Acetic Acid (Activator-3) Is a Potent Activator of AMPK
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Magnesium Plays a Salient Role in the Cells
341 Journal of Clinical and Biomedical Sciences Journal homepage: www.jcbsonline.ac.in Review Article Magnesium Plays a Salient Role in the Cells R Deepti1*, G Nalini2 Department of Biochemistry, Sri Muthukumaran Medical college Hospital and Research Institute, Chennai, Tamilnadu, India. Department of Biochemistry, Sri Ramachandra Medical college and Research Institute, Chennai, Tamilnadu, India. Received: 17th October-2014 Accepted: 11th December-2014 Published: 31st –December 2014. Abstract Magnesium is an important macromineral. Major amount of magnesium is present in the bones. Magnesium ab- sorption takes place at the small intestine and magnesium levels are maintained by the kidneys. Magnesium is a fundamen- tal mineral in the mammalian cells. Magnesium acts as a co-factor for many enzymes, especially enzymes involved in carbo- hydrate and lipid metabolism. Magnesium is necessary for muscle contraction by acting as a calcium antagonist, cellular proliferation, apoptosis, immune response, etc. Now a days hypomagnesemia is very commonly seen condition associated with predominant diseases like diabetes, hypertension, cardiovascular diseases, obesity, etc. Several authors have reported that low serum magnesium levels, insulin resistance and hyperlipidemia are interrelated. Hypomagnesemia may play an causative role in the development of diabetes, oxidative stress, thrombosis, atherosclerosis, etc. Hence magnesium impor- tances should be highlighted in the research field. Keywords: hypomagnesemia, hyperlipidemia and atherosclerosis. Introduction Magnesium Homeostasis Magnesium is the fourth most abundant cation and Recommended daily allowance (RDA) for magne- the second most abundant intracellular cation next to potas- sium is 400 mg for men and 300 mg for female. Major sium in the human body.(1,2) sources for magnesium are cereals, beans, leafy vegetables and fish. -
Deep Profiling of Protease Substrate Specificity Enabled by Dual Random and Scanned Human Proteome Substrate Phage Libraries
Deep profiling of protease substrate specificity enabled by dual random and scanned human proteome substrate phage libraries Jie Zhoua, Shantao Lib, Kevin K. Leunga, Brian O’Donovanc, James Y. Zoub,d, Joseph L. DeRisic,d, and James A. Wellsa,d,e,1 aDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158; bDepartment of Biomedical Data Science, Stanford University, Stanford, CA 94305; cDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA 94158; dChan Zuckerberg Biohub, San Francisco, CA 94158; and eDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158 Edited by Benjamin F. Cravatt, Scripps Research Institute, La Jolla, CA, and approved August 19, 2020 (received for review May 11, 2020) Proteolysis is a major posttranslational regulator of biology inside lysate and miss low abundance proteins and those simply not and outside of cells. Broad identification of optimal cleavage sites expressed in cell lines tested that typically express only half their and natural substrates of proteases is critical for drug discovery genomes (13). and to understand protease biology. Here, we present a method To potentially screen a larger and more diverse sequence that employs two genetically encoded substrate phage display space, investigators have developed genetically encoded substrate libraries coupled with next generation sequencing (SPD-NGS) that phage (14, 15) or yeast display libraries (16, 17). Degenerate DNA allows up to 10,000-fold deeper sequence coverage of the typical six- sequences (up to 107) encoding random peptides were fused to a to eight-residue protease cleavage sites compared to state-of-the-art phage or yeast coat protein gene for a catch-and-release strategy synthetic peptide libraries or proteomics. -
Inhibitors of Pyruvate Carboxylase Tonya N
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by epublications@Marquette Marquette University e-Publications@Marquette Biological Sciences Faculty Research and Biological Sciences, Department of Publications 1-1-2010 Inhibitors of Pyruvate Carboxylase Tonya N. Zeczycki University of Wisconsin - Madison Martin St. Maurice Marquette University, [email protected] Paul V. Attwood University of Western Australia Published version. The Open Enzyme Inhibition Journal, Vol. 3 (2010): 8-26. DOI. © 2010 Bentham Open. Used with permission. This is an open access article licensed under the terms of the Creative Commons Attribution Non- Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) 8 The Open Enzyme Inhibition Journal, 2010, 3, 8-26 Open Access Inhibitors of Pyruvate Carboxylase Tonya N. Zeczycki1, Martin St. Maurice2 and Paul V. Attwood3,* 1Department of Biochemistry, University of Wisconsin, Madison, WI 53726, USA 