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Luigi Servillo, Nunzia D'Onofrio, Alfonso Giovane, Rosario Casale, Domenico Cautela, Domenico Castaldo, Francesco Iannaccone, Gianluca Neglia, Giuseppe Campanile, Maria Luisa Balestrieri
Quaternary ammonium compounds containing N-trimethylamino moiety, such as choline derivatives and carnitine, abundant in meat and dairy products, are metabolic precursors of trimethylamine (TMA). A similar fate is reported for Nε -trimethyllysine and γ-butyrobetaine. With the aim at investigating the metabolic profile of such metabolites in most employed animal dietary sources, HPLC-ESI-MS/MS analyses on ruminant and non-ruminant milk and meat were performed. Results demonstrate, for the first time, the presence of δ-valerobetaine, occurring at levels higher than γ-butyrobetaine in all ruminant samples compared to non-ruminants...
September 15, 2018: Food Chemistry
Xinmin S Li, Zeneng Wang, Tomas Cajka, Jennifer A Buffa, Ina Nemet, Alex G Hurd, Xiaodong Gu, Sarah M Skye, Adam B Roberts, Yuping Wu, Lin Li, Christopher J Shahen, Matthew A Wagner, Jaana A Hartiala, Robert L Kerby, Kymberleigh A Romano, Yi Han, Slayman Obeid, Thomas F Lüscher, Hooman Allayee, Federico E Rey, Joseph A DiDonato, Oliver Fiehn, W H Wilson Tang, Stanley L Hazen
Using an untargeted metabolomics approach in initial (N = 99 subjects) and replication cohorts (N = 1,162), we discovered and structurally identified a plasma metabolite associated with cardiovascular disease (CVD) risks, N6,N6,N6-trimethyl-L-lysine (trimethyllysine, TML). Stable-isotope-dilution tandem mass spectrometry analyses of an independent validation cohort (N = 2,140) confirmed TML levels are independently associated with incident (3-year) major adverse cardiovascular event risks (hazards ratio [HR], 2...
March 22, 2018: JCI Insight
Meagan A Beatty, Jorge Borges-González, Nicholas J Sinclair, Aidan T Pye, Fraser Hof
Many indicator displacement assays can detect biological analytes in water, but these often have reduced performance in the presence of an unavoidable component: NaCl. We report here a new self-assembled sensor, DimerDye, that uses a novel photochemical guest-sensing mechanism and that is intrinsically tolerant of cosolutes. We synthetically integrated a dye into a calixarene macrocycle, forming two new merocyanine calixarenes (MCx-1 and MCx-2). Both compounds self-assemble into nonemissive dimers in water...
March 14, 2018: Journal of the American Chemical Society
Abbas H K Al Temimi, Roman Belle, Kiran Kumar, Jordi Poater, Peter Betlem, Bas J G E Pieters, Robert S Paton, F Matthias Bickelhaupt, Jasmin Mecinović
Histone Nε -lysine methylation is a widespread posttranslational modification that is specifically recognised by a diverse class of Nε -methyllysine binding reader proteins. Combined thermodynamic data, molecular dynamics simulations, and quantum chemical studies reveal that reader proteins efficiently bind trimethylornithine and trimethylhomolysine, the simplest Nε -trimethyllysine analogues that differ in the length of the side chain.
March 7, 2018: Chemical Communications: Chem Comm
Elin Strand, Eirik W Rebnord, Malin R Flygel, Vegard Lysne, Gard F T Svingen, Grethe S Tell, Kjetil H Løland, Rolf K Berge, Asbjørn Svardal, Ottar Nygård, Eva R Pedersen
Context: Carnitine and its metabolites are centrally involved in fatty acid metabolism. Although elevated circulating concentrations have been observed in obesity and insulin resistance, prospective studies examining whether these metabolites are associated with incident type 2 diabetes mellitus (T2D) are sparse. Objective: We performed a comprehensive evaluation of metabolites along the carnitine pathway relative to incident T2D. Design: A total of 2519 patients (73...
March 1, 2018: Journal of Clinical Endocrinology and Metabolism
Kyle E Denton, Sijie Wang, Michael C Gignac, Natalia Milosevich, Fraser Hof, Emily C Dykhuizen, Casey J Krusemark
The identification of protein ligands from a DNA-encoded library is commonly conducted by an affinity selection assay. These assays are often not validated for robustness, raising questions about selections that fail to identify ligands and the utility of enrichment values for ranking ligand potencies. Here, we report a method for optimizing and utilizing affinity selection assays to identify potent and selective peptidic ligands to the highly related chromodomains of CBX proteins. To optimize affinity selection parameters, statistical analyses (Z' factors) were used to define the ability of selection assay conditions to identify and differentiate ligands of varying affinity...
