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Metabolites
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Stable Isotope Guided Metabolomics II
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Stable Isotope Guided Metabolomics II

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Advances in Metabolomics".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 14169

Special Issue Editor

Dr. Pawel Lorkiewicz

E-Mail Website
Guest Editor
Diabetes and Obesity Center, Christina Lee Brown Envirome Institute, Louisville, KY 40202, USA
Interests: stable isotope resolved metabolomics; method development; fluxomics; metabolic pathway activity; high-resolution mass spectrometry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The use of stable isotope-labeled compounds in studying metabolism and biological processes is widespread. The Special Issue of Metabolites, "Stable Isotope-Guided Metabolomics", will focus on cutting-edge and newly established metabolomics technologies and workflows that significantly benefit from the use of stable isotopically labeled compounds. This includes methodologies for in vitro and in vivo stable metabolite pathway tracing and flux analyses, as well as applications that improve quality, confidence, and validation of metabolomics analyses and aid in metabolite assignments and quantification. In this Special Issue, we aim to cover a variety of topics, including experimental design, workflows for the analysis of isotopically enriched data, statistical and computational approaches for data analysis and interpretation, and other important topics.

Dr. Pawel Lorkiewicz
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. 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

  • stable isotopes
  • flux analysis
  • pathway tracing
  • isotope labeling

Published Papers (5 papers)

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Research

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15 pages, 3237 KiB  
Article
Estradiol, Estrone and Ethinyl Estradiol Metabolism Studied by High Resolution LC-MS/MS Using Stable Isotope Labeling and Trapping of Reactive Metabolites
by Kahina Chabi and Lekha Sleno
Metabolites 2022, 12(10), 931; https://doi.org/10.3390/metabo12100931 - 30 Sep 2022
Cited by 1 | Viewed by 1891
Abstract
Biotransformation reactions that xenobiotics undergo during their metabolism are crucial for their proper excretion from the body, but can also be a source of toxicity, especially in the case of reactive metabolite formation. Unstable, reactive metabolites are capable of covalent binding to proteins, [...] Read more.
Biotransformation reactions that xenobiotics undergo during their metabolism are crucial for their proper excretion from the body, but can also be a source of toxicity, especially in the case of reactive metabolite formation. Unstable, reactive metabolites are capable of covalent binding to proteins, and have often been linked to liver damage and other undesired side effects. A common technique to assess the formation of reactive metabolites employs trapping them in vitro with glutathione and characterizing the resulting adducts by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Some endogenous compounds, however, can interfere with xenobiotic metabolites of interest, making the analysis more difficult. This study demonstrates the usefulness of isotope-labeled compounds to detect and elucidate the structures of both stable metabolites and trapped adducts of three estrogen analogs using an untargeted LC-MS/MS workflow. The metabolism of estradiol, estrone and ethinyl estradiol was investigated. Unlabeled and deuterated versions of these three compounds were incubated with human or rat liver microsomes in the presence of two different trapping agents, namely glutathione and N-acetylcysteine. The detection of closely eluting deuterated peaks allowed us to confirm the formation of several known metabolites, as well as many previously uncharacterized ones. The structure of each adduct was elucidated by the detailed analysis of high-resolution MS/MS spectra for elucidating fragmentation pathways with accurate mass measurements. The use of isotopic labeling was crucial in helping confirm many metabolites and adduct structures, as well as removing endogenous interferences. Full article
(This article belongs to the Special Issue Stable Isotope Guided Metabolomics II)
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10 pages, 2506 KiB  
Article
A Flexible Tool to Correct Superimposed Mass Isotopologue Distributions in GC-APCI-MS Flux Experiments
by Jennifer Langenhan, Carsten Jaeger, Katharina Baum, Mareike Simon and Jan Lisec
Metabolites 2022, 12(5), 408; https://doi.org/10.3390/metabo12050408 - 29 Apr 2022
Viewed by 1599
Abstract
The investigation of metabolic fluxes and metabolite distributions within cells by means of tracer molecules is a valuable tool to unravel the complexity of biological systems. Technological advances in mass spectrometry (MS) technology such as atmospheric pressure chemical ionization (APCI) coupled with high [...] Read more.
The investigation of metabolic fluxes and metabolite distributions within cells by means of tracer molecules is a valuable tool to unravel the complexity of biological systems. Technological advances in mass spectrometry (MS) technology such as atmospheric pressure chemical ionization (APCI) coupled with high resolution (HR), not only allows for highly sensitive analyses but also broadens the usefulness of tracer-based experiments, as interesting signals can be annotated de novo when not yet present in a compound library. However, several effects in the APCI ion source, i.e., fragmentation and rearrangement, lead to superimposed mass isotopologue distributions (MID) within the mass spectra, which need to be corrected during data evaluation as they will impair enrichment calculation otherwise. Here, we present and evaluate a novel software tool to automatically perform such corrections. We discuss the different effects, explain the implemented algorithm, and show its application on several experimental datasets. This adjustable tool is available as an R package from CRAN. Full article
(This article belongs to the Special Issue Stable Isotope Guided Metabolomics II)
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14 pages, 1891 KiB  
Article
Nitrogen Availability Affects the Metabolic Profile in Cyanobacteria
by Kosuke Inabe, Ayaka Miichi, Mami Matsuda, Takanobu Yoshida, Yuichi Kato, Ryota Hidese, Akihiko Kondo and Tomohisa Hasunuma
Metabolites 2021, 11(12), 867; https://doi.org/10.3390/metabo11120867 - 14 Dec 2021
Cited by 4 | Viewed by 2622
Abstract
Nitrogen is essential for the biosynthesis of various molecules in cells, such as amino acids and nucleotides, as well as several types of lipids and sugars. Cyanobacteria can assimilate several forms of nitrogen, including nitrate, ammonium, and urea, and the physiological and genetic [...] Read more.
Nitrogen is essential for the biosynthesis of various molecules in cells, such as amino acids and nucleotides, as well as several types of lipids and sugars. Cyanobacteria can assimilate several forms of nitrogen, including nitrate, ammonium, and urea, and the physiological and genetic responses to these nitrogen sources have been studied previously. However, the metabolic changes in cyanobacteria caused by different nitrogen sources have not yet been characterized. This study aimed to elucidate the influence of nitrate and ammonium on the metabolic profiles of the cyanobacterium Synechocystis sp. strain PCC 6803. When supplemented with NaNO3 or NH4Cl as the nitrogen source, Synechocystis sp. PCC 6803 grew faster in NH4Cl medium than in NaNO3 medium. Metabolome analysis indicated that some metabolites in the CBB cycle, glycolysis, and TCA cycle, and amino acids were more abundant when grown in NH4Cl medium than NaNO3 medium. 15N turnover rate analysis revealed that the nitrogen assimilation rate in NH4Cl medium was higher than in NaNO3 medium. These results indicate that the mechanism of nitrogen assimilation in the GS-GOGAT cycle differs between NaNO3 and NH4Cl. We conclude that the amounts and biosynthetic rate of cyanobacterial metabolites varies depending on the type of nitrogen. Full article
(This article belongs to the Special Issue Stable Isotope Guided Metabolomics II)
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21 pages, 3738 KiB  
Article
In Vivo Estimation of Ketogenesis Using Metabolic Flux Analysis—Technical Aspects and Model Interpretation
by Stanislaw Deja, Blanka Kucejova, Xiaorong Fu, Jeffrey D. Browning, Jamey D. Young and Shawn Burgess
Metabolites 2021, 11(5), 279; https://doi.org/10.3390/metabo11050279 - 28 Apr 2021
Cited by 10 | Viewed by 3667
Abstract
Ketogenesis occurs in liver mitochondria where acetyl-CoA molecules, derived from lipid oxidation, are condensed into acetoacetate (AcAc) and reduced to β-hydroxybutyrate (BHB). During carbohydrate scarcity, these two ketones are released into circulation at high rates and used as oxidative fuels in peripheral tissues. [...] Read more.
Ketogenesis occurs in liver mitochondria where acetyl-CoA molecules, derived from lipid oxidation, are condensed into acetoacetate (AcAc) and reduced to β-hydroxybutyrate (BHB). During carbohydrate scarcity, these two ketones are released into circulation at high rates and used as oxidative fuels in peripheral tissues. Despite their physiological relevance and emerging roles in a variety of diseases, endogenous ketone production is rarely measured in vivo using tracer approaches. Accurate determination of this flux requires a two-pool model, simultaneous BHB and AcAc tracers, and special consideration for the stability of the AcAc tracer and analyte. We describe the implementation of a two-pool model using a metabolic flux analysis (MFA) approach that simultaneously regresses liquid chromatography-tandem mass spectrometry (LC-MS/MS) ketone isotopologues and tracer infusion rates. Additionally, 1H NMR real-time reaction monitoring was used to evaluate AcAc tracer and analyte stability during infusion and sample analysis, which were critical for accurate flux calculations. The approach quantifies AcAc and BHB pool sizes and their rates of appearance, disposal, and exchange. Regression analysis provides confidence intervals and detects potential errors in experimental data. Complications for the physiological interpretation of individual ketone fluxes are discussed. Full article
(This article belongs to the Special Issue Stable Isotope Guided Metabolomics II)
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Review

