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acid pocket

Dina Robaa, Daria Monaldi, Nathalie Wössner, Norio, Kudo, Tobias Rumpf, Matthias Schiedel, Minoru Yoshida, Manfred Jung
Reversible lysine deacetylation is exerted by both zinc and NAD+ -dependent deacetylases. It is an important factor in epigenetic regulation and more generally in the posttranslational regulation of protein stability, association and activity. Some of these enzymes can also cleave off fatty acids or dicarboxylic acids from lysines in proteins. The NAD+ -dependent deacetylases are termed Sirtuins and are implicated in the pathogenesis of different diseases. For the isotype Sirt2 highly selective inhibitors have been identified in the last few years...
June 21, 2018: Chemical Record: An Official Publication of the Chemical Society of Japan ... [et Al.]
Run-Ze Li, Xing-Xing Fan, Dan-Feng Shi, Guo-Yuan Zhu, Yu-Wei Wang, Lian-Xiang Luo, Hu-Dan Pan, Xiao-Jun Yao, Elaine Lai-Han Leung, Liang Liu
OBJECTIVE: Lung cancer is the number one cancer in terms of both mortality and incidence. Cancer cells differ from normal cells in that they can reprogram their metabolism to support a rapid proliferation rate and alter oxidative phosphorylation processes toward lactic acid fermentation, even under aerobic conditions. Therefore we aimed to identify new compounds that might act as Pyruvate kinase M2 isoform (PKM2) activators and to investigate their anti-cancer efficacy in non-small cell lung cancer (NSCLC) cells...
June 21, 2018: Chemical Biology & Drug Design
Jagadeesan Ganapathy, Malathy Palayam, Gautam Pennathur, Aravindhan Sanmargam, Gunasekaran Krishnasamy
BACKGROUND: Hemoglobin (Hb) molecule consists of α2β2 dimers arranged in fashion having pseudo-222 symmetry. The subunits are composed of the specific functional prosthetic group "heme'' and a protein moiety "globin". Bird Hbs are functionally similar to mammalian Hbs and regulated by inositol pentaphosphate (IPP) but they are structurally dissimilar with mammalian Hbs in adaptation to vital environment such as high altitudes, high speed flights and oxygen affinity. The insufficient structural studies on avian Hbs limit us to understand their degree of adaptation to such critical environments...
June 20, 2018: Protein and Peptide Letters
Paola Estrada, Maho Morita, Yue Hao, Eric W Schmidt, Satish Nair
Mutation at a single amino acid alters the isoprene donor specificity of prenyltransferases involved in the modification of ribosomally synthesized and post-translationally modified peptides (RiPPs). While most characterized RiPP prenyltransferases carry out the regiospecific transfer of C5 dimethylallyl donor to the side chain atoms on macrocyclic acceptor substrates, the elucidation of the cyanobactin natural product piricyclamide 70005E1 identifies an O-geranyl modification on Tyr, a reaction with little prior biochemical precedence...
June 20, 2018: Journal of the American Chemical Society
Kimio Sumaru, Toshiyuki Takagi, Kana Morishita, Taku Satoh, Toshiyuki Kanamori
Photolithographic fabrication of unique microstructures composed of flexible hydrogel sheets is proposed and demonstrated by using photo-acid-generating poly(methyl methacrylate). Crosslinking of a hydroxyl-rich polymer and lifting off of the crosslinked polymer layer from the substrate are controlled respectively in an area-selective manner upon micropatterned light irradiation, and various pocket-like microstructures are fabricated resultantly.
June 20, 2018: Soft Matter
Jiah Lim, Yoojin Song, Jung-Hee Jang, Chul-Ho Jeong, Sooyeun Lee, Byoungduck Park, Young Ho Seo
Aspirin is one of the oldest drugs for the treatment of inflammation, fever, and pain. It is reported to covalently modify COX-2 enzyme by acetylating a serine amino acid residue. By virtue of aspirin's acetylating potential, we for the first time developed novel acetyl-donating HDAC inhibitors. In this study, we report the design, synthesis, in silico docking study, and biological evaluation of acetyl-donating HDAC inhibitors. The exposure of MDA-MB-231 cells with compound 4c significantly promotes the acetylation of α-tubulin and histone H3, which are substrates of HDAC6 and HDAC1, respectively...
