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Derivatization Techniques in Mass Spectrometry: Unlocking the Low-Abundance Metabolome
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Derivatization Techniques in Mass Spectrometry: Unlocking the Low-Abundance Metabolome

A Special Issue of Metabolites (ISSN 2218-1989) belonging to the section "Metabolomic Profiling Technology".

Deadline for manuscript submissions: 20 November 2026 | Viewed by 1633

Editors

Prof. Dr. Yuqi Feng

E-Mail Website
Guest Editor
School of Biomedical Engineering and Health, Wuhan Textile University, Wuhan 430200, China
Interests: separation and analysis technologies; novel mass spectrometry-based metabolomics analysis methods; sub-metabolome database construction; chromatography-mass spectrometry analysis; metabolomics
Prof. Dr. Quanfei Zhu

E-Mail Website
Guest Editor
School of Biomedical Engineering and Health, Wuhan Textile University, Wuhan 430200, China
Interests: separation and analysis technologies; novel mass spectrometry-based metabolomics analysis methods; sub-metabolome database construction; chromatography–mass spectrometry analysis; metabolomics

Special Issue Information

Dear Colleagues,

The comprehensive characterization of the metabolome remains a significant challenge, particularly for low-abundance metabolites that often possess critical biological functions but suffer from poor ionization efficiency or low concentrations in complex matrices. This Special Issue, titled "Derivatization Techniques in Mass Spectrometry: Unlocking the Low-Abundance Metabolome," aims to highlight recent advancements in chemical derivatization and probe-based strategies designed to overcome these analytical barriers.

We invite researchers to submit original articles, reviews, and method developments focusing on novel tagging reagents, isotope-coded probes, and affinity enrichment strategies that enhance detection sensitivity, selectivity, and structural elucidation in mass spectrometry. Topics of interest include, but are not limited to, the following:

  • Design and synthesis of new MS probes for specific functional groups (e.g., amines, carboxyls, carbonyls).
  • Strategies to improve ionization efficiency and chromatographic behavior.
  • Applications of derivatization in targeted and untargeted metabolomics for biomarker discovery.
  • Integration of chemical labeling with advanced MS platforms.
  • Quantitative metabolomics using stable isotope-labeled probes.

By showcasing cutting-edge methodologies and their applications in biology, medicine, and environmental science, this issue seeks to provide a comprehensive overview of how derivatization techniques are reshaping our ability to explore the "dark matter" of the metabolome.

Prof. Dr. Yuqi Feng
Prof. Dr. Quanfei Zhu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chemical derivatization
  • mass spectrometry probes
  • low-abundance metabolites

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Published Papers (3 papers)