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17 pages, 1168 KiB  
Review
Stable Isotope Abundance and Fractionation in Human Diseases
by Illa Tea, Arnaud De Luca, Anne-Marie Schiphorst, Mathilde Grand, Sophie Barillé-Nion, Eric Mirallié, Delphine Drui, Michel Krempf, Régis Hankard and Guillaume Tcherkez
Metabolites 2021, 11(6), 370; https://doi.org/10.3390/metabo11060370 - 09 Jun 2021
Cited by 13 | Viewed by 3572
Abstract
The natural abundance of heavy stable isotopes (13C, 15N, 18O, etc.) is now of considerable importance in many research fields, including human physiology. In fact, it varies between tissues and metabolites due to isotope effects in biological processes, that [...] Read more.
The natural abundance of heavy stable isotopes (13C, 15N, 18O, etc.) is now of considerable importance in many research fields, including human physiology. In fact, it varies between tissues and metabolites due to isotope effects in biological processes, that is, isotope discriminations between heavy and light isotopic forms during enzyme or transporter activity. The metabolic deregulation associated with many diseases leads to alterations in metabolic fluxes, resulting in changes in isotope abundance that can be identified easily with current isotope ratio technologies. In this review, we summarize the current knowledge on changes in natural isotope composition in samples (including various tissues, hair, plasma, saliva) found in patients compared to controls, caused by human diseases. We discuss the metabolic origin of such isotope fractionations and highlight the potential of using isotopes at natural abundance for medical diagnosis and/or prognostic. Full article
(This article belongs to the Special Issue Stable Isotope Guided Metabolomics II)
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