2Department of Biological Sciences, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA 3School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, WA6009, Australia Abstract: This review aims to discuss the varied types of inhibitors of biotin-dependent carboxylases, with an emphasis on the inhibitors of pyruvate carboxylase. Some of these inhibitors are physiologically relevant, in that they provide ways of regulating the cellular activities of the enzymes e.g. aspartate and prohibitin inhibition of pyruvate carboxylase. Most of the inhibitors that will be discussed have been used to probe various aspects of the structure and function of these enzymes. They target particular parts of the structure e.g. avidin – biotin, FTP – ATP binding site, oxamate – pyruvate binding site, phosphonoacetate – binding site of the putative carboxyphosphate intermediate. -
Understanding the Structure and Function of Catalases: Clues from Molecular Evolution and in Vitro Mutagenesis
PERGAMON Progress in Biophysics & Molecular Biology 72 (1999) 19±66 Understanding the structure and function of catalases: clues from molecular evolution and in vitro mutagenesis Marcel Za mocky *, Franz Koller Institut fuÈr Biochemie and Molekulare Zellbiologie and Ludwig Boltzmann Forschungsstelle fuÈr Biochemie, Vienna Biocenter, Dr. Bohr-Gasse 9, A-1030 Wien, Austria Abstract This review gives an overview about the structural organisation of dierent evolutionary lines of all enzymes capable of ecient dismutation of hydrogen peroxide. Major potential applications in biotechnology and clinical medicine justify further investigations. According to structural and functional similarities catalases can be divided in three subgroups. Typical catalases are homotetrameric haem proteins. The three-dimensional structure of six representatives has been resolved to atomic resolution. The central core of each subunit reveals a chracteristic ``catalase fold'', extremely well conserved among this group. In the native tetramer structure pairs of subunits tightly interact via exchange of their N- terminal arms. This pseudo-knot structures implies a highly ordered assembly pathway. A minor subgroup (``large catalases'') possesses an extra ¯avodoxin-like C-terminal domain. A r25AÊ long channel leads from the enzyme surface to the deeply buried active site. It enables rapid and selective diusion of the substrates to the active center. In several catalases NADPH is tightly bound close to the surface. This cofactor may prevent and reverse the formation of compound II, an inactive reaction intermediate. Bifunctional catalase-peroxidases are haem proteins which probably arose via gene duplication of an ancestral peroxidase gene. No detailed structural information is currently available. Even less is know about manganese catalases. -
Drug Conjugates Based on a Monovalent Affibody Targeting
cancers Article Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model Tianqi Xu 1,† , Haozhong Ding 2,† , Anzhelika Vorobyeva 1,3 , Maryam Oroujeni 1, Anna Orlova 3,4 , Vladimir Tolmachev 1,3 and Torbjörn Gräslund 2,* 1 Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden; [email protected] (T.X.); [email protected] (A.V.); [email protected] (M.O.); [email protected] (V.T.) 2 Department of Protein Science, KTH Royal Institute of Technology, Roslagstullsbacken 21, 114 17 Stockholm, Sweden; [email protected] 3 Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia; [email protected] 4 Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden * Correspondence: [email protected]; Tel.: +46-(0)8-790-96-27 † Equal contribution. Simple Summary: Drug conjugates, consisting of a tumor targeting part coupled to a highly toxic molecule, are promising for treatment of many different types of cancer. However, for many patients it is not curative, and investigation of alternative or complimentary types of drug conjugates is motivated. Here, we have devised and studied a novel cancer cell-directed drug conjugate ZHER2:2891- ABD-E3-mcDM1. We found that it could induce efficient shrinkage and, in some cases, complete Citation: Xu, T.; Ding, H.; Vorobyeva, regression of human tumors implanted in mice, and thus holds promise to become a therapeutic A.; Oroujeni, M.; Orlova, A.; agent for clinical use in the future. -
Download Author Version (PDF)
MedChemComm Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/medchemcomm Page 1 of 6 Journal Name Medicinal Chemistry Communications Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE Optimizing Glucokinase Activator Binding Kinetics to Lower in vivo Hypoglycemia Risk Manuscript Kris A. Borzilleri ‡ Jeffrey A. Pfefferkorn ╢, Angel Guzman-Perez ¥, Shenping Liu ‡, Xiayang Qiu ‡, Boris A. Chrunyk ‡, Xi Song ‡ Meihua Tu ╢, Kevin J. Filipski ╢, Robert Aiello ±, David R. Derksen ‡, Francis J. ‡ † ± ┴ ┼ ± 5 Bourbonais , James Landro , Patricia Bourassa , Theresa D’Aquila , Levenia Baker , Nicole Barrucci , John Litchfield ‡, Karen Atkinson ‡ Timothy P. Rolph ╢ and Jane M. Withka ‡* Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X DOI: 10.1039/b000000x Accepted Activation of glucokinase represents a promising strategy for the treatment of type 2 diabetes; however, 10 drug candidates have failed in clinical trials due to narrow therapeutic index between glucose-lowering efficacy and hypoglycemia. -
