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Sarder Arifuzzaman, Md Saidur Rahman, Myung-Geol Pang
With the continued increase in global human population, diverse contraception approaches have become increasingly essential, including non-hormonal male contraception. Non-hormonal approaches to contraception are very convenient; however, such options are limited because data regarding the identification and characterization of tissue/cell-specific targets and appropriate small molecule candidate contraceptives are lacking. Based on in-silico studies of genomics, transcriptomics, and proteomics, performed by mining datasets in PubMed, we first reviewed testis-, epididymis-, and germline cell-specific genes/proteins, with the aim of presenting evidence that many of these could become 'druggable' targets for the development of non-hormonal male contraceptives in the future...
December 11, 2018: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Gunnar B Sandholt, Bjarki Stefansson, Reynir Scheving, Ágústa Gudmundsdottir
Atlantic cod trypsin ZT is biochemically characterized for the first time in this report in comparison to a group I trypsin (cod trypsin I). To our knowledge, trypsin ZT is the first thoroughly characterized group III trypsin. A more detailed understanding of trypsin ZT biochemistry may give insight into its physiological role as well as its potential use within the biotechnology sector. Stability is an important factor when it comes to practical applications of enzymes. Compared to trypsin I, trypsin ZT shows differences in pH and heat stability, sensitivity to inhibitors and sub-site substrate specificity as shown by multiplex substrate profiling analysis...
December 11, 2018: International Journal of Biological Macromolecules
Francesco Francia, Bahia Khalfaoui-Hassani, Pascal Lanciano, Francesco Musiani, Louis Noodleman, Giovanni Venturoli, Fevzi Daldal
The ubihydroquinone:cytochrome (cyt) c oxidoreductase (or cyt bc1 ) is an important enzyme for photosynthesis and respiration. In bacteria like Rhodobacter capsulatus, this membrane complex has three subunits, the iron‑sulfur protein (ISP) with its Fe2 S2 cluster, cyt c1 and cyt b, forming two catalytic domains, the Qo (hydroquinone (QH2 ) oxidation) and Qi (quinone (Q) reduction) sites. At the Qo site, the electron transfer pathways originating from QH2 oxidation are known, but their associated proton release routes are less well defined...
December 11, 2018: Biochimica et biophysica acta. Bioenergetics
Moon-Ju Kim, Jong-Min Park, Joo-Yoon Noh, Tae Gyeong Yun, Min-Jung Kang, Jae-Chul Pyun
RATIONALE: Magnetic particles coated with Au NPs (Au-MAGs) were developed and used (1) for sample concentration and (2) as a solid matrix for laser adsorption/desorption (LDI)-mass spectrometry. METHODS: The Au-MAGs were prepared by (1) coating polystyrene on iron oxide NPs (PS-MNPs), (2) coating poly-l-lysine on the PS-MNPs (PLL-coated PS-MNPs), and (3) coating negatively charged Au NPs on the PLL-coated PS-MNPs (Au-MAGs). RESULTS: The Au-MAGs were used to concentrate the target analyte by means of electrostatic interactions between the positively charged GHP9 and the negatively charged Au-MAGs as well as selective interactions (such as gold-sulfur interactions) between glutathione (GSH) and Au-MAGs...
December 13, 2018: Rapid Communications in Mass Spectrometry: RCM
Jacques Teulon, Gabrielle Planelles, Francisco V Sepúlveda, Olga Andrini, Stéphane Lourdel, Marc Paulais
The many mechanisms governing NaCl absorption in the diverse parts of the renal tubule have been largely elucidated, although some of them, as neutral NaCl absorption across the cortical collecting duct or regulation through with-no-lysine (WNK) kinases have emerged only recently. Chloride channels, which are important players in these processes, at least in the distal nephron, are the focus of this review. Over the last 20-year period, experimental studies using molecular, electrophysiological, and physiological/functional approaches have deepened and renewed our views on chloride channels and their role in renal function...