June 20, 2018: Archives of Pharmacal Research
Mansour Sobeh, Mona F Mahmoud, Ganna Petruk, Samar Rezq, Mohamed L Ashour, Fadia S Youssef, Assem M El-Shazly, Daria M Monti, Ashraf B Abdel-Naim, Michael Wink
Syzygium aqueum is widely used in folk medicine. A polyphenol-rich extract from its leaves demonstrated a plethora of substantial pharmacological properties. The extract showed solid antioxidant properties in vitro and protected human keratinocytes (HaCaT cells) against UVA damage. The extract also reduced the elevated levels of ALT, AST, total bilirubin (TB), total cholesterol (TC) and triglycerides (TG) in rats with acute CCl4 intoxication. In addition to reducing the high MDA level, the extract noticeably restored GSH and SOD to the normal control levels in liver tissue homogenates and counteracted the deleterious histopathologic changes in liver after CCl4 injection...
2018: Frontiers in Pharmacology
Luca Neri, Ketty Peris, Caterina Longo, Stefano Calvieri, Pasquale Frascione, Aurora Parodi, Eibenschuz Laura, Ugo Bottoni, Giovanni Pellacani
BACKGROUND: Patients with multiple actinic keratoses (AK) should be treated with field-directed therapy. Such treatments challenge patients' adherence due out-of-pocket costs, length of treatment and severity of Local Skin Reactions (LSRs). Effective physician-patient communication (PPC) may buffer therapy-related distress thus improving quality of life, treatment satisfaction and adherence. OBJECTIVES: We evaluated the interplay between PPC, LSR intensity (safety) and lesion clearance rates (effectiveness) on treatment satisfaction, quality of life and treatment adherence among patients with multiple AK receiving topical field-directed therapies...
June 19, 2018: Journal of the European Academy of Dermatology and Venereology: JEADV
Jing Hou, Heping Zheng, Wen-Shyong Tzou, David R Cooper, Maksymilian Chruszcz, Mahendra D Chordia, Keehwan Kwon, Marek Grabowski, Wladek Minor
Vibrio cholerae, the causative pathogen of the life-threatening infection cholera, encodes two copies of β-ketoacyl-ACP synthase III (vcFabH1 and vcFabH2). vcFabH1 and vcFabH2 are pathogenic proteins associated with fatty acid synthesis, lipid metabolism, and potential applications in biofuel production. Our biochemical assays characterize vcFabH1 as exhibiting specificity for acetyl-CoA and CoA thioesters with short acyl chains, similar to that observed for FabH homologs found in most Gram-negative bacteria...
June 19, 2018: FEBS Journal
Tingting Yang, Huiru Yang, Yan Fan, Bafang Li, Hu Hou
Some small bioactive molecules from food show the potential health benefits, but with poor chemical stability and bioavailability. The interactions between small molecules and gelatin were investigated. Fluorescence experiments demonstrated that the bimolecular quenching constants (kq ) of complexes (gelatin-quercetin, gelatin-curcumin, gelatin-epigallocatechin gallate, gelatin-folic acid) were 3.7 × 1012  L·mol-1 ·s-1 , 1.4 × 1012  L·mol-1 ·s-1 , 2.7 × 1012  L·mol-1 ·s-1 and 8.5 × 1012  L·mol-1 ·s-1 , indicating that fluorescence quenching did not arise from a dynamical mechanism, but from gelatin-small molecules binding...
