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Special Issue "High Resolution Mass Spectrometry in Molecular Sciences"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 March 2021.

Special Issue Editor

Prof. Dr. Laszlo Prokai
Website
Guest Editor
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, Texas 76107, USA
Interests: chemical neuroscience; CNS drug discovery; neurobiochemistry of estrogens; biomedical mass spectrometry; chemical proteomics; omics-driven research in molecular sciences
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

An aspiration for high resolution, accuracy and sensitivity in spectroscopic and spectrometric methods can be paraphrased by the Olympic motto of Citius, Altius, Fortius (faster, higher, stronger). Demands for high mass-resolving power and mass-measurement accuracy, as well as for speedy data acquisition, have been the driving forces toward advances of instrumentation that facilitate the pursuit of challenging applications of mass spectrometry. The introduction of the Fourier transform (FT) approach and the development of the high-resolution time-of-flight (TOF) method of ion sorting have enabled a paradigm shift to meet these challenges. FT ion cyclotron resonance (FT-ICR), Orbitrap and TOF instruments are commercially available in many of today’s mass spectrometers and often in “hybrid” configurations that bring them together seamlessly with other analyzers, such as quadrupoles and ion traps within one instrument. They now deliver superior performance to the delight of the broad scientific community—the masses, when one plays with the multiple meanings of the word. In addition to conventional research articles and reviews, this Special Issue (expanded in breadth from an earlier series of IJMS articles devoted to Fourier transform mass spectrometry) also welcomes commentaries, opinions and perspectives on the progress and applications of high-resolution mass spectrometry in broad areas of the molecular sciences.

Prof. Dr. Laszlo Prokai
Guest Editor

Manuscript Submission Information

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Keywords

  • antibodies
  • astrobiology
  • biomarkers
  • drug discovery
  • drug development
  • drug metabolism
  • Fourier transform
  • glycomics
  • lipids
  • lipidomics
  • mass spectrometry
  • metabolomics
  • nucleic acids
  • Orbitrap
  • organometallics
  • petroleomics
  • polymers
  • peptides
  • proteins
  • proteomics
  • structural biology
  • structure elucidation
  • tandem mass spectrometry
  • time-of-flight

Published Papers (9 papers)

