determination and quantification of fatty acid c=c isomers by epoxidation reaction and liquid chromatography-mass spectrometry[J]. Analytica Chimica Acta, 2019, 1086: 82-89. doi: 10.1016/j.aca.2019.08.023 [57] LUO K, CHEN H, ZARE R N. Location of carbon-carbon double bonds in unsaturated lipids using microdroplet mass spectrometry[J]. The Analyst, 2021, 146(8): 2550-2558. doi: 10.1039/D0AN02396E [58] WAN L, GONG G, LIANG H, et al. In situ analysis of unsaturated fatty acids in human serum by negative-ion paper spray mass spectrometry[J]. Analytica Chimica Acta, 2019, 1075: 120-127. doi: 10.1016/j.aca.2019.05.055 [59] TANG S, CHENG H, YAN X. On-demand electrochemical epoxidation in nano-electrospray ionization mass spectrometry to locate carbon-carbon double bonds[J]. Angewandte Chemie (International Ed. in English), 2020, 59(1): 209-214. doi: 10.1002/anie.201911070 [60] TANG S, FAN L, CHENG H, et al. Incorporating electro-epoxidation into electrospray ionization mass spectrometry for simultaneous analysis of negatively and positively charged unsaturated glycerophospholipids[J]. Journal of the American Society for Mass Spectrometry, 2021, 32(9): 2288-2295. doi: 10.1021/jasms.0c00356 [61] CAO W, CHENG S, YANG J, et al. Large-scale lipid analysis with c=c location and sn-position isomer resolving power[J]. Nature Communications, 2020, 11(1): 375. doi: 10.1038/s41467-019-14180-4