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Research

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24 pages, 33615 KB  
Article
Spatial Metabolomics Reveals Microregion-Specific Neurochemical Perturbations in the Brains of PCPA-Induced Insomniac Rats: Integration of MALDI-MSI and Targeted LC-MS/MS
by Yan Yan, Jiaying Liu, Yingjian Deng, Yu Tao, Xinxin Li, Chenhui Du, Kun Yang and Ruiping Zhang
Metabolites 2026, 16(8), 543; https://doi.org/10.3390/metabo16080543 - 31 Jul 2026
Viewed by 446
Abstract
Objectives: Insomnia is a highly prevalent sleep disorder involving complex neurochem-ical dysregulation; however, the spatial distribution of neurotransmitters and small-molecule metabolites across distinct brain microregions in the insomniac state re-mains poorly characterized. This study aimed to map region-specific metabolic perturba-tions in situ in [...] Read more.
Objectives: Insomnia is a highly prevalent sleep disorder involving complex neurochem-ical dysregulation; however, the spatial distribution of neurotransmitters and small-molecule metabolites across distinct brain microregions in the insomniac state re-mains poorly characterized. This study aimed to map region-specific metabolic perturba-tions in situ in a p-chlorophenylalanine (PCPA)-induced insomnia rat model using opti-mized matrix-assisted laser desorption/ionization mass spectrometry imaging (MAL-DI-MSI) integrated with targeted metabolomics validation. Methods: On-tissue chemical derivatization MALDI-MSI was optimized using α-cyano-4-hydroxycinnamic acid (CHCA) as the matrix on a Bruker tims TOF flex mass spectrometer. The rats received PCPA (400 mg/kg, intraperitoneal) for three days to establish the insomnia model. Metabolite identifi-cation was conducted using MetaboScape® software (2020b) and the Human Metabolome Database. Ultra-performance liquid chromatography–tandem mass spectrometry was em-ployed to quantify nine key neurotransmitters and metabolites across six brain microre-gions. Key synthetic enzyme expression was evaluated by immunofluorescence and West-ern blotting analyses. Results: TMP-TFB-derived brain slices clearly showed the distribu-tion of neurotransmitters in brain microregions. MALDI-MSI demonstrated that the spatial distribution and abundance of eight neurotransmitters were disturbed in brains of PCPA-induced insomniac rats. A total of 346 metabolites were characterized across six brain microregions (cerebellum, cortex, hippocampus, brainstem, hypothalamus, and stri-atum), with principal coordinate analysis revealing clear metabolic separation between control and insomniac rats. PCPA treatment markedly disrupted tryptophan and tyrosine metabolism, evidenced by decreased 5-HT, 5-HTP, and 5-HIAA, alongside region-specific alterations in DA, NE, HVA, and Ach. Additionally, GABA levels decreased in the hippo-campus, striatum, and hypothalamus, whereas glutamate increased throughout the brain. Targeted metabolomics validated the MSI findings, and Bland–Altman analysis confirmed good consistency between the two analytical platforms. PCPA further disturbed the meta-bolic enzymes MAOA, DDC, and TPH2 within the Trp-5-HTP-5-HT-5-HIAA metabolic pathway in the brainstem and TYH and DBA within the tyrosine-DA-NE metabolic pathway in the striatum. Conclusions: This study demonstrates that region-specific altera-tions in tryptophan and tyrosine metabolism pathways provide mechanistic insights into insomnia pathogenesis and potential therapeutic targets. Full article
(This article belongs to the Special Issue Derivatization Techniques in Mass Spectrometry: Unlocking the Low-Abundance Metabolome)
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14 pages, 3480 KB  
Article
Iodoacetamine-Alkyne Derivatization-Based Liquid Chromatography–Mass Spectrometry Method for Quantification of Thiol Metabolites in Serum Samples of Hepatocellular Carcinoma Patients
by Chun Mei, Xin-Ze Wu, Hua-Ming Xiao, Azamat Temerdashev, Na An, Quan-Fei Zhu and Yu-Qi Feng
Metabolites 2026, 16(5), 345; https://doi.org/10.3390/metabo16050345 - 20 May 2026
Viewed by 610
Abstract
Background/Objectives: The dysregulation of thiol metabolites is strongly linked to hepatocellular carcinoma (HCC) pathogenesis. However, quantifying these highly polar and oxidation-prone thiols in clinical serum samples via conventional liquid chromatography–mass spectrometry (LC-MS) remains challenging due to their poor sensitivity and reproducibility. Methods [...] Read more.
Background/Objectives: The dysregulation of thiol metabolites is strongly linked to hepatocellular carcinoma (HCC) pathogenesis. However, quantifying these highly polar and oxidation-prone thiols in clinical serum samples via conventional liquid chromatography–mass spectrometry (LC-MS) remains challenging due to their poor sensitivity and reproducibility. Methods: We developed a sensitive and robust iodoacetamine-alkyne (IAM) derivatization–based LC-MS method for quantification of seven trans-sulfuration pathway thiols in human serum. Results: IAM derivatization markedly improved the method’s specificity due to enhanced chromatographic retention and diagnostic MS/MS fragments containing both the alkyne tag and analyte backbone. Sensitivity increased 33-to-160-fold versus underivatized analytes, with limits of detection of 0.02–0.1 nM. All analytes exhibited good linearity, acceptable precision with intra-day and inter-day relative standard deviations in the range of 1.2–13.8%, and high recovery from 88.6% to 102.9%. Conclusions: From the thiol quantification in human serum from 40 HCC patients and 40 healthy controls, it was found that levels of cysteine, homocysteine, glutathione, and cysteinylglycine were significantly lower in HCC patients (p < 0.05). A two-variable logistic regression model using cysteine and cysteinylglycine achieved 90.0% specificity and 80.0% sensitivity for robust HCC discrimination between HCC patients and healthy controls to some extent, with an area under the receiver operating characteristic curve of 0.88 (95% confidence interval: 0.792–0.968). Full article
(This article belongs to the Special Issue Derivatization Techniques in Mass Spectrometry: Unlocking the Low-Abundance Metabolome)
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Review

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21 pages, 2007 KB  
Review
Chemical Derivatization Strategies for Expanding Small Biomolecule Analysis by MALDI-MS
by Xintong Hu, Qinxue Wang, Yingying Lin and Jingjing Wan
Metabolites 2026, 16(9), 654; https://doi.org/10.3390/metabo16090654 - 7 Sep 2026
Viewed by 153
Abstract
Small biomolecules provide important information on cellular metabolism, signaling and disease-associated molecular changes. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) enables rapid, high-throughput and spatially resolved molecular analysis, but its application to small biomolecules is often limited by poor ionization, low-mass background interference, ion [...] Read more.
Small biomolecules provide important information on cellular metabolism, signaling and disease-associated molecular changes. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) enables rapid, high-throughput and spatially resolved molecular analysis, but its application to small biomolecules is often limited by poor ionization, low-mass background interference, ion suppression and insufficient structural information. To address these analytical challenges, this review summarizes chemical derivatization strategies that improve MALDI-MS analysis of small biomolecules. The representative strategies are discussed according to reaction mode and target functional group, including solution-phase, on-target, on-tissue, reactive-matrix-assisted and photo-/in-source approaches, with emphasis on amine-, carbonyl-, carboxyl- and double-bond-containing biomolecules. Chemical derivatization improves MALDI-MS performance by selectively modifying target functional groups, introducing charged or ionizable tags, enhancing molecular discrimination and providing additional structural information. These strategies have expanded the detection and annotation of neuroactive amines, carbonyl compounds, glycans, carboxylic acid metabolites and lipid double-bond isomers, while also extending MALDI-MS analysis to other specific functional groups, natural products and drug-related molecules. Overall, chemical derivatization is an important approach for improving the sensitivity, selectivity, structural annotation and analytical coverage of MALDI-MS-based small biomolecule analysis. Future developments should further address reaction selectivity, spatial fidelity, quantitative reliability and confident identification of derivatization products. Full article
(This article belongs to the Special Issue Derivatization Techniques in Mass Spectrometry: Unlocking the Low-Abundance Metabolome)
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