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Research

Open AccessCommunication
Proteomics Complementation of the Rat Uterotrophic Assay for Estrogenic Endocrine Disruptors: A Roadmap of Advancing High Resolution Mass Spectrometry-Based Shotgun Survey to Targeted Biomarker Quantifications
Int. J. Mol. Sci. 2021, 22(4), 1686; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041686 - 08 Feb 2021
Abstract
The widely used rat uterotrophic assay to assess known and potential estrogenic compounds only considers uterine weight gain as endpoint measurement. To complement this method with an advanced technology that reveals molecular targets, we analyzed changes in protein expression using label-free quantitative proteomics [...] Read more.
The widely used rat uterotrophic assay to assess known and potential estrogenic compounds only considers uterine weight gain as endpoint measurement. To complement this method with an advanced technology that reveals molecular targets, we analyzed changes in protein expression using label-free quantitative proteomics by nanoflow liquid chromatography coupled with high-resolution mass spectrometry and tandem mass spectrometry from uterine protein extracts of ovariectomized rats after daily 17β-estradiol exposure for five days in comparison with those of vehicle-treated control animals. Our discovery-driven study revealed 165 uterine proteins significantly regulated by estrogen treatment and mapped by pathway analyses. Estrogen-regulated proteins represented cell death, survival and development, cellular growth and proliferation, and protein synthesis as top molecular and cellular functions, and a network found with the presence of nuclear estrogen receptor(s) as a prominent molecular node confirmed the relevance of our findings to hormone-associated events. An exploratory application of targeted proteomics to bisphenol A as a well-known example of an estrogenic endocrine disruptor is also presented. Overall, the results of this study have demonstrated the power of combining untargeted and targeted quantitative proteomic strategies to identify and verify candidate molecular markers for the evaluation of endocrine-disrupting chemicals to complement a conventional bioassay. Full article
(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)
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Open AccessArticle
Structural Characterization of Daunomycin-Peptide Conjugates by Various Tandem Mass Spectrometric Techniques
Int. J. Mol. Sci. 2021, 22(4), 1648; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041648 - 06 Feb 2021
Abstract
The use of peptide-drug conjugates has generated wide interest as targeted antitumor therapeutics. The anthracycline antibiotic, daunomycin, is a widely used anticancer agent and it is often conjugated to different tumor homing peptides. However, comprehensive analytical characterization of these conjugates via tandem mass [...] Read more.
The use of peptide-drug conjugates has generated wide interest as targeted antitumor therapeutics. The anthracycline antibiotic, daunomycin, is a widely used anticancer agent and it is often conjugated to different tumor homing peptides. However, comprehensive analytical characterization of these conjugates via tandem mass spectrometry (MS/MS) is challenging due to the lability of the O-glycosidic bond and the appearance of MS/MS fragment ions with little structural information. Therefore, we aimed to investigate the optimal fragmentation conditions that suppress the prevalent dissociation of the anthracycline drug and provide good sequence coverage. In this study, we comprehensively compared the performance of common fragmentation techniques, such as higher energy collisional dissociation (HCD), electron transfer dissociation (ETD), electron-transfer higher energy collisional dissociation (EThcD) and matrix-assisted laser desorption/ionization–tandem time-of-flight (MALDI-TOF/TOF) activation methods for the structural identification of synthetic daunomycin-peptide conjugates by high-resolution tandem mass spectrometry. Our results showed that peptide backbone fragmentation was inhibited by applying electron-based dissociation methods to conjugates, most possibly due to the “electron predator” effect of the daunomycin. We found that efficient HCD fragmentation was largely influenced by several factors, such as amino acid sequences, charge states and HCD energy. High energy HCD and MALDI-TOF/TOF combined with collision induced dissociation (CID) mode are the methods of choice to unambiguously assign the sequence, localize different conjugation sites and differentiate conjugate isomers. Full article
(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)
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Open AccessArticle
Mass Spectral Filtering by Mass-Remainder Analysis (MARA) at High Resolution and Its Application to Metabolite Profiling of Flavonoids
Int. J. Mol. Sci. 2021, 22(2), 864; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020864 - 16 Jan 2021
Abstract
Flavonoids represent an important class of secondary metabolites because of their potential health benefits and functions in plants. We propose a novel method for the comprehensive flavonoid filtering and screening based on direct infusion mass spectrometry (DIMS) analysis. The recently invented data mining [...] Read more.
Flavonoids represent an important class of secondary metabolites because of their potential health benefits and functions in plants. We propose a novel method for the comprehensive flavonoid filtering and screening based on direct infusion mass spectrometry (DIMS) analysis. The recently invented data mining procedure, the multi-step mass-remainder analysis (M-MARA) technique is applied for the effective mass spectral filtering of the peak rich spectra of natural herb extracts. In addition, our flavonoid-filtering algorithm facilitates the determination of the elemental composition. M-MARA flavonoid-filtering uses simple mathematical and logical operations and thus, it can easily be implemented in a regular spreadsheet software. A huge benefit of our method is the high speed and the low demand for computing power and memory that enables the real time application even for tandem mass spectrometric analysis. Our novel method was applied for the electrospray ionization (ESI) DIMS spectra of various herb extract, and the filtered mass spectral data were subjected to chemometrics analysis using principal component analysis (PCA). Full article