December 13, 2018: Comprehensive Physiology
Pengfei Bai, Chan-Ho Park, Gautam Shirsekar, Pattavipha Songkumarn, Maria Bellizzi, Guo-Liang Wang
Magnaporthe oryzae is an important fungal pathogen of both rice and wheat. However, how M. oryzae effectors modulate plant immunity is not fully understood. Previous studies showed that the M. oryzae effector AvrPiz-t targets the host ubiquitin-proteasome system to manipulate plant defense. In return, two rice ubiquitin E3 ligases, APIP6 and APIP10, ubiquitinate AvrPiz-t for degradation. To determine how lysine residues contribute to AvrPiz-t stability and function, we generated double (K1,2R-AvrPiz-t), triple (K1,2,3R-AvrPiz-t) and lysine-free (LF-AvrPiz-t) mutants by mutating lysines into arginines in AvrPiz-t...
December 12, 2018: Molecular Plant Pathology
Ning Ding, Sam A Miller, Sudha S Savant, Heather M O'Hagan
At sites of chronic inflammation epithelial cells undergo aberrant DNA methylation that contributes to tumorigenesis. Inflammation is associated with an increase in reactive oxygen species (ROS) that cause oxidative DNA damage, which has also been linked to epigenetic alterations. We previously demonstrated that in response to ROS, mismatch repair (MMR) proteins MSH2 and MSH6 recruit epigenetic silencing proteins DNA methyltransferase 1 (DNMT1) and Polycomb repressive complex 2 (PRC2) members to sites of DNA damage, resulting in transcriptional repression of tumor suppressor genes (TSGs)...
December 11, 2018: Environmental and Molecular Mutagenesis
Tetsuya Miyamoto, Masumi Katane, Yasuaki Saitoh, Masae Sekine, Hiroshi Homma
Various D-amino acids are involved in peptidoglycan and biofilm metabolism in bacteria, suggesting that these compounds are necessary for successful adaptation to environmental changes. In addition to the conventional D-alanine (D-Ala) and D-glutamate, the peptidoglycan of the hyperthermophilic bacterium Thermotoga maritima contains both L-lysine (L-Lys) and D-Lys, but not meso-diaminopimelate (meso-Dpm). D-Lys is an uncommon component of peptidoglycan, and its biosynthetic pathway remains unclear. In this study, we identified and characterised a novel Lys racemase (TM1597) and Dpm epimerase (TM1522) associated with the D-Lys biosynthetic pathway in T...
December 7, 2018: FEBS Journal
Fernando Meza Gutierrez, Deniz Simsek, Arda Mizrak, Adam Deutschbauer, Hannes Braberg, Jeffrey Johnson, Jiewei Xu, Michael Shales, Michelle Nguyen, Raquel Tamse-Kuehn, Curt Palm, Lars M Steinmetz, Nevan J Krogan, David P Toczyski
Although polyubiquitin chains linked through all lysines of ubiquitin exist, specific functions are well-established only for lysine-48 and lysine-63 linkages in Saccharomyces cerevisiae. To uncover pathways regulated by distinct linkages, genetic interactions between a gene deletion library and a panel of lysine-to-arginine ubiquitin mutants were systematically identified. The K11R mutant had strong genetic interactions with threonine biosynthetic genes. Consistently, we found that K11R mutants import threonine poorly...
December 14, 2018: ELife
Kaylee Gaspar, Kimberly Fabijanczuk, Tara Otegui, Jose Acosta, Jinshan Gao
By incorporating a high proton affinity moiety to the charge localized free radical-initiated peptide sequencing (CL-FRIPS) reagent, FRIPS-MS technique has extended the applicability to hydrophobic peptides and peptides without basic amino acid residues (lysine, arginine, and histidine). Herein, the CL-FRIPS reagent has three moieties: (1) pyridine acting as the basic site to locate the proton, (2) 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, a stable free radical) acting as the free radical precursor to generate the nascent free radical in the gas phase, and (3) N-hydroxysuccinimide (NHS) activated carboxylic acid acting as the coupling site to derivatize the N-terminus of peptides...
