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化学进展 2021, Vol. 33 Issue (3): 406-416 DOI: 10.7536/PC200555 前一篇   后一篇

• 综述 •

化学衍生用于代谢物异构体质谱分析

王子璇1, 厉欣1,*(), 再帕尔·阿不力孜1,2   

  1. 1 中国医学科学院/北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室 北京 100050
    2 中央民族大学生物成像与系统生物学研究中心 北京 100081
  • 收稿日期:2020-05-22 修回日期:2020-08-01 出版日期:2021-03-20 发布日期:2020-09-30
  • 通讯作者: 厉欣
  • 作者简介:
    * Corresponding author e-mail:
  • 基金资助:
    国家自然科学基金项目(21927808); 中国医学科学院医学与健康科技创新工程协同创新团队项目(2017-I2M-3-010)
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Chemical Derivatization for Mass Spectrometric Analysis of Metabolite Isomers

Zixuan Wang1, Xin Li1,*(), Zeper Abliz1,2   

  1. 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050, China
    2 Center for Imaging and Systems Biology, Minzu University of China,Beijing 100081, China
  • Received:2020-05-22 Revised:2020-08-01 Online:2021-03-20 Published:2020-09-30
  • Contact: Xin Li
  • Supported by:
    the National Natural Science Foundation of China(21927808); the Medical Science and Health Technology Innovation Project of Chinese Academy of Medical Sciences(2017-I2M-3-010)

内源性代谢物是机体生命活动的中间体和终产物,对其进行定性和定量分析在生命科学研究中具有重要意义。质谱能够同时提供化合物的定性和定量信息,已经成为一种通用的内源性代谢物分析技术。由于质谱是通过检测离子质荷比获取化合物组成信息,区分生物体内复杂多样代谢物同分异构体仍然是质谱分析亟待解决的难题之一。化学衍生通过放大同分异构体理化性质差异,能够增强质谱检测的灵敏度和特异性。本文介绍了化学衍生用于代谢物异构体质谱检测的研究进展,对用于脂质、糖类和手性氨基酸等精细结构异构体的化学衍生质谱分析方法及应用进行了综述。特别强调了微液滴化学反应加速在衍生化质谱分析中的发展,其有望成为代谢物实时原位衍生化检测的新方法。此外,将生物组织原位衍生化与质谱成像分析技术相结合,对于研究低丰度、非极性和异构体代谢物的空间分布及其功能具有重要价值。

关键词： 质谱分析, 化学衍生, 异构体, 代谢物分析, 反应质谱

Being the intermediates and final products of life metabolic activities, endogenous metabolites precisely mirror metabolic changes in vivo, providing clues for the study of diseases and other life processes. Mass spectrometry has become a universal technique for qualitative and quantitative analysis of endogenous metabolites, with high sensitivity, high specificity and wide dynamic range. However, it remains a limitation on the detection and differentiation of subtle structural differences of metabolite isomers in heterogeneous biological tissue using mass spectrometry. Therefore, how to improve sensitivity and specificity of mass spectrometry needs to be solved in the study of metabolite isomers’ analysis. Chemical derivatization takes advantage of bringing high proton affinity groups, hydrophobicity or chiral selectors to desired analytes, which is expected to broaden the applications of mass spectrometry for analysis of metabolite isomers. In this review, advances in chemical derivatization-based mass spectrometric analysis of metabolic isomers are summarized, including(1) reaction approaches and(2) methods and applications of lipids, carbohydrates and chiral amino acids. Special emphasis is placed on on-line derivatization microdroplet accelerate reaction by mass spectrometry, in which chemical derivatization of analytes occurring simultaneously with spray ionization, providing a promising way for instant and in-situ metabolite derivatization. The emerging study of on-tissue derivatization mass spectrometry imaging is of great value for providing spatial distribution of low abundance, non-polar and isomer metabolites. In the second part, different approach of detailed structural characterization of various compound classes are discussed, with a focus on lipids, carbohydrates and chiral amino acids.