January 1, 2018: SLAS Discovery
Stefanie A Baril, Amber L Koenig, Mackenzie W Krone, Katherine I Albanese, Cyndi Qixin He, Ga Young Lee, Kendall N Houk, Marcey L Waters, Eric M Brustad
Trimethyllysine (Kme3) reader proteins are targets for inhibition due to their role in mediating gene expression. Although all such reader proteins bind Kme3 in an aromatic cage, the driving force for binding may differ; some readers exhibit evidence for cation-π interactions whereas others do not. We report a general unnatural amino acid mutagenesis approach to quantify the contribution of individual tyrosines to cation binding using the HP1 chromodomain as a model system. We demonstrate that two tyrosines (Y24 and Y48) bind to a Kme3-histone tail peptide via cation-π interactions, but linear free energy trends suggest they do not contribute equally to binding...
December 6, 2017: Journal of the American Chemical Society
Zhonglei Chen, Ryan Q Notti, Beatrix Ueberheide, Alexander J Ruthenburg
Methyllysine analogues (MLAs), furnished by aminoethylation of engineered cysteine residues, are widely used surrogates of histone methyllysine and are considered to be effective proxies for studying these epigenetic marks in vitro. Here we report the first structure of a trimethyllysine MLA histone in complex with a protein binding partner, quantify the thermodynamic distinctions between MLAs and their native methyllysine counterparts, and demonstrate that these differences can compromise qualitative interpretations of binding at the nucleosome level...
November 10, 2017: Biochemistry
Xiaolei Shi, Alpaslan Tasdogan, Fang Huang, Zeping Hu, Sean J Morrison, Ralph J DeBerardinis
Metabolic reprogramming is a major factor in transformation, and particular metabolic phenotypes correlate with oncogenotype, tumor progression, and metastasis. By profiling metabolites in 17 patient-derived xenograft melanoma models, we identified durable metabolomic signatures that correlate with biological features of the tumors. BRAF mutant tumors had metabolomic and metabolic flux features of enhanced glycolysis compared to BRAF wild-type tumors. Tumors that metastasized efficiently from their primary sites had elevated levels of metabolites related to protein methylation, including trimethyllysine (TML)...
November 2017: Science Advances
David C H Yang, Amila H Abeykoon, Bok-Eum Choi, Wei-Mei Ching, P Boon Chock
Methylation of outer membrane proteins (OMPs) has been implicated in bacterial virulence. Lysine methylation in rickettsial OmpB is correlated with rickettsial virulence, and N- and O-methylations are also observed in virulence-relevant OMPs from several pathogenic bacteria that cause typhus, leptospirosis, tuberculosis, and anaplasmosis. We summarize recent findings on the structure of methylated OmpB, biochemical characterization, and crystal structures of OmpB methyltransferases. Native rickettsial OmpB purified from highly virulent strains contains multiple clusters of trimethyllysine, in contrast with mostly monomethyllysine, and no trimethyllysine is found in an avirulent strain...
December 2017: Trends in Biochemical Sciences
Isaiah N Gober, Marcey L Waters
In the design of small molecule receptors for polar guests, much inspiration has been taken from proteins that have adapted effective ways to selectively bind polar molecules in aqueous environments. Nonetheless, molecular recognition of hydrophilic guests in water by synthetic receptors remains a challenging task. Here we report a new synthetic receptor, A2I, with improved affinity and selectivity for a biologically important polar guest, dimethyllysine (Kme2). A2I was prepared via redesign of a small molecule receptor (A2B) that preferentially binds trimethyllysine (Kme3) using dynamic combinatorial chemistry (DCC)...
September 26, 2017: Organic & Biomolecular Chemistry
Luigi Servillo, Nunzia D'Onofrio, Alfonso Giovane, Rosario Casale, Domenico Cautela, Giovanna Ferrari, Domenico Castaldo, Maria Luisa Balestrieri
We report the LC-ESI-MS/MS determination of betaines in commercial flours of cereals and pseudocereals most utilized in human nutrition. Results showed that glycine betaine, trigonelline, proline betaine, Nε -trimethyllysine were metabolites common to all examined flours, whereas an uncommon betaine, valine betaine, and glutamine betaine were present only in flours of barley, rye, oat, durum wheat, winter wheat, Triticum dicoccum and Triticum monococcum. Valine betaine and glutamine betaine, the latter never reported before in plants and animals, are not evenly distributed in the Poaceae family, but their presence or absence in flours depends on the subfamily to which the plant belongs...
January 15, 2018: Food Chemistry
Andrea E Steuer, Kim Arnold, Tom D Schneider, Michael Poetzsch, Thomas Kraemer
Urine adulteration to circumvent positive drug testing represents a problem for toxicological laboratories. While creatinine is a suitable marker for dilution, detection of chemicals is often performed by dipstick tests associated with high rates of false positives. Several methods would be necessary to check for all possible adulterants. Untargeted mass spectrometry (MS) methods used in metabolomics should theoretically allow detecting concentration changes of any endogenous urinary metabolite or presence of new biomarkers produced by chemical adulteration...