December 13, 2018: Journal of the American Society for Mass Spectrometry
Edgar López-López, Fernando D Prieto-Martínez, José L Medina-Franco
In this work we discuss the insights from activity landscape, docking and molecular dynamics towards the understanding of the structure-activity relationships of dual inhibitors of major epigenetic targets: lysine methyltransferase (G9a) and DNA methyltranferase 1 (DNMT1). The study was based on a novel data set of 50 published compounds with reported experimental activity for both targets. The activity landscape analysis revealed the presence of activity cliffs, e.g., pairs of compounds with high structure similarity but large activity differences...
December 11, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Nolan T Carew, Ashley M Nelson, Zhitao Liang, Sage M Smith, Christine Milcarek
RNA splicing patterns in antibody-secreting cells are shaped by endoplasmic reticulum stress, ELL2 (eleven-nineteen lysine-rich leukemia gene 2) induction, and changes in the levels of snRNA s. Endoplasmic reticulum stress induces the unfolded protein response comprising a highly conserved set of genes crucial for cell survival; among these is Ire1, whose auto-phosphorylation drives it to acquire a regulated mRNA decay activity. The mRNA-modifying function of phosphorylated Ire1 non-canonically splices Xbp1 mRNA and yet degrades other cellular mRNAs with related motifs...
December 7, 2018: International Journal of Molecular Sciences
(no author information available yet)
OBJECTIVEPediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma, present a prognostic challenge given their lethality and rarity. A substitution mutation of lysine for methionine at position 27 in histone H3 (H3K27M) has been shown to be highly specific to these tumors. Data are accumulating regarding the poor outcomes of patients with these tumors; however, the quantification of pooled outcomes has yet to be done, which could assist in prioritizing management. The aim of this study was to quantitatively pool data in the current literature on the H3K27M mutation as an independent prognostic factor in pHGG...
November 1, 2018: Journal of Neurosurgery. Pediatrics
Chen-Hsi Chu, Cheng-Yi Yen, Bo-Wei Chen, Min-Guan Lin, Lyu-Han Wang, Kai-Zhi Tang, Chwan-Deng Hsiao, Yuh-Ju Sun
ParABS, an important DNA partitioning process in chromosome segregation, includes ParA (an ATPase), ParB (a parS binding protein) and parS (a centromere-like DNA). The homologous proteins of ParA and ParB in Helicobacter pylori are HpSoj and HpSpo0J, respectively. We analyzed the ATPase activity of HpSoj and found that it is enhanced by both DNA and HpSpo0J. Crystal structures of HpSoj and its DNA complexes revealed a typical ATPase fold and that it is dimeric. DNA binding by HpSoj is promoted by ATP. The HpSoj-ATP-DNA complex non-specifically binds DNA through a continuous basic binding patch formed by lysine residues, with a single DNA-binding site...
December 14, 2018: Nucleic Acids Research
Luofang Peng, Maoen Zhu, Yong Yang, Yingqi Weng, Wangyuan Zou, Xiaoyan Zhu, Qulian Guo, Tao Zhong
Neonatal inflammation induces long-term effects on brain function. We investigated the effects of systematic neonatal inflammation using lipopolysaccharide (LPS) injection at postnatal day 3 (P3) and P5 in a mouse model of spatial memory capacity measured using a Morris water maze (MWM) task in adulthood. Subsequently, we assessed histone acetylation and immediate-early response gene expression (c-Fos and brain-derived neurotrophic factor) in the hippocampus in response to MWM acquisition training. The LPS-treated mice exhibited a significant spatial cognitive impairment, which was accompanied by insufficient histone acetylation of the H4K12 specific lysine residue and repressed c-Fos gene expression immediately after acquisition training...
