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Joanna C Evans, Carolina Trujillo, Zhe Wang, Hyungjin Eoh, Sabine Ehrt, Dirk Schnappinger, Helena I M Boshoff, Kyu Y Rhee, Clifton E Barry, Valerie Mizrahi
Mycobacterium tuberculosis relies on its own ability to biosynthesize coenzyme A to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the essential pantothenate and coenzyme A biosynthesis pathways have attracted attention as targets for tuberculosis drug development. To identify the optimal step for coenzyme A pathway disruption in M. tuberculosis, we constructed and characterized a panel of conditional knockdown mutants in coenzyme A pathway genes. Here, we report that silencing of coaBC was bactericidal in vitro, whereas silencing of panB, panC, or coaE was bacteriostatic over the same time course...
October 5, 2016: ACS Infectious Diseases
Christopher Sayer, William Finnigan, Michail N Isupov, Mark Levisson, Servé W M Kengen, John van der Oost, Nicholas J Harmer, Jennifer A Littlechild
A new carboxyl esterase, AF-Est2, from the hyperthermophilic archaeon Archaeoglobus fulgidus has been cloned, over-expressed in Escherichia coli and biochemically and structurally characterized. The enzyme has high activity towards short- to medium-chain p-nitrophenyl carboxylic esters with optimal activity towards the valerate ester. The AF-Est2 has good solvent and pH stability and is very thermostable, showing no loss of activity after incubation for 30 min at 80 °C. The 1.4 Å resolution crystal structure of AF-Est2 reveals Coenzyme A (CoA) bound in the vicinity of the active site...
2016: Scientific Reports
Andrew Proudfoot, Andreas O Frank, Fiorella Ruggiu, Mulugeta Mamo, Andreas Lingel
The deuteration of proteins and selective labeling of side chain methyl groups has greatly enhanced the molecular weight range of proteins and protein complexes which can be studied using solution NMR spectroscopy. Protocols for the selective labeling of all six methyl group containing amino acids individually are available, however to date, only a maximum of five amino acids have been labeled simultaneously. Here, we describe a new methodology for the simultaneous, selective labeling of all six methyl containing amino acids using the 115 kDa homohexameric enzyme CoaD from E...
May 2016: Journal of Biomolecular NMR
Rakesh Chatterjee, Abhisek Mondal, Abhishek Basu, Saumen Datta
BACKGROUND: Phosphopantetheine adenylyltransferase (PPAT) is a rate limiting enzyme which catalyzes the conversion of ATP and pantetheine to dephosphocoenzyme and pyrophosphate. The enzyme is allosteric in nature and regulated by Coenzyme A (CoA) through feedback inhibition. So far, several structures have been solved to decipher the catalytic mechanism of this enzyme. METHODS: To address catalytic and inhibitory mechanisms of PPAT, structural insights from single crystal X-ray diffraction method were primarily used, followed by biophysical and biochemical analysis...
July 2016: Biochimica et Biophysica Acta
Janna A van Diepen, Patrick A Jansen, Dov B Ballak, Anneke Hijmans, Floris P J T Rutjes, Cees J Tack, Mihai G Netea, Joost Schalkwijk, Rinke Stienstra
Vanins are enzymes that convert pantetheine to pantothenic acid (vitamin B5). Insights into the function of vanins have evolved lately, indicating vanin-1 to play a role in inflammation, oxidative stress and cell migration. Moreover, vanin-1 has recently gained attention as a novel modulator of hepatic glucose and lipid metabolism. In the present study, we investigated the role of vanin-1 in the development of hepatic steatosis and insulin resistance in animal models of obesity and diabetes. In addition, we evaluated the potency of RR6, a novel pharmacological vanin-1 inhibitor, as an anti-diabetic drug...
2016: Scientific Reports
Ping Liu, Chu-Bo Qi, Quan-Fei Zhu, Bi-Feng Yuan, Yu-Qi Feng
Precursor ion scan and multiple reaction monitoring scan (MRM) are two typical scan modes in mass spectrometry analysis. Here, we developed a strategy by combining stable isotope labeling (IL) with liquid chromatography-mass spectrometry (LC-MS) under double precursor ion scan (DPI) and MRM for analysis of thiols in 5 types of human cancer urine. Firstly, the IL-LC-DPI-MS method was applied for non-targeted profiling of thiols from cancer samples. Compared to traditional full scan mode, the DPI method significantly improved identification selectivity and accuracy...
