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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 N(ε)-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 N(ε)-trimethyllysine analogue that contains the fluoromethyl group can be used as a (1)H and (19)F NMR probe for studies on TMLH catalysis.
January 24, 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 3, 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
Nicola Longo
Carnitine is needed for transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. Carnitine can be synthesized by the body and is also obtained in the diet through consumption of meat and dairy products. Defects in carnitine transport such as those caused by defective activity of the OCTN2 transporter encoded by the SLC22A5 gene result in primary carnitine deficiency, and newborn screening programmes can identify patients at risk for this condition before irreversible damage...
2016: Annals of Nutrition & Metabolism
Abbas H K Al Temimi, Bas J G E Pieters, Y Vijayendar Reddy, Paul B White, Jasmin Mecinović
Trimethyllysine hydroxylase (TMLH) is a non-haem Fe(ii) and 2-oxoglutarate dependent oxygenase that catalyses the C-3 hydroxylation of an unactivated C-H bond in l-trimethyllysine in the first step of carnitine biosynthesis. The examination of trimethyllysine analogues as substrates for human TMLH reveals that the enzyme does hydroxylate substrates other than natural l-trimethyllysine.
October 12, 2016: Chemical Communications: Chem Comm
Yang Liu, Lizeth Perez, Magi Mettry, Connor J Easley, Richard J Hooley, Wenwan Zhong
A dual-mode aggregative host:guest indicator displacement sensing system has been created for the detection of trimethylated peptides and determination of histone demethylase activity. The combination of selective recognition of suitably sized trimethylammonium salts and reversible lipophilic aggregation of the host:guest complex provides a unique quenching mechanism that is not only dependent on affinity for sensitivity but the lipophilicity of the indicator. In addition, aggregation can be controlled by the application of chaotropic anions in the mixture, allowing a second level of discrimination between hard lysine groups and softer trimethyllysines...
August 31, 2016: Journal of the American Chemical Society
Isaiah N Gober, Marcey L Waters
Lysine methylation is an important histone post-translational modification (PTM) for manipulating chromatin structure and regulating gene expression, and its dysregulation is associated with various diseases including many cancers. While characterization of Lys methylation has seen improvements over the past decade due to advances in proteomic mass spectrometry and methods involving antibodies, chemical methods for selective detection of proteins containing PTMs are still lacking. Here, we detail the development of a unique labeling method wherein a synthetic receptor probe for trimethyl lysine (Kme3), CX4-ONBD, is used to direct selective fluorescent labeling of Kme3 histone peptides...
August 3, 2016: Journal of the American Chemical Society
Karolina Skagen, Marius Trøseid, Thor Ueland, Sverre Holm, Azhar Abbas, Ida Gregersen, Martin Kummen, Vigdis Bjerkeli, Frode Reier-Nilsen, David Russell, Asbjørn Svardal, Tom Hemming Karlsen, Pål Aukrust, Rolf K Berge, Johannes E R Hov, Bente Halvorsen, Mona Skjelland
BACKGROUND AND PURPOSE: γ-butyrobetaine (γBB) is a metabolite from dietary Carnitine, involved in the gut microbiota-dependent conversion from Carnitine to the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). Orally ingested γBB has a pro-atherogenic effect in experimental studies, but γBB has not been studied in relation to atherosclerosis in humans. The aim of this study was to evaluate associations between serum levels of γBB, TMAO and their common precursors Carnitine and trimethyllysine (TML) and carotid atherosclerosis and adverse outcome...
April 2016: Atherosclerosis
Jos J A G Kamps, Jiaxin Huang, Jordi Poater, Chao Xu, Bas J G E Pieters, Aiping Dong, Jinrong Min, Woody Sherman, Thijs Beuming, F Matthias Bickelhaupt, Haitao Li, Jasmin Mecinović
A large number of structurally diverse epigenetic reader proteins specifically recognize methylated lysine residues on histone proteins. Here we describe comparative thermodynamic, structural and computational studies on recognition of the positively charged natural trimethyllysine and its neutral analogues by reader proteins. This work provides experimental and theoretical evidence that reader proteins predominantly recognize trimethyllysine via a combination of favourable cation-π interactions and the release of the high-energy water molecules that occupy the aromatic cage of reader proteins on the association with the trimethyllysine side chain...
November 18, 2015: Nature Communications
Nicholas K Pinkin, Ina Liu, Jessicca D Abron, Marcey L Waters
We have systematically studied how secondary interactions with neighboring lysine (Lys) and arginine (Arg) residues influence the binding and selectivity of the synthetic receptor A2 N for trimethyllysine (Kme3 ). Multiple secondary binding sites on A2 N are formed by carboxylates rigidly positioned over aromatic rings, a motif that has been shown to stabilize salt bridges. We varied the spacing between KmeX (X=0, 3) and an ancillary Lys or Arg and measured binding by isothermal titration calorimetry (ITC)...