Contents

1 Introduction

2 Chemical derivatization for mass spectrometric analysis of metabolites

2.1 Online chemical derivatization of metabolites

2.2 Offline chemical derivatization of metabolites

2.3 Chemical derivatization for mass spectrometry imaging of metabolites

3 Chemical derivatization for mass spectrometric analysis of metabolite isomers

3.1 Chemical derivatization for mass spectrometric analysis of lipids

3.2 Chemical derivatization for mass spectrometric analysis of glycans

3.3 Chemical derivatization for mass spectrometric analysis of chiral amino acids

4 Conclusion and outlook

Key words: mass spectrometry analysis, chemical derivatization, isomer, metabolite analysis, reactive mass spectrometry
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图1 在线微液滴加速反应方式: (a)带有传输管的反应电喷雾电离;(b) 反应电喷雾萃取电离;(c) 反应解吸电喷雾电离;(d) 反应纸喷雾电离
Fig.1 Methods applied to cause highly accelerated microdroplet reactions for mass spectrometry, schematic of(a) reactive ESI with a transfer tube,(b) reactive EESI,(c) reactive DESI and (d) reactive paper spray
表1 化学衍生在代谢物质谱分析中的方法和应用
Table 1 Methods and applications of chemical derivatization-based mass spectrometry analysis of metabolites
Reaction mode Analytical method Derivatization reagent Sample ref
Online rDESI-MSI Dication(DC9) Phosphoethanolamines in rat brain and zebra fish tissues 25
Online rDESI、EESI MS Benzeneboronate anions cis/trans-diol isomers 27
Online nanoESI-MS、rDESI-MS Girard T Ketosteroid 34
Online MALDI-MSI O3 Lipid isomers in rat brain 35
Online ESSI-MS M2+、amino acids Reaction chiral enantiomer products 36
Online nanoESI-MSn 2-Acetylpyridine Lipid isomers in human breast cancer cells and lung cancer tissues 37
Online LC-OzID-IMS-MS O3 Lipid isomers in human plasma 38
Online APIMS-TOF MS Ag+, Pb2+, Hg2+,et al. High-mannose 39
Online ESI-DMS-MS BBS Chiral amino acids 40
Online rELDI-MS Dithiothreitol Oxidized glutathione and insulin 41
Online ESI-MS/MS L-amino acids and divalent metal cations Fructose, galactose, and glucose isomers 42
Online IMS-MS Metal ions(Na+, K+, Mg2+, Ca2+) and transition metal ions(Mn2+, Co2+, Fe2+, Ni2+) Heparin octasaccharides 43
Online TWIM-MS Chira slelector(Y) and transition metal ion(CuCl2) Chiral amino acids 44
Online rDESI-MS/MS Hydroxylamine Anabolic steroids in raw urine 24
Online rDESI-MS 3-nitrophenylboronic acid 、N-methyl-4-pyridineboronic acid iodide Saccharides in urine and serum samples 26
Online Micro-thin film-nESI-MS Butylamine、DMEA、DEEA、EDPA、DBPA 29 reducing sugars in single onion epidermis cell 28
Online noncontact nCFI-MS d0-/d5-pyridine Fatty alcohols and sterols in single cell 45
Offline nano LC-MS 12C-/13C DnsCl Amine, phenol, carboxylic, hydroxyl submetabolomes in human breast cancer cells 8
Offline CIL-LC-MS DMED, d4-DMED、HIQB, d7-HIQB、DMAP, d4-DMAP、BQB, d7-BQB Carboxyl, carbonyl, amine, and thiol submetabolomes in mice feces 9