2016: Scientific Reports
Xinqiang Xie, Ashish Garg, Adrian T Keatinge-Clay, Chaitan Khosla, David E Cane
The role of the conserved active site tyrosine and serine residues in epimerization catalyzed by polyketide synthase ketoreductase (PKS KR) domains has been investigated. Both mutant and wild-type forms of epimerase-active KR domains, including the intrinsically redox-inactive EryKR3° and PicKR3° as well as redox-inactive mutants of EryKR1, were incubated with [2-(2)H]-(2R,3S)-2-methyl-3-hydroxypentanoyl-SACP ([2-(2)H]-2) and 0.05 equiv of NADP(+) in the presence of the redox-active, epimerase-inactive EryKR6 domain...
March 1, 2016: Biochemistry
Janice M Reimer, Martin N Aloise, Paul M Harrison, T Martin Schmeing
Nonribosomal peptide synthetases (NRPSs) are very large proteins that produce small peptide molecules with wide-ranging biological activities, including environmentally friendly chemicals and many widely used therapeutics. NRPSs are macromolecular machines, with modular assembly-line logic, a complex catalytic cycle, moving parts and many active sites. In addition to the core domains required to link the substrates, they often include specialized tailoring domains, which introduce chemical modifications and allow the product to access a large expanse of chemical space...
January 14, 2016: Nature
Eric J Drake, Bradley R Miller, Ce Shi, Jeffrey T Tarrasch, Jesse A Sundlov, C Leigh Allen, Georgios Skiniotis, Courtney C Aldrich, Andrew M Gulick
Many important natural products are produced by multidomain non-ribosomal peptide synthetases (NRPSs). During synthesis, intermediates are covalently bound to integrated carrier domains and transported to neighbouring catalytic domains in an assembly line fashion. Understanding the structural basis for catalysis with non-ribosomal peptide synthetases will facilitate bioengineering to create novel products. Here we describe the structures of two different holo-non-ribosomal peptide synthetase modules, each revealing a distinct step in the catalytic cycle...
January 14, 2016: Nature
Panagiotis Arapitsas, Maurizio Ugliano, Daniele Perenzoni, Andrea Angeli, Paolo Pangrazzi, Fulvio Mattivi
The impact of minute amounts of oxygen in the headspace on the post-bottling development of wine is generally considered to be very important, since oxygen can either damage or improve the quality of wine. This project aimed to gain new experimental evidence about the chemistry of the interaction between wine and oxygen. The experimental design included 216 bottles of 12 different white wines produced from 6 different cultivars (Inzolia, Muller Thurgau, Chardonnay, Grillo, Traminer and Pinot gris). Half of them were bottled using the standard industrial process with inert headspace and the other half without inert gas and with extra headspace...
January 15, 2016: Journal of Chromatography. A
Zhen Qin, Yibei Xiao, Xinbin Yang, Jeroen R Mesters, Shaoqing Yang, Zhengqiang Jiang
Glycoside hydrolase (GH) family 3 β-N-acetylglucosaminidases widely exist in the filamentous fungi, which may play a key role in chitin metabolism of fungi. A multi-domain GH family 3 β-N-acetylglucosaminidase from Rhizomucor miehei (RmNag), exhibiting a potential N-acetyltransferase region, has been recently reported to show great potential in industrial applications. In this study, the crystal structure of RmNag was determined at 2.80 Å resolution. The three-dimensional structure of RmNag showed four distinctive domains, which belong to two distinguishable functional regions--a GH family 3 β-N-acetylglucosaminidase region (N-terminal) and a N-acetyltransferase region (C-terminal)...
2015: Scientific Reports
Daniel W Ferreira, Philippe Naquet, Jose E Manautou
In liver, cysteamine in all probability represents a "low-capacity, high-affinity" scavenger of ROS. The available body of evidence suggests that reduced cysteamine and oxidized cystamine exist in equilibrium and that this ratio acts as an active redox sensor within the cell much like GSH. During normal liver homeostasis cysteamine's antioxidant properties are evident. Highly metabolic and/or pro-oxidative conditions, such as in mice treated with peroxisome proliferators, shift this equilibrium to favor the oxidized form...
2015: Current Medicinal Chemistry
Goodluck U Onwukwe, M Kristian Koski, Petri Pihko, Werner Schmitz, Rik K Wierenga
Δ(3),Δ(2)-Enoyl-CoA isomerases (ECIs) catalyze the shift of a double bond from 3Z- or 3E-enoyl-CoA to 2E-enoyl-CoA. ECIs are members of the crotonase superfamily. The crotonase framework is used by many enzymes to catalyze a wide range of reactions on acyl-CoA thioesters. The thioester O atom is bound in a conserved oxyanion hole. Here, the mode of binding of acyl-CoA substrate analogues to peroxisomal Saccharomyces cerevisiae ECI (ScECI2) is described. The best defined part of the bound acyl-CoA molecules is the 3',5'-diphosphate-adenosine moiety, which interacts with residues of loop 1 and loop 2, whereas the pantetheine part is the least well defined...
