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Journal of Labelled Compounds &... Mar 2023Selective deuterium installation into small molecules is becoming increasingly desirable not only for the elucidation of mechanistic pathways and studying biological...
Selective deuterium installation into small molecules is becoming increasingly desirable not only for the elucidation of mechanistic pathways and studying biological processes but also because of deuterium's ability to favorably adjust the pharmacokinetic parameters of bioactive molecules. Fused bicyclic moieties, especially those containing heteroatoms, are prevalent in drug discovery and pharmaceuticals. Herein, we report a copper-catalyzed transfer hydrodeuteration of cyclic and heterocyclic alkenes, which enables the synthesis of chromans, quinolinones, and tetrahydronaphthalenes that are precisely deuterated at the benzylic position. We also demonstrate the ability to place one deuterium atom at the homobenzylic site of these scaffolds with high regioselectivity by swapping transfer reagents for their isotopic analogs. Furthermore, examples of chemoselective transfer hydrogenation and transfer deuteration are disclosed, allowing for the simultaneous incorporation of two vicinal hydrogen or deuterium atoms into a double bond.
Topics: Deuterium; Cycloparaffins; Hydrogen; Copper; Catalysis; Alkenes
PubMed: 36772856
DOI: 10.1002/jlcr.4015 -
Molecules (Basel, Switzerland) Sep 2022The structure and function of biological macromolecules change due to intermolecular deuterium bond formation or deuterium substitution with environmental DO. In this...
The structure and function of biological macromolecules change due to intermolecular deuterium bond formation or deuterium substitution with environmental DO. In this study, surface-enhanced Raman spectroscopy (SERS) was used to detect interaction sites between DO and ssDNA and their action mechanisms. SERS peaks of ssDNA changed with increasing DO proportions, and the site of action mainly involved A and G bases, whose number strengthened the interaction between sequences and DO and hence the SERS peak intensities. Fixing the number of A and G bases prevented changes in their positions from significantly altering the map. We also identified the interaction between ssDNA sequences that easily formed a G-quadruplex structure and DO. The amplitude of the SERS peak intensity change reflected the ssDNA structural stability and number of active sites. These findings are highly significant for exploring genetic exchanges and mutations and could be used to determine the stability and structural changes of biological macromolecules.
Topics: DNA, Single-Stranded; Deuterium; Deuterium Oxide; G-Quadruplexes; Spectrum Analysis, Raman
PubMed: 36144761
DOI: 10.3390/molecules27186023 -
International Journal of Molecular... Mar 2022Much of the work probing antimicrobial peptide (AMP) mechanisms has focussed on how these molecules permeabilize lipid bilayers. However, AMPs must also traverse a... (Review)
Review
Much of the work probing antimicrobial peptide (AMP) mechanisms has focussed on how these molecules permeabilize lipid bilayers. However, AMPs must also traverse a variety of non-lipid cell envelope components before they reach the lipid bilayer. Additionally, there is a growing list of AMPs with non-lipid targets inside the cell. It is thus useful to extend the biophysical methods that have been traditionally applied to study AMP mechanisms in liposomes to the full bacteria, where the lipids are present along with the full complexity of the rest of the bacterium. This review focusses on what can be learned about AMP mechanisms from solid-state NMR of AMP-treated intact bacteria. It also touches on flow cytometry as a complementary method for measuring permeabilization of bacterial lipid membranes in whole bacteria.
Topics: Antimicrobial Cationic Peptides; Antimicrobial Peptides; Bacteria; Cell Membrane; Deuterium; Lipid Bilayers
PubMed: 35269882
DOI: 10.3390/ijms23052740 -
Mass Spectrometry Reviews Jan 2018Over a century ago, Frederick Soddy provided the first evidence for the existence of isotopes; elements that occupy the same position in the periodic table are... (Review)
Review
Over a century ago, Frederick Soddy provided the first evidence for the existence of isotopes; elements that occupy the same position in the periodic table are essentially chemically identical but differ in mass due to a different number of neutrons within the atomic nucleus. Allied to the discovery of isotopes was the development of some of the first forms of mass spectrometers, driven forward by the Nobel laureates JJ Thomson and FW Aston, enabling the accurate separation, identification, and quantification of the relative abundance of these isotopes. As a result, within a few years, the number of known isotopes both stable and radioactive had greatly increased and there are now over 300 stable or radioisotopes presently known. Unknown at the time, however, was the potential utility of these isotopes within biological disciplines, it was soon discovered that these stable isotopes, particularly those of carbon ( C), nitrogen ( N), oxygen ( O), and hydrogen ( H) could be chemically introduced into organic compounds, such as fatty acids, amino acids, and sugars, and used to "trace" the metabolic fate of these compounds within biological systems. From this important breakthrough, the age of the isotope tracer was born. Over the following 80 yrs, stable isotopes would become a vital tool in not only the biological sciences, but also areas as diverse as forensics, geology, and art. This progress has been almost exclusively driven through the development of new and innovative mass spectrometry equipment from IRMS to GC-MS to LC-MS, which has allowed for the accurate quantitation of isotopic abundance within samples of complex matrices. This historical review details the development of stable isotope tracers as metabolic tools, with particular reference to their use in monitoring protein metabolism, highlighting the unique array of tools that are now available for the investigation of protein metabolism in vivo at a whole body down to a single protein level. Importantly, it will detail how this development has been closely aligned to the technological development within the area of mass spectrometry. Without the dedicated development provided by these mass spectrometrists over the past century, the use of stable isotope tracers within the field of protein metabolism would not be as widely applied as it is today, this relationship will no doubt continue to flourish in the future and stable isotope tracers will maintain their importance as a tool within the biological sciences for many years to come. © 2016 The Authors. Mass Spectrometry Reviews Published by Wiley Periodicals, Inc. Mass Spec Rev.
