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

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 30393

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Special Issue Editor

Prof. Dr. Laszlo Prokai

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

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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

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 100 words) can be sent to the Editorial Office for announcement on this website.

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-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

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

Related Special Issue

High Resolution Mass Spectrometry in Molecular Sciences: 2nd Edition in International Journal of Molecular Sciences

Published Papers (10 papers)

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Research

24 pages, 2142 KiB

Open AccessArticle

Compatibility of Distinct Label-Free Proteomic Workflows in Absolute Quantification of Proteins Linked to the Oocyte Quality in Human Follicular Fluid

by Aleksandra E. Lewandowska, Anna Fel, Marcel Thiel, Paulina Czaplewska, Krzysztof Łukaszuk, Jacek R. Wiśniewski and Stanisław Ołdziej

Int. J. Mol. Sci. 2021, 22(14), 7415; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147415 - 10 Jul 2021

Cited by 4 | Viewed by 2722

Abstract

We present two separate label-free quantitative workflows based on different high-resolution mass spectrometers and LC setups, which are termed after the utilized instrument: Quad-Orbitrap (nano-LC) and Triple Quad-TOF (micro-LC) and their directed adaptation toward the analysis of human follicular fluid proteome. We identified about 1000 proteins in each distinct workflow using various sample preparation methods. With assistance of the Total Protein Approach, we were able to obtain absolute protein concentrations for each workflow. In a pilot study of twenty samples linked to diverse oocyte quality status from four donors, 455 and 215 proteins were quantified by the Quad-Orbitrap and Triple Quad-TOF workflows, respectively. The concentration values obtained from both workflows correlated to a significant degree. We found reasonable agreement of both workflows in protein fold changes between tested groups, resulting in unified lists of 20 and 22 proteins linked to oocyte maturity and blastocyst development, respectively. The Quad-Orbitrap workflow was best suited for an in-depth analysis without the need of extensive fractionation, especially of low abundant proteome, whereas the Triple Quad-TOF workflow allowed a more robust approach with a greater potential to increase in effectiveness with the growing number of analyzed samples after the initial effort of building a comprehensive spectral library. Full article

(This article belongs to the Special Issue High Resolution Mass Spectrometry in Molecular Sciences)

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13 pages, 1058 KiB

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

by Laszlo Prokai, Fatima Rahlouni, Khadiza Zaman, Vien Nguyen and Katalin Prokai-Tatrai

Int. J. Mol. Sci. 2021, 22(4), 1686; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041686 - 08 Feb 2021

Cited by 2 | Viewed by 2713

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 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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Graphical abstract

15 pages, 4013 KiB

Open AccessArticle

Structural Characterization of Daunomycin-Peptide Conjugates by Various Tandem Mass Spectrometric Techniques

by Adina Borbély, Lilla Pethő, Ildikó Szabó, Mohammed Al-Majidi, Arnold Steckel, Tibor Nagy, Sándor Kéki, Gergő Kalló, Éva Csősz, Gábor Mező and Gitta Schlosser

Int. J. Mol. Sci. 2021, 22(4), 1648; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041648 - 06 Feb 2021

Cited by 1 | Viewed by 2629

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 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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12 pages, 2963 KiB

Open AccessArticle

Mass Spectral Filtering by Mass-Remainder Analysis (MARA) at High Resolution and Its Application to Metabolite Profiling of Flavonoids

by Tibor Nagy, Gergő Róth, Ákos Kuki, Miklós Zsuga and Sándor Kéki

Int. J. Mol. Sci. 2021, 22(2), 864; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020864 - 16 Jan 2021

Cited by 6 | Viewed by 2492

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 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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26 pages, 9318 KiB

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

by Joanna Fedorowicz, Magdalena Wierzbicka, Marek Cebrat, Paulina Wiśniewska, Rafał Piątek, Beata Zalewska-Piątek, Zbigniew Szewczuk and Jarosław Sączewski

Int. J. Mol. Sci. 2020, 21(24), 9643; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249643 - 17 Dec 2020

Cited by 5 | Viewed by 2542

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 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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20 pages, 1998 KiB

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

by Gergő Kalló, Balázs Kunkli, Zoltán Győri, Zoltán Szilvássy, Éva Csősz and József Tőzsér

Int. J. Mol. Sci. 2020, 21(24), 9547; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249547 - 15 Dec 2020

Cited by 9 | Viewed by 3075

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 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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13 pages, 1306 KiB

Open AccessArticle

High-Resolution Mass Spectrometry for In Vivo Proteome Dynamics using Heavy Water Metabolic Labeling

by Rovshan G. Sadygov

Int. J. Mol. Sci. 2020, 21(21), 7821; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21217821 - 22 Oct 2020

Cited by 5 | Viewed by 2243

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 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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14 pages, 1923 KiB

Open AccessArticle

Fractionation of Enriched Phosphopeptides Using pH/Acetonitrile-Gradient-Reversed-Phase Microcolumn Separation in Combination with LC–MS/MS Analysis

by Martin Ondrej, Pavel Rehulka, Helena Rehulkova, Rudolf Kupcik and Ales Tichy

Int. J. Mol. Sci. 2020, 21(11), 3971; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113971 - 01 Jun 2020

Cited by 5 | Viewed by 3822

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 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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12 pages, 1055 KiB

Open AccessArticle

Untargeted Metabolomics for Metabolic Diagnostic Screening with Automated Data Interpretation Using a Knowledge-Based Algorithm

by Hanneke A. Haijes, Maria van der Ham, Hubertus C.M.T. Prinsen, Melissa H. Broeks, Peter M. van Hasselt, Monique G.M. de Sain-van der Velden, Nanda M. Verhoeven-Duif and Judith J.M. Jans

Int. J. Mol. Sci. 2020, 21(3), 979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030979 - 01 Feb 2020

Cited by 15 | Viewed by 3962

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 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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11 pages, 1534 KiB

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

by Feifei Sun, Haiguang Tan, Yanshen Li, Marthe De Boevre, Sarah De Saeger, Jinhui Zhou, Yi Li, Zhenghua Rao, Shupeng Yang and Huiyan Zhang

Int. J. Mol. Sci. 2019, 20(21), 5473; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215473 - 03 Nov 2019

Cited by 12 | Viewed by 2507

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. 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 (V_Z), 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; V_Z, 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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