November 2015: Acta Crystallographica. Section D, Biological Crystallography
Marianne de Villiers, Erick Strauss
No abstract text is available yet for this article.
October 2015: Nature Chemical Biology
Balaji Srinivasan, Madina Baratashvili, Marianne van der Zwaag, Bart Kanon, Cristina Colombelli, Roald A Lambrechts, Onno Schaap, Ellen A Nollen, Ajda Podgoršek, Gregor Kosec, Hrvoje Petković, Susan Hayflick, Valeria Tiranti, Dirk-Jan Reijngoud, Nicola A Grzeschik, Ody C M Sibon
The metabolic cofactor coenzyme A (CoA) gained renewed attention because of its roles in neurodegeneration, protein acetylation, autophagy and signal transduction. The long-standing dogma is that eukaryotic cells obtain CoA exclusively via the uptake of extracellular precursors, especially vitamin B5, which is intracellularly converted through five conserved enzymatic reactions into CoA. This study demonstrates an alternative mechanism that allows cells and organisms to adjust intracellular CoA levels by using exogenous CoA...
October 2015: Nature Chemical Biology
László Vécsei, Zoltán Horváth, Bernadett Tuka
The aim of this review is to commemorate Hans Selye, endocrinologist, the most famous researchers of stress and to briefly summarize the major features of somatostatin (SST), cysteamine (CysA) and patethine (PAN) in neuroendocrinological aspect, which are closely related to his scientific work. In addition, some metabolites of kynurenine pathway (KP) were also mentioned in this paper, as new, possible target molecules in neuroendocrinology. R. Guillemin and A. V. Schally were the main pioneers of the discovery of SST in the 1970's...
March 30, 2014: Ideggyógyászati Szemle
T A Keĭnanen, T Khivonen, Ĭ Vepsalajnen, L Alhonen, A R Homutov, Iu Ianne
Convenient two-step synthesis of conjugates of HS-CoA and D-pantetheine with aminooxy analogues of Spm, Spd and Put was suggested. The use of acetone linker provided target conjugates with quantitative yields. The activity of CoA-derived "bisubstrate" inhibitors being active at microM concentrations was at least 100 times better than that of corresponding derivatives of D-pantetheine.
March 2014: Bioorganicheskaia Khimiia
Niloufar Kavian, Wioleta Marut, Amélie Servettaz, Carole Nicco, Christiane Chéreau, Hervé Lemaréchal, Philippe Guilpain, Giovanna Chimini, Franck Galland, Bernard Weill, Philippe Naquet, Frédéric Batteux
OBJECTIVE: Endothelial cell (EC) damage in systemic sclerosis (SSc) is reflected by the shedding of microparticles (MPs). The aim of this study was to show that inhibiting MP release using pantethine or by inactivating ATP-binding cassette transporter A1 (ABCA1) ameliorates murine SSc. METHODS: First, the effects of pantethine on MP shedding and on basal oxidative and nitrosative stresses in ECs and fibroblasts were determined in vitro. The effects of pantethine were then tested in vivo...
July 2015: Arthritis & Rheumatology
Manuel van Gijsel-Bonnello, Niyazi Acar, Yves Molino, Lionel Bretillon, Michel Khrestchatisky, Max de Reggi, Bouchra Gharib
Pantethine, a natural low-molecular-weight thiol, shows a broad activity in a large range of essential cellular pathways. It has been long known as a hypolipidemic and hypocholesterolemic agent. We have recently shown that it exerts a neuroprotective action in mouse models of cerebral malaria and Parkinson's disease through multiple mechanisms. In the present study, we looked at its effects on membrane lipid rafts that serve as platforms for molecules engaged in cell activity, therefore providing a target against inappropriate cell response leading to a chronic inflammation...
October 2015: Journal of Cellular Physiology
Ariane Roseblade, Frederick Luk, Alison Ung, Mary Bebawy
Microparticles (MPs) are released from most eukaryotic cells after the vesiculation of the plasma membrane and serve as vectors of long and short-range signaling. MPs derived from multidrug resistant (MDR) cancer cells carry molecular components of the donor cell such as nucleic acids and proteins, and can alter the activity of drug-sensitive recipient cells through the transfer of their cargo. Given the substantial role of MPs in the acquisition and dissemination of MDR, we propose that the inhibition of MP release provides a novel therapeutic approach...
2015: Current Cancer Drug Targets
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