Topics: Animals; Carbon Isotopes; Deuterium; Equipment Design; History, 20th Century; History, 21st Century; Humans; Isotope Labeling; Mass Spectrometry; Nitrogen Isotopes; Oxygen Isotopes; Proteins
PubMed: 27182900
DOI: 10.1002/mas.21507 -
International Journal of Medical... 2022Heavy water is an ideal contrast agent for metabolic activity and can be adapted to a wide range of biological systems owing to its non-invasiveness, universal... (Review)
Review
Heavy water is an ideal contrast agent for metabolic activity and can be adapted to a wide range of biological systems owing to its non-invasiveness, universal applicability, and cost-effectiveness. As a new type of probe, the heavy isotope of water has been widely used in the study of cell development, metabolism, tissue homeostasis, aging, and tumor heterogeneity. Herein, we review findings supporting the applications of and research on heavy water in monitoring of bacterial metabolism, rapid detection of drug sensitivity, identification of tumor cells, precision medicine, and evaluation of skin barrier function and promote the use of heavy water as a suitable marker for the development of detection and treatment methodologies.
Topics: Bacteria; Deuterium Oxide; Spectrum Analysis, Raman; Water
PubMed: 35928718
DOI: 10.7150/ijms.73150 -
Molecules (Basel, Switzerland) Apr 2022This review is giving a short introduction to the techniques used to investigate isotope effects on NMR chemical shifts. The review is discussing how isotope effects on... (Review)
Review
This review is giving a short introduction to the techniques used to investigate isotope effects on NMR chemical shifts. The review is discussing how isotope effects on chemical shifts can be used to elucidate the importance of either intra- or intermolecular hydrogen bonding in ionic liquids, of ammonium ions in a confined space, how isotope effects can help define dimers, trimers, etc., how isotope effects can lead to structural parameters such as distances and give information about ion pairing. Tautomerism is by advantage investigated by isotope effects on chemical shifts both in symmetric and asymmetric systems. The relationship between hydrogen bond energies and two-bond deuterium isotope effects on chemical shifts is described. Finally, theoretical calculations to obtain isotope effects on chemical shifts are looked into.
Topics: Deuterium; Hydrogen Bonding; Magnetic Resonance Spectroscopy
PubMed: 35458603
DOI: 10.3390/molecules27082405 -
Journal of the American Chemical Society Apr 2022Deuterated amino acids have been recognized for their utility in drug development, for facilitating nuclear magnetic resonance (NMR) analysis, and as probes for enzyme...
Deuterated amino acids have been recognized for their utility in drug development, for facilitating nuclear magnetic resonance (NMR) analysis, and as probes for enzyme mechanism. Small molecule-based methods for the site-selective synthesis of deuterated amino acids typically involve de novo synthesis of the compound from deuterated precursors. In comparison, enzymatic methods for introducing deuterium offer improved efficiency, operating directly on free amino acids to achieve hydrogen-deuterium (H/D) exchange. However, site selectivity remains a significant challenge for enzyme-mediated deuteration, limiting access to desirable deuteration motifs. Here, we use enzyme-catalyzed deuteration, combined with steady-state kinetic analysis and ultraviolet (UV)-vis spectroscopy to probe the mechanism of a two-protein system responsible for the biosynthesis of l--Ile. We show that an aminotransferase (DsaD) can pair with a small partner protein (DsaE) to catalyze Cα and Cβ H/D exchange of amino acids, while reactions without DsaE lead exclusively to Cα-deuteration. With conditions for improved catalysis, we evaluate the substrate scope for Cα/Cβ-deuteration and demonstrate the utility of this system for preparative-scale, selective labeling of amino acids.