October 2017: Analytical and Bioanalytical Chemistry
Jessica Lasky-Su, Amber Dahlin, Augusto A Litonjua, Angela J Rogers, Michael J McGeachie, Rebecca M Baron, Lee Gazourian, Diana Barragan-Bradford, Laura E Fredenburgh, Augustine M K Choi, Kris M Mogensen, Sadeq A Quraishi, Karin Amrein, Kenneth B Christopher
BACKGROUND: Metabolic homeostasis is substantially disrupted in critical illness. Given the pleiotropic effects of vitamin D, we hypothesized that metabolic profiles differ between critically ill patients relative to their vitamin D status. METHODS: We performed a metabolomics study on biorepository samples collected from a single academic medical center on 65 adults with systemic inflammatory response syndrome or sepsis treated in a 20-bed medical ICU between 2008 and 2010...
July 28, 2017: Critical Care: the Official Journal of the Critical Care Forum
Yang Liu, Lizeth Perez, Magi Mettry, Adam D Gill, Samantha R Byers, Connor J Easley, Christopher J Bardeen, Wenwan Zhong, Richard J Hooley
Variably functionalized self-folding deep cavitands form an arrayed, fluorescent indicator displacement assay system for the detection of post-translationally modified (PTM) histone peptides. The hosts bind trimethyllysine (KMe3) groups, and use secondary upper rim interactions to provide more sensitive discrimination between targets with identical KMe3 binding handles. The sensor array uses multiple different recognition modes to distinguish between miniscule differences in target, such as identical lysine modifications at different sites of histone peptides...
May 1, 2017: Chemical Science
Mitsuyoshi Ohshima, Keisuke Sugahara, Kiyohiro Kasahara, Akira Katakura
The aim of the present study was to characterize the metabolic systems in Japanese patients with oral squamous cell carcinoma (OSCC) using capillary electrophoresis-mass spectrometry (CE-MS) metabolome analysis of saliva samples. A previous study showed variations among ethnicities and tumor sites in the saliva metabolome of patients with OSCC using CE-MS. In the present study, saliva was obtained from 22 Japanese patients with OSCC and from 21 healthy controls who visited the Department of Dentistry, Oral and Maxillofacial Surgery, Tokyo Dental Collage Ichikawa General Hospital, Tokyo, Japan, and all samples were subject to comprehensive quantitative metabolome analysis using CE-MS...
May 2017: Oncology Reports
Y Vijayendar Reddy, Abbas H K Al Temimi, Jasmin Mecinović
Trimethyllysine hydroxylase (TMLH) catalyses C-3 hydroxylation of Nε -trimethyllysine in the first step of carnitine biosynthesis in humans. Studies on TMLH have been hampered by the lack of established chemical methods. We report that an Nε -trimethyllysine analogue that contains the fluoromethyl group can be used as a1 H and19 F NMR probe for studies on TMLH catalysis.
February 7, 2017: Organic & Biomolecular Chemistry
Y Vijayendar Reddy, Abbas H K Al Temimi, Paul B White, Jasmin Mecinović
Trimethyllysine hydroxylase (TMLH) is an Fe(II) and 2-oxoglutarate (2OG) dependent oxygenase involved in the biomedically important carnitine biosynthesis pathway. A combination of synthetic and NMR studies provides direct evidence that human TMLH catalyzes the stereoselective conversion of (2S)-N(ε)-trimethyllysine to (2S,3S)-3-hydroxy-N(ε)-trimethyllysine.
January 3, 2017: Organic Letters
Andreas Lingel, Martin Sendzik, Ying Huang, Michael D Shultz, John Cantwell, Michael P Dillon, Xingnian Fu, John Fuller, Tobias Gabriel, Justin Gu, Xiangqing Jiang, Ling Li, Fang Liang, Maureen McKenna, Wei Qi, Weijun Rao, Xijun Sheng, Wei Shu, James Sutton, Benjamin Taft, Long Wang, Jue Zeng, Hailong Zhang, Maya Zhang, Kehao Zhao, Mika Lindvall, Dirksen E Bussiere
PRC2 is a multisubunit methyltransferase involved in epigenetic regulation of early embryonic development and cell growth. The catalytic subunit EZH2 methylates primarily lysine 27 of histone H3, leading to chromatin compaction and repression of tumor suppressor genes. Inhibiting this activity by small molecules targeting EZH2 was shown to result in antitumor efficacy. Here, we describe the optimization of a chemical series representing a new class of PRC2 inhibitors which acts allosterically via the trimethyllysine pocket of the noncatalytic EED subunit...
January 12, 2017: Journal of Medicinal Chemistry
Robert K Leśniak, Suzana Markolovic, Kaspars Tars, Christopher J Schofield
N(ε)-Trimethyllysine hydroxylase (TMLH) catalyses the first step in mammalian biosynthesis of carnitine, which plays a crucial role in fatty acid metabolism. The stereochemistry of the 3-hydroxy-N(ε)-trimethyllysine product of TMLH has not been defined. We report enzymatic and asymmetric synthetic studies, which define the product of TMLH catalysis as (2S,3S)-3-hydroxy-N(ε)-trimethyllysine.
December 22, 2016: Chemical Communications: Chem Comm
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