Offline MALDI-MSI Benzaldehyde Lipid db-positional isomers in mouse brain 46
Offline MALDI-MSI DMPI Free fatty acids(FFAs) in thyroid cancer tissues 11
Offline MALDI-TOF-MS DHB/3HBA and DHB/Q3CH N-glycans in blood samples 47
Offline Full scan MS Stereodynamic chiral benzylicaldehyde probes Chiral amino acids residues in peptides 48
Offline HILIC-MALDI-MSI Stable-isotope labeled hydrazide reagents N-glycans in human serum 49
Offline RPLC-MS/MS 12CH3I、13CH3I Neutral glycolipids in mammalian cells 50
Offline nano-HILIC-Orbitrap-MS DMT-MM N-glycans in haptoglobin and human plasma 51
Offline MALDI-TOF-MS DMT-MM α-(2, 3)/ α-(2, 6) Sialic acid in blood serum glycoproteins 52
Offline ESI-MS Butanol Amino acids in serum 19
Offline MALDI-TOF-MS EDC α-(2, 3)/ α-(2, 6) Sialic acid inhuman plasma 53
Offline HPLC-MS/MS Bbromine-isotope probe D-BPBr Chiral amino acids in human biofluid 54
Offline TIMS-TOF MS FLEC Chiral amino acids 55
Offline UPLC-MS/MS,PRM
mode 		d0/d6-DHPP SCFAs and OHeSCFAs in mouse fecal, serum, and liver tissue samples 33
Offline InESI-MS NCBT Cysteine in single cell 56
Offline HPLC-ESI-IM-MS d0-/d5-pyridine and thionyl chloride Fatty alcohols, fatty aldehydes and sterols in thyroid tissues 57
图2 苯甲醛为衍生化试剂的P-B反应-MALDI-2-质谱成像分析小鼠脑切片中的脂质[46]:A)~F)小鼠脑切片PC 36∶1和PS 36∶2db-位置异构体特异性离子的PB-MALDI-2-MS/MS质谱成像图,异构体在小脑白质和灰质区域呈特异性表达;G) MSI分析后除去基质后切片的H&E染色结果;H) PC 36∶1和PS 36∶2 PB反应产物的MS/MS谱图
Fig.2 MALDI-2-MSI of lipids in mouse brain after P-B reaction with benzaldehyde as derivatization reagent[46]. A)~F) PB-MALDI-2-MS/MS images of diagnostic ion pairs representing PC 36∶1 and PS 36∶2 db-positional isomers. For both groups of phospholipids highly differential isomer-specific expression levels are found in the white and gray brain areas of the cerebellum. G) H&E stain of the tissue sections obtained after the MSI analysis and washing of matrix. H) MS/MS spectrum of the PB adducts of PC 36∶1 and PS 36∶2.©2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
图3 MALDI-OzID-MSI分析鼠脑中PC(36∶1) 四个sn-位置异构体(PC(18∶0/18∶1)、PC(18∶1/18∶0)、PC(16∶0/20∶1)和PC(20∶1/16∶0)的(a) MALDI-CID/OZID谱图;(b) [PC(36∶1)+Na]+全扫描FTMS成像图;(c) PC(18∶0/18∶1)/PC(18∶0_18∶1)的质谱成像结果;d) PC(16∶0/20∶1)/PC(16∶0_20∶1) 的质谱成像结果[35]
Fig.3 (a) MALDI-CID/OZID spectrum and(b) full-scan FTMS image of [PC(36∶1)+Na]+ revealing the presence of four distinct sn-positional isomers(PC(18∶0/18∶1), PC(18∶1/18∶0), PC(16∶0/20∶1) and PC(20∶1/16∶0) in rat brain section. The corresponding fractional distribution images of (c) PC(18∶0/18∶1) as a fraction of PC(18∶0_18∶1); and (d) PC(16∶0/20∶1) as a fraction of PC(16∶0_20∶1)-related ions[35].©Wiley-VCH Verlag GmbH & Co. KGaA
图4 (a) 金属离子三聚体配合物手性识别法;(b) 三聚体离子[A(RorS)M2+(ref*)2-H]+的二级质谱结果
Fig.4 (a) Chiral recognition of metal ion-bound complexes;(b) Competitive dissociation MS2 spectrum of metal ion-bound complexes [A(RorS)M2+(ref*)2-H]+
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