June 13, 2018: International Journal of Biological Macromolecules
Kalyanasundaram Subramanian, Artur Góra, Ruud Spruijt, Karolina Mitusińska, Maria Suarez-Diez, Vitor Martins Dos Santos, Peter J Schaap
D-amino acid oxidase (DAAO) degrades D-amino acids to produce α-ketoacids, hydrogen peroxide and ammonia. DAAO has often been investigated and engineered for industrial and clinical applications. We combined information from literature with a detailed analysis of the structure to engineer mammalian DAAOs. The structural analysis was complemented with molecular dynamics simulations to characterize solvent accessibility and product release mechanisms. We identified non-obvious residues located on the loops on the border between the active site and the secondary binding pocket essential for pig and human DAAO substrate specificity and activity...
2018: PloS One
Baoping Ling, Xiya Wang, Hao Su, Rutao Liu, Yongjun Liu
Linalool dehydratase/isomerase (LinD) from Castellaniella defragrans is a bifunctional enzyme that catalyzes the hydration of β-myrcene to (S)-linalool and the isomerization of (S)-linalool to geraniol. In this paper, on the basis of recently obtained crystal structures, the catalytic mechanism of LinD has been explored by a combined quantum mechanics and molecular mechanics (QM/MM) approach. Two computational models have been constructed. Model I (LinD-linalool) was derived from the crystal structure of the selenomethionine derivative of LinD (Semet-LinD) in complex with the natural substrate geraniol, whereas model II (LinD-β-myrcene) was constructed from the crystal structure of LinD in complex with β-myrcene...
June 15, 2018: Physical Chemistry Chemical Physics: PCCP
Przemyslaw Nogly, Tobias Weinert, Daniel James, Sergio Carbajo, Dmitry Ozerov, Antonia Furrer, Dardan Gashi, Veniamin Borin, Petr Skopintsev, Kathrin Jaeger, Karol Nass, Petra Båth, Robert Bosman, Jason Koglin, Matthew Seaberg, Thomas Lane, Demet Kekilli, Steffen Brünle, Tomoyuki Tanaka, Wenting Wu, Christopher Milne, Thomas White, Anton Barty, Uwe Weierstall, Valerie Panneels, Eriko Nango, So Iwata, Mark Hunter, Igor Schapiro, Gebhard Schertler, Richard Neutze, Jörg Standfuss
Ultrafast isomerization of retinal is the primary step in photoresponsive biological functions including vision in humans and ion-transport across bacterial membranes. We studied the sub-picosecond structural dynamics of retinal isomerization in the light-driven proton pump bacteriorhodopsin using an x-ray laser. A series of structural snapshots with near-atomic spatial and temporal resolution in the femtosecond regime show how the excited all- trans retinal samples conformational states within the protein binding pocket prior to passing through a twisted geometry and emerging in the 13 -cis conformation...
June 14, 2018: Science
Michele R Richards, Tianlin Guo, Carmanah D Hunter, Christopher W Cairo
Inhibitors of viral neuraminidase enzymes have been previously developed as therapeutics. Humans can express multiple forms of neuraminidase enzymes (NEU1, NEU2, NEU3, NEU4) that share a similar active site and enzymatic mechanism with their viral counterparts. Using a panel of purified human neuraminidase enzymes, we tested the inhibitory activity of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA), zanamivir, oseltamivir, and peramivir against each of the human isoenzymes. We find that, with the exceptions of DANA and zanamivir, these compounds show generally poor activity against the human neuraminidase enzymes...
May 23, 2018: Bioorganic & Medicinal Chemistry
Jenna L Mueller, Christopher T Lam, Denali Dahl, Mercy Nyamewaa Asiedu, Marlee S Krieger, Yenny Bellido-Fuentes, Mark Kellish, Jenna Peters, Alaattin Erkanli, Ernesto J Ortiz, Lisa C Muasher, Peyton T Taylor, John W Schmitt, Gino Venegas, Nirmala Ramanujam
OBJECTIVE: Our goal is to develop a tele-colposcopy platform for primary care clinics to improve screening sensitivity and access. Specifically, we developed a low-cost, portable Pocket colposcope and evaluated its performance in a tertiary healthcare center in Perú. DESIGN AND SETTING: Images of the cervix were captured with a standard-of-care and Pocket colposcope at la Liga Contra el Cáncer in Lima, Perú. POPULATION: 200 Peruvian women with abnormal cytology and/or HPV positivity were enrolled...