Inhibitors of Pyruvate Carboxylase Tonya N
Marquette University e-Publications@Marquette Biological Sciences Faculty Research and Biological Sciences, Department of Publications 1-1-2010 Inhibitors of Pyruvate Carboxylase Tonya N. Zeczycki University of Wisconsin - Madison Martin St. Maurice Marquette University, [email protected] Paul V. Attwood University of Western Australia Published version. The Open Enzyme Inhibition Journal, Vol. 3 (2010): 8-26. DOI. © 2010 Bentham Open. Used with permission. This is an open access article licensed under the terms of the Creative Commons Attribution Non- Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) 8 The Open Enzyme Inhibition Journal, 2010, 3, 8-26 Open Access Inhibitors of Pyruvate Carboxylase Tonya N. Zeczycki1, Martin St. Maurice2 and Paul V. Attwood3,* 1Department of Biochemistry, University of Wisconsin, Madison, WI 53726, USA 2Department of Biological Sciences, Marquette University, P.O. Box 1881, Milwaukee, WI 53201-1881, USA 3School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, WA6009, Australia Abstract: This review aims to discuss the varied types of inhibitors of biotin-dependent carboxylases, with an emphasis on the inhibitors of pyruvate carboxylase. Some of these inhibitors are physiologically relevant, in that they provide ways of regulating the cellular activities of the enzymes e.g. aspartate and prohibitin inhibition of pyruvate carboxylase. Most of the inhibitors that will be discussed have been used to probe various aspects of the structure and function of these enzymes. They target particular parts of the structure e.g. avidin – biotin, FTP – ATP binding site, oxamate – pyruvate binding site, phosphonoacetate – binding site of the putative carboxyphosphate intermediate. Keywords: Pyruvate carboxylase, biotin-dependent enzyme, avidin, biotin, nucleotide inhibitors, acetyl coenzyme A, allosteric inhibitors, chlorothricin. -
GTP Activator and Dntp Substrates of HIV-1 Restriction Factor SAMHD1
GTP activator and dNTP substrates of HIV-1 restriction PNAS PLUS factor SAMHD1 generate a long-lived activated state Erik C. Hansen, Kyle J. Seamon, Shannen L. Cravens, and James T. Stivers1 Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD 21205-2185 Edited by Myron F. Goodman, University of Southern California, Los Angeles, CA, and accepted by the Editorial Board March 26, 2014 (received for review January 27, 2014) The HIV-1 restriction factor sterile α-motif/histidine-aspartate phatases (14). Presumably, degradation to the level of nucleoside domain-containing protein 1 (SAMHD1) is a tetrameric protein that rather than deoxynucleoside diphosphate (dNDP) or deoxy- catalyzes the hydrolysis of all dNTPs to the deoxynucleoside and nucleoside monophosphate (dNMP) is to make the process tripolyphosphate, which effectively depletes the dNTP substrates energetically or kinetically costly to reverse, with the additional of HIV reverse transcriptase. Here, we establish that SAMHD1 is possibility that the neutral nucleoside will be irreversibly trans- activated by GTP binding to guanine-specific activator sites (A1) as ported out of the cell (9). The unusual triphosphohydrolase activity well as coactivation by substrate dNTP binding to a distinct set of of SAMHD1 in quiescent immune cells has received significant nonspecific activator sites (A2). Combined activation by GTP and attention, because HIV-1 and HSV-1 are severely restricted in their dNTPs results in a long-lived tetrameric form of SAMHD1 that ability to infect quiescent cells that have severely depressed dNTP persists for hours, even after activating nucleotides are withdrawn pools, which has been directly linked to SAMHD1 enzymatic ac- from the solution. -
EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis Through ATF4 and C-MYC