December 10, 2018: Neuroscience
Anokha S Ratnayake, Li-Ping Chang, L Nathan Tumey, Frank Loganzo, Joseph A Chemler, Melissa Wagenaar, Sylvia Musto, Fengping Li, Jeffrey E Janso, T Eric Ballard, Brian Rago, Greg L Steele, WeiDong Ding, Xidong Feng, Christine Hosselet, Vlad Buklan, Judy Lucas, Frank E Koehn, Christopher J O'Donnell, Edmund I Graziani
A potent class of DNA-damaging agents, natural product bis-intercalator depsipeptides (NPBIDs), was evaluated as ultrapotent payloads for use in antibody-drug conjugates (ADCs). Detailed investigation of potency (both in cells and via biophysical characterization of DNA binding), chemical tractability, and in vitro and in vivo stability of the compounds in this class eliminated a number of potential candidates, greatly reducing the complexity and resources required for conjugate preparation and evaluation. This effort yielded a potent, stable, and efficacious ADC, PF-06888667, consisting of the bis-intercalator, SW-163D, conjugated via an N-acetyl-lysine-valine-citrulline- p-aminobenzyl alcohol- N, N-dimethylethylenediamine (AcLysValCit-PABC-DMAE) linker to an engineered variant of the anti-Her2 mAb, trastuzumab, catalyzed by transglutaminase...
December 13, 2018: Bioconjugate Chemistry
Sindy J Rodríguez, Eduardo A Albanesi
We modeled a type of field-effect transistor device based on graphene for the recognition of amino acids with a potential application in the building of a protein sequencer. The theoretical model used was a combination of density functional theory (DFT) with the non-equilibrium Green's function (NEGF) in order to describe the coherent transport in molecular devices. First, we studied the physisorption of each amino acid on a graphene sheet and we reported the adsorption energy, the adsorption distances, the equilibrium configuration and the charge transfer of ten amino acids that can be considered as representative of all of the amino acids: histidine (His), alanine (Ala), aspartic acid (Asp), tyrosine (Tyr), arginine (Arg), glutamic acid (Glu), glycine (Gly), phenylalanine (Phe), proline (Pro) and lysine (Lys)...
December 13, 2018: Physical Chemistry Chemical Physics: PCCP
Sanja Škulj, Katarina Vazdar, Davor Margetić, Mario Vazdar
We revisit the reaction mechanism of reaction between model lysine side chain and reactive aldehyde 4-hydroxynonenal in different solvents with increasing water content. We show by model organic reactions and qualitative spectrometric analysis that non-polar pyrrole adduct is dominantly formed in non-aqueous solvents dichloromethane and acetonitrile. On the other hand, in aqueous acetonitrile and neat water, other polar products are also isolated including Michael adducts, hemiacetal adducts and pyridinium salt adducts, at the same time decreasing the ratio of non-polar products vs polar products...
December 13, 2018: Journal of Organic Chemistry
Lianhua Piao, Xiaofeng Yuan, Ming Zhuang, Xubin Qiu, Xiaoshuang Xu, Ren Kong, Zhiwei Liu
Suppressor of variegation 3‑9 homologue 2 (SUV39H2), a SET domain‑containing histone methyl-transferase, trimethylates histone H3 at lysine 9 and serves crucial roles in heterochromatin organization and genome stability. SUV39H2 is overexpressed in various types of human cancer, whereas it is almost undetectable in normal adult tissues, except testis. The aim of this study was to investigate a potential role of SUV39H2 in osteosarcoma. In the present study, increased SUV39H2 expression levels were observed in osteosarcoma, the most common primary bone cancer in children and adolescents, and the knockdown of SUV39H2 expression by specific small interfering RNAs in osteosarcoma cells markedly suppressed cancer cell growth and led to a notable reduction in cell viability...
November 1, 2018: Oncology Reports
Rui Zhang, Jing-Jing Hong, Qiaoyun Yang, Chin-Tong Ong, Bo-An Li, Yih-Cherng Liou
Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification by which poly ADP-ribose (PAR) polymers are covalently added to proteins through a PAR polymerase (PARP). Here, using proteomic approach, we identify the transcriptional regulator, OVOL2, is a novel substrate of PARP1 and can be PARylated at residues Lysine 145, Lysine 176, and Lysine 212 within its C2H2 zinc finger domains. Overexpression of PARylated OVOL2 alters cell morphology and induces lagging chromosomes and aneuploidy. To define the underlying molecular mechanism by which OVOL2 induces abnormal cell cycle and centrosome amplification, we uncover that the OVOL2 elevates the protein levels of Cyclin E by enhancing its stability...
December 12, 2018: Oncogene
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