December 1, 2015: Chemistry: a European Journal
Bodil Bjørndal, Marie S Ramsvik, Carine Lindquist, Jan E Nordrehaug, Inge Bruheim, Asbjørn Svardal, Ottar Nygård, Rolf K Berge
Seafood is assumed to be beneficial for cardiovascular health, mainly based on plasma lipid lowering and anti-inflammatory effects of n-3 polyunsaturated fatty acids. However, other plasma risk factors linked to cardiovascular disease are less studied. This study aimed to penetrate the effect of a phospholipid-protein complex (PPC) from Antarctic krill on one-carbon metabolism and production of trimethylamine-N-oxide (TMAO) in rats. Male Wistar rats were fed isoenergetic control, 6%, or 11% PPC diets for four weeks...
September 2015: Marine Drugs
Kathrin Cordts, Dorothee Atzler, Vazhma Qaderi, Karsten Sydow, Rainer H Böger, Chi-Un Choe, Edzard Schwedhelm
Homoarginine (hArg) is a non-essential amino acid that was identified as a risk marker for cardiovascular disease. Several analytical methods have been described for the quantification of hArg in biological samples. The aim of this study was to compare a liquid chromatography-tandem mass spectrometric (LC-MS/MS) approach with a commercially available enzyme-linked immunosorbent assay (ELISA). Determination of hArg concentrations in ELISA calibration standards measured by both methods revealed a correlation coefficient r (2) of 0...
September 2015: Amino Acids
Levi J McClelland, Sean M Seagraves, Md Khurshid Alam Khan, Melisa M Cherney, Swati Bandi, Justin E Culbertson, Bruce E Bowler
Trimethyllysine 72 (tmK72) has been suggested to play a role in sterically constraining the heme crevice dynamics of yeast iso-1-cytochrome c mediated by the Ω-loop D cooperative substructure (residues 70-85). A tmK72A mutation causes a gain in peroxidase activity, a function of cytochrome c that is important early in apoptosis. More than one higher energy state is accessible for the Ω-loop D substructure via tier 0 dynamics. Two of these are alkaline conformers mediated by Lys73 and Lys79. In the current work, the effect of the tmK72A mutation on the thermodynamic and kinetic properties of wild-type iso-1-cytochrome c (yWT versus WT*) and on variants carrying a K73H mutation (yWT/K73H versus WT*/K73H) is studied...
July 2015: Journal of Biological Inorganic Chemistry: JBIC
Jaco Franken, Anita Burger, Jan H Swiegers, Florian F Bauer
Industrial synthesis of L-carnitine is currently performed by whole-cell biotransformation of industrial waste products, mostly D-carnitine and cronobetaine, through specific bacterial species. No comparable system has been established using eukaryotic microorganisms, even though there is a significant and growing international demand for either the pure compound or carnitine-enriched consumables. In eukaryotes, including the fungus Neurospora crassa, L-carnitine is biosynthesized through a four-step metabolic conversion of trimethyllysine to L-carnitine...
August 2015: Applied Microbiology and Biotechnology
Robyn J Eisert, Sarah A Kennedy, Marcey L Waters
Methylated lysine 9 on the histone 3 (H3) tail recruits heterochromatin protein 1 from Drosophila (dHP1) via its chromodomain and results in gene silencing. The dHP1 chromodomain binds H3 K9Me3 with an aromatic cage surrounding the trimethyllysine. The sequence selectivity of binding comes from insertion of the histone tail between two β-strands of the chromodomain to form a three-stranded β-sheet. Herein, we investigated the sequence selectivity provided by the β-sheet interactions and how those interactions compare to other model systems...
April 14, 2015: Biochemistry
Manuel Liebeke, Michael W Bruford, Robert K Donnelly, Timothy M D Ebbels, Jie Hao, Peter Kille, Elma Lahive, Rachael M Madison, A John Morgan, Gabriela A Pinto-Juma, David J Spurgeon, Claus Svendsen, Jacob G Bundy
Molecular genetic methods can distinguish divergent evolutionary lineages in what previously appeared to be single species, but it is not always clear what functional differences exist between such cryptic species. We used a metabolomic approach to profile biochemical phenotype (metabotype) differences between two putative cryptic species of the earthworm Lumbricus rubellus. There were no straightforward metabolite biomarkers of lineage, i.e. no metabolites that were always at higher concentration in one lineage...
September 2014: Biology Letters
Andris Kazaks, Marina Makrecka-Kuka, Janis Kuka, Tatyana Voronkova, Inara Akopjana, Solveiga Grinberga, Osvalds Pugovics, Kaspars Tars
Trimethyllysine hydroxylase (TMLH) catalyses the first step in carnitine biosynthesis - the conversion of N6,N6,N6-trimethyl-l-lysine to 3-hydroxy-N6,N6,N6-trimethyl-l-lysine. By changing carnitine availability it is possible to optimise cardiac energy metabolism, that is beneficial under certain ischemic conditions. Previous efforts have been devoted towards the inhibition of gamma-butyrobetaine dioxygenase, which catalyses the last step in carnitine biosynthesis. However, the effects of TMLH activity regulation are currently unexplored...
December 2014: Protein Expression and Purification
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