(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)
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Open AccessArticle
Application of Safirinium N-Hydroxysuccinimide Esters to Derivatization of Peptides for High-Resolution Mass Spectrometry, Tandem Mass Spectrometry, and Fluorescent Labeling of Bacterial Cells
Int. J. Mol. Sci. 2020, 21(24), 9643; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249643 - 17 Dec 2020
Abstract
Mass spectrometry methods are commonly used in the identification of peptides and biomarkers. Due to a relatively low abundance of proteins in biological samples, there is a need for the development of novel derivatization methods that would improve MS detection limits. Hence, novel [...] Read more.
Mass spectrometry methods are commonly used in the identification of peptides and biomarkers. Due to a relatively low abundance of proteins in biological samples, there is a need for the development of novel derivatization methods that would improve MS detection limits. Hence, novel fluorescent N–hydroxysuccinimide esters of dihydro-[1,2,4]triazolo[4,3-a]pyridin-2-ium carboxylates (Safirinium P dyes) have been synthesized. The obtained compounds, which incorporate quaternary ammonium salt moieties, easily react with aliphatic amine groups of peptides, both in solution and on the solid support; thus, they can be applied for derivatization as ionization enhancers. Safirinium tagging experiments with ubiquitin hydrolysate revealed that the sequence coverage level was high (ca. 80%), and intensities of signals were enhanced up to 8-fold, which proves the applicability of the proposed tags in the bottom–up approach. The obtained results confirmed that the novel compounds enable the detection of trace amounts of peptides, and fixed positive charge within the tags results in high ionization efficiency. Moreover, Safirinium NHS esters have been utilized as imaging agents for fluorescent labeling and the microscopic visualization of living cells such as E. coli Top10 bacterial strain. Full article
(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)
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Open AccessArticle
Compounds with Antiviral, Anti-Inflammatory and Anticancer Activity Identified in Wine from Hungary’s Tokaj Region via High Resolution Mass Spectrometry and Bioinformatics Analyses
Int. J. Mol. Sci. 2020, 21(24), 9547; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249547 - 15 Dec 2020
Abstract
(1) Background: Wine contains a variety of molecules with potential beneficial effects on human health. Our aim was to examine the wine components with high-resolution mass spectrometry including high-resolution tandem mass spectrometry in two wine types made from grapes with or without the [...] Read more.
(1) Background: Wine contains a variety of molecules with potential beneficial effects on human health. Our aim was to examine the wine components with high-resolution mass spectrometry including high-resolution tandem mass spectrometry in two wine types made from grapes with or without the fungus Botrytis cinerea, or “noble rot”. (2) For LC-MS/MS analysis, 12 wine samples (7 without and 5 with noble rotting) from 4 different wineries were used and wine components were identified and quantified. (3) Results: 288 molecules were identified in the wines and the amount of 169 molecules was statistically significantly different between the two wine types. A database search was carried out to find the molecules, which were examined in functional studies so far, with high emphasis on molecules with antiviral, anti-inflammatory and anticancer activities. (4) Conclusions: A comprehensive functional dataset related to identified wine components is also provided highlighting the importance of components with potential health benefits. Full article
(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)
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Open AccessArticle
High-Resolution Mass Spectrometry for In Vivo Proteome Dynamics using Heavy Water Metabolic Labeling
Int. J. Mol. Sci. 2020, 21(21), 7821; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217821 - 22 Oct 2020
Abstract
Cellular proteins are continuously degraded and synthesized. The turnover of proteins is essential to many cellular functions. Combined with metabolic labeling using stable isotopes, LC–MS estimates proteome dynamics in high-throughput and on a large scale. Modern mass spectrometers allow a range of instrumental [...] Read more.
Cellular proteins are continuously degraded and synthesized. The turnover of proteins is essential to many cellular functions. Combined with metabolic labeling using stable isotopes, LC–MS estimates proteome dynamics in high-throughput and on a large scale. Modern mass spectrometers allow a range of instrumental settings to optimize experimental output for specific research goals. One such setting which affects the results for dynamic proteome studies is the mass resolution. The resolution is vital for distinguishing target species from co-eluting contaminants with close mass-to-charge ratios. However, for estimations of proteome dynamics from metabolic labeling with stable isotopes, the spectral accuracy is highly important. Studies examining the effects of increased mass resolutions (in modern mass spectrometers) on the proteome turnover output and accuracy have been lacking. Here, we use a publicly available heavy water labeling and mass spectral data sets of murine serum proteome (acquired on Orbitrap Fusion and Agilent 6530 QToF) to analyze the effect of mass resolution of the Orbitrap mass analyzer on the proteome dynamics estimation. Increased mass resolution affected the spectral accuracy and the number acquired tandem mass spectra. Full article
(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)
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Open AccessArticle
Fractionation of Enriched Phosphopeptides Using pH/Acetonitrile-Gradient-Reversed-Phase Microcolumn Separation in Combination with LC–MS/MS Analysis
Int. J. Mol. Sci. 2020, 21(11), 3971; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113971 - 01 Jun 2020
Abstract
Mass spectrometry (MS) is a powerful and sensitive method often used for the identification of phosphoproteins. However, in phosphoproteomics, there is an identified need to compensate for the low abundance, insufficient ionization, and suppression effects of non-phosphorylated peptides. These may hamper the subsequent [...] Read more.