Topics: Amines; Amino Acids; Catalysis; Deuterium; Hydrogen; Kinetics; Proteins
PubMed: 35416652
DOI: 10.1021/jacs.2c00608 -
Philosophical Transactions of the Royal... Aug 2020To understand consumer dietary requirements and resource use across ecosystems, researchers have employed a variety of methods, including bulk stable isotope and fatty... (Review)
Review
To understand consumer dietary requirements and resource use across ecosystems, researchers have employed a variety of methods, including bulk stable isotope and fatty acid composition analyses. Compound-specific stable isotope analysis (CSIA) of fatty acids combines both of these tools into an even more powerful method with the capacity to broaden our understanding of food web ecology and nutritional dynamics. Here, we provide an overview of the potential that CSIA studies hold and their constraints. We first review the use of fatty acid CSIA in ecology at the natural abundance level as well as enriched physiological tracers, and highlight the unique insights that CSIA of fatty acids can provide. Next, we evaluate methodological best practices when generating and interpreting CSIA data. We then introduce three cutting-edge methods: hydrogen CSIA of fatty acids, and fatty acid isotopomer and isotopologue analyses, which are not yet widely used in ecological studies, but hold the potential to address some of the limitations of current techniques. Finally, we address future priorities in the field of CSIA including: generating more data across a wider range of taxa; lowering costs and increasing laboratory availability; working across disciplinary and methodological boundaries; and combining approaches to answer macroevolutionary questions. This article is part of the theme issue 'The next horizons for lipids as 'trophic biomarkers': evidence and significance of consumer modification of dietary fatty acids'.
Topics: Carbon Isotopes; Deuterium; Ecology; Fatty Acids; Food Chain; Nitrogen Isotopes
PubMed: 32536315
DOI: 10.1098/rstb.2019.0641 -
Journal of Oleo Science 2013Human studies using deuterium-labeled fatty acids have answered many questions related to the metabolism and health effects of dietary fats. These studies also raised a... (Review)
Review
Human studies using deuterium-labeled fatty acids have answered many questions related to the metabolism and health effects of dietary fats. These studies also raised a number of unanswered questions and unresolved issues. For example, studies with cis and trans positional isomers dispelled concerns and allegations that the isomers in partially hydrogenated fats were poorly absorbed, accumulate in undesirable phospholipid acyl positions, mimic stearic acid and competed with oleic acid. Trans 18:1 isomers were metabolically intermediate between 16:0 and 18:0, so the unanswered question is why are the metabolic properties of trans fatty acids not consistent with their physiological effects? Results from ²H-18:0 studies address questions regarding stearic acid absorption and desaturation. Contrary to accepted dogma, stearic acid was well absorbed and less than 10% was desaturation to oleic acid. The still unanswered question is what is the metabolic basis for why 18:0 is less hypercholesterolemic than other saturated fatty acids? The question of whether humans convert 18:3n-3 to EPA and DHA was investigated by feeding male subjects a mixture of ²H-18:3n-3 and ²H-18:2n-6. The unequivocal answer was that 18:3n-3 is converted to EPA and DHA and the conversions for 18:3n-3 to 20:5n-3 and 18:2n-6 to 20:4n-6 were about equal. A major issue that remains unresolved is the wide variability between studies for the estimated conversion of 18:3n-3 to 20:5n-3 and 22:6n-3. The commercial availability of liquid oils hardened by interesterified with 18:0 has raised the question of whether fatty acids in the sn-2 and sn-1,3 TAG positions are metabolically equivalent. To answer this question, subjects were fed triglycerides containing ²H-16:0 and ²H-18:2n-6 at specific sn-1(3) and sn-2 acyl positions. The result was that dietary fatty acids at the sn-1(3) and sn-2 triacylglycerol positions are essentially metabolically equivalent.
Topics: Deuterium; Humans; Hypercholesterolemia; Isotope Labeling; Lipid Metabolism; Oleic Acid; Stearic Acids
PubMed: 23648399
DOI: 10.5650/jos.62.245 -
Journal of Labelled Compounds &... Apr 2022Base catalysed exchange with sodium hydroxide, calcium oxide or N,N,N,N-tetramethylguanidine in deuterium oxide is a viable procedure for the preparation of terminally...
Base catalysed exchange with sodium hydroxide, calcium oxide or N,N,N,N-tetramethylguanidine in deuterium oxide is a viable procedure for the preparation of terminally deuterated alkynes for those alkynes stable to strong base. The use of silver perchlorate as a catalyst is an alternative practical option when labelling alkynes which are sensitive to base or contain functionalities which would lead to labelling elsewhere in the molecule. Labelling with this catalyst takes place smoothly at ambient temperature in a mixture of N,N-dimethylformamide and deuterium oxide.
Topics: Alkynes; Catalysis; Deuterium
PubMed: 35067956
DOI: 10.1002/jlcr.3963