June 12, 2018: BJOG: An International Journal of Obstetrics and Gynaecology
Benoît Desguin, Matthias Fellner, Olivier Riant, Jian Hu, Robert Hausinger, Pascal Hols, Patrice Soumillion
Bacterial lactate racemase is a nickel-dependent enzyme that contains a cofactor, nickel pyridinium-3,5-bisthiocarboxylic acid mononucleotide, hereafter named nickel-pincer nucleotide (NPN). The LarC enzyme from the bacterium Lactobacillus plantarum participates in NPN biosynthesis by inserting nickel ion into pyridinium-3,5-bisthiocarboxylic acid mononucleotide,. This reaction, known in organometallic chemistry as a cyclometalation, is characterized by the formation of new metal-carbon and metal-sulfur σ bonds...
June 10, 2018: Journal of Biological Chemistry
Huiqun Wang, Glen E Kellogg, Ping Xu, Yan Zhang
Meso-Diaminopimelic acid (meso-2,6-diamino-heptanedioic acid, DAP) is an important component of the cell wall of many bacteria. Meso-diaminopimelate dehydrogenase (m-Ddh) is a critical enzyme in the process of converting tetrahydrodipicolinate to DAP. Here, we are proposing that DAP analogs targeting m-Ddh may be considered as potential antibiotics. Four DAP analogs without significant structural change from DAP have been obtained and their inhibitory potencies against m-Ddh from the P. gingivalis strain W83 show significant differences from that of DAP...
June 2, 2018: Journal of Molecular Graphics & Modelling
Magdalini Rovoli, Trias Thireou, Yvan Choiset, Thomas Haertlé, Lindsay Sawyer, Elias Eliopoulos, George Kontopidis
The milk protein β-lactoglobulin has been widely studied since its discovery, both as a purified protein and in mixtures with other milk proteins, where its effect on the processing properties is of importance to the dairy industry. The protein can bind a variety of small hydrophobic molecules, which may allow its use as an oral delivery vehicle. In the present study we have examined the binding of odd-numbered fatty acids by isothermal calorimetry (ITC), X-ray crystallography and computer modelling to provide a clearer picture of the extent and variability of the central binding pocket...
June 4, 2018: International Journal of Biological Macromolecules
Demeng Sun, You Yu, Xiaobin Xue, Man Pan, Ming Wen, Siyu Li, Qian Qu, Xiaorun Li, Longhua Zhang, Xueming Li, Lei Liu, Maojun Yang, Changlin Tian
Acid-sensing ion channels (ASICs) are neuronal voltage-independent Na+ channels that are activated by extracellular acidification. ASICs play essential roles in a wide range of physiological processes, including sodium homeostasis, synaptic plasticity, neurodegeneration, and sensory transduction. Mambalgins, a family of three-finger toxins isolated from black mamba venom, specifically inhibit ASICs to exert strong analgesic effects in vivo, thus are thought to have potential therapeutic values against pain...
2018: Cell Discovery
Zihui Fang, Jiujiu Huang, Jie Chen, Shaopeng Xu, Zhaojian Xiang, Mei Hong
Organic anion transporting polypeptides (OATPs, gene symbol SLCO) are important membrane transporter proteins that mediate the uptake of wide ranges of endogenous and exogenous compounds. OATP2B1 has been found in multiple organs and tissues including the liver, small intestine, kidney, brain, placenta, heart, skin as well as skeletal muscle and is proposed to be involved in the uptake of orally administered drugs. Quite a few reports have demonstrated that transmembrane domains (TMs) are crucial for proper functions of OATP family members...
June 5, 2018: Molecular Pharmacology
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