Mass spectrometry (MS) is a powerful and sensitive method often used for the identification of phosphoproteins. However, in phosphoproteomics, there is an identified need to compensate for the low abundance, insufficient ionization, and suppression effects of non-phosphorylated peptides. These may hamper the subsequent liquid chromatography–mass spectrometry/mass spectrometry (LC–MS/MS) analysis, resulting in incomplete phosphoproteome characterization, even when using high-resolution instruments. To overcome these drawbacks, we present here an effective microgradient chromatographic technique that yields specific fractions of enriched phosphopeptides compatible with LC–MS/MS analysis. The purpose of our study was to increase the number of identified phosphopeptides, and thus, the coverage of the sample phosphoproteome using the reproducible and straightforward fractionation method. This protocol includes a phosphopeptide enrichment step followed by the optimized microgradient fractionation of enriched phosphopeptides and final LC–MS/MS analysis of the obtained fractions. The simple fractionation system consists of a gas-tight microsyringe delivering the optimized gradient mobile phase to reversed-phase microcolumn. Our data indicate that combining the phosphopeptide enrichment with the microgradient separation is a promising technique for in-depth phosphoproteomic analysis due to moderate input material requirements and more than 3-fold enhanced protein identification. Full article
(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)
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Open AccessArticle
Untargeted Metabolomics for Metabolic Diagnostic Screening with Automated Data Interpretation Using a Knowledge-Based Algorithm
Int. J. Mol. Sci. 2020, 21(3), 979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030979 - 01 Feb 2020
Cited by 3
Abstract
Untargeted metabolomics may become a standard approach to address diagnostic requests, but, at present, data interpretation is very labor-intensive. To facilitate its implementation in metabolic diagnostic screening, we developed a method for automated data interpretation that preselects the most likely inborn errors of [...] Read more.
Untargeted metabolomics may become a standard approach to address diagnostic requests, but, at present, data interpretation is very labor-intensive. To facilitate its implementation in metabolic diagnostic screening, we developed a method for automated data interpretation that preselects the most likely inborn errors of metabolism (IEM). The input parameters of the knowledge-based algorithm were (1) weight scores assigned to 268 unique metabolites for 119 different IEM based on literature and expert opinion, and (2) metabolite Z-scores and ranks based on direct-infusion high resolution mass spectrometry. The output was a ranked list of differential diagnoses (DD) per sample. The algorithm was first optimized using a training set of 110 dried blood spots (DBS) comprising 23 different IEM and 86 plasma samples comprising 21 different IEM. Further optimization was performed using a set of 96 DBS consisting of 53 different IEM. The diagnostic value was validated in a set of 115 plasma samples, which included 58 different IEM and resulted in the correct diagnosis being included in the DD of 72% of the samples, comprising 44 different IEM. The median length of the DD was 10 IEM, and the correct diagnosis ranked first in 37% of the samples. Here, we demonstrate the accuracy of the diagnostic algorithm in preselecting the most likely IEM, based on the untargeted metabolomics of a single sample. We show, as a proof of principle, that automated data interpretation has the potential to facilitate the implementation of untargeted metabolomics for metabolic diagnostic screening, and we provide suggestions for further optimization of the algorithm to improve diagnostic accuracy. Full article
(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)
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Open AccessArticle
Metabolic Profile, Bioavailability and Toxicokinetics of Zearalenone-14-Glucoside in Rats after Oral and Intravenous Administration by Liquid Chromatography High-Resolution Mass Spectrometry and Tandem Mass Spectrometry
Int. J. Mol. Sci. 2019, 20(21), 5473; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215473 - 03 Nov 2019
Cited by 3
Abstract
Zearalenone-14-glucoside (ZEN-14G), a key modified mycotoxin, has attracted a great deal of attention due to the possible conversion to its free form of zearalenone (ZEN) exerting toxicity. In this study, the toxicokinetics of ZEN-14G were investigated in rats after oral and intravenous administration. [...] Read more.
Zearalenone-14-glucoside (ZEN-14G), a key modified mycotoxin, has attracted a great deal of attention due to the possible conversion to its free form of zearalenone (ZEN) exerting toxicity. In this study, the toxicokinetics of ZEN-14G were investigated in rats after oral and intravenous administration. The plasma concentrations of ZEN-14G and its major five metabolites were quantified using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The data were analyzed via non-compartmental analysis using software WinNonlin 6.3. The results indicated that ZEN-14G was rapidly hydrolyzed into ZEN in vivo. In addition, the major parameters of ZEN-14G following intravenous administration were: area under the plasma concentration–time curve (AUC), 1.80 h·ng/mL; the apparent volume of distribution (VZ), 7.25 L/kg; and total body clearance (CL), 5.02 mL/h/kg, respectively. After oral administration, the typical parameters were: AUC, 0.16 h·ng/mL; VZ, 6.24 mL/kg; and CL, 4.50 mL/h/kg, respectively. The absolute oral bioavailability of ZEN-14G in rats was about 9%, since low levels of ZEN-14G were detected in plasma, which might be attributed to its extensive metabolism. Therefore, liquid chromatography high-resolution mass spectrometry (LC-HRMS) was adopted to clarify the metabolic profile of ZEN-14G in rats’ plasma. As a result, eight metabolites were identified in which ZEN-14-glucuronic acid (ZEN-14GlcA) had a large yield from the first time-point and continued accumulating after oral administration, indicating that ZEN-14-glucuronic acid could serve a potential biomarker of ZEN-14G. The obtained outcomes would prompt the accurate safety evaluation of ZEN-14G. Full article
(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)
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