Published OnlineFirst October 10, 2018; DOI: 10.1158/2159-8290.CD-18-0606 RESEARCH ARTICLE EIF1AX and RAS Mutations Cooperate to Drive Thyroid Tumorigenesis through ATF4 and c-MYC Gnana P. Krishnamoorthy 1 , Natalie R. Davidson 2 , Steven D. Leach 1 , Zhen Zhao 3 , Scott W. Lowe 3 , Gina Lee 4 , Iňigo Landa 1 , James Nagarajah 1 , Mahesh Saqcena 1 , Kamini Singh 3 , Hans-Guido Wendel3 , Snjezana Dogan 5 , Prasanna P. Tamarapu 1 , John Blenis 4 , Ronald A. Ghossein 5 , Jeffrey A. Knauf 1 , 6 , Gunnar Rätsch 2 , and James A. Fagin 1 , 6 ABSTRACT Translation initiation is orchestrated by the cap binding and 43S preinitiation com- plexes (PIC). Eukaryotic initiation factor 1A (EIF1A) is essential for recruitment of the ternary complex and for assembling the 43S PIC. Recurrent EIF1AX mutations in papillary thyroid cancers are mutually exclusive with other drivers, including RAS . EIF1AX mutations are enriched in advanced thyroid cancers, where they display a striking co-occurrence with RAS , which cooperates to induce tumorigenesis in mice and isogenic cell lines. The C-terminal EIF1AX-A113splice mutation is the most prevalent in advanced thyroid cancer. EIF1AX-A113splice variants stabilize the PIC and induce ATF4, a sensor of cellular stress, which is co-opted to suppress EIF2α phosphorylation, enabling a gen- eral increase in protein synthesis. RAS stabilizes c-MYC, an effect augmented by EIF1AX-A113splice. ATF4 and c-MYC induce expression of amino acid transporters and enhance sensitivity of mTOR to amino acid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4, and mTOR kinase inhibitors. SIGNIFICANCE: Mutations of EIF1AX, a component of the translation PIC, co-occur with RAS in advanced thyroid cancers and promote tumorigenesis. -
Acute Hypoxia-Ischemia Results in Hydrogen Peroxide Accumulation in Neonatal but Not Adult Mouse Brain
0031-3998/06/5905-0680 PEDIATRIC RESEARCH Vol. 59, No. 5, 2006 Copyright © 2006 International Pediatric Research Foundation, Inc. Printed in U.S.A. Acute Hypoxia-Ischemia Results in Hydrogen Peroxide Accumulation in Neonatal But Not Adult Mouse Brain MICHAEL J. LAFEMINA, R. ANN SHELDON, AND DONNA M. FERRIERO Departments of Neurology [M.J.L., R.A.S., D.M.F.] and Pediatrics [D.M.F.], University of California San Francisco, San Francisco, CA 94143 ABSTRACT: The neonatal brain responds differently to hypoxic- stress (4). Several cellular and molecular mechanisms may be ischemic injury and may be more vulnerable than the mature brain responsible for this increased susceptibility, including the due to a greater susceptibility to oxidative stress. As a measure of enzymatic activities of superoxide dismutase (SOD), glutathi- oxidative stress, the immature brain should accumulate more hydro- one peroxidase (GPx), and catalase. After a hypoxic-ischemic gen peroxide (H O ) than the mature brain after a similar hypoxic- 2 2 insult, these defense mechanisms can become overwhelmed, ischemic insult. To test this hypothesis, H2O2 accumulation was measured in postnatal day 7 (P7, neonatal) and P42 (adult) CD1 resulting in accumulation of oxygen free radicals and neuronal mouse brain regionally after inducing HI by carotid ligation followed death through reactions involving lipid peroxidation, protein oxidation, and DNA damage (5). In addition, the neonatal by systemic hypoxia. H2O2 accumulation was quantified at 2, 12, 24, and 120 h after HI using the aminotriazole (AT)-mediated inhibition brain is particularly susceptible to oxidative damage because of catalase spectrophotometric method. Histologic injury was deter- of its high concentration of unsaturated fatty acids, high rate of mined by an established scoring system, and infarction volume was oxygen consumption, and availability of redox-active iron (2). -
Myoglobin/Hemoglobin O2 Binding and Allosteric Properties
Myoglobin/Hemoglobin O2 Binding and Allosteric Properties of Hemoglobin •Hemoglobin binds and transports H+, O2 and CO2 in an allosteric manner •Allosteric interaction - a regulatory mechanism where a small molecule (effector) binds and alters an enzymes activity ‘globin Function O does not easily diffuse in muscle and O is toxic to biological 2 2 systems, so living systems have developed a way around this. Physiological roles of: – Myoglobin • Transports O2 in rapidly respiring muscle • Monomer - single unit • Store of O2 in muscle high affinity for O2 • Diving animals have large concentration of myoglobin to keep O2 supplied to muscles – Hemoglobin • Found in red blood cells • Carries O2 from lungs to tissues and removes CO2 and H+ from blood to lungs • Lower affinity for O2 than myoglobin • Tetrameter - two sets of similar units (α2β2) Myo/Hemo-globin • Hemoglobin and myoglobin are oxygen- transport and oxygen-storage proteins, respectively • Myoglobin is monomeric; hemoglobin is tetrameric – Mb: 153 aa, 17,200 MW – Hb: two α chains of 141 residues, 2 β chains of 146 residues X-ray crystallography of myoglobin – mostly α helix (proline near end of each helix WHY?) – very small due to the folding – hydrophobic residues oriented towards the interior of the protein – only polar aas inside are 2 histidines Structure of heme prosthetic group Protoporphyrin ring w/ iron = heme Oxygenation changes state of Fe – Purple to red color of blood, Fe+3 - brown Oxidation of Fe+2 destroys biological activity of myoglobin Physical barrier of protein -
HER2/Neu: Mechanisms of Dimerization/Oligomerization
Oncogene (2000) 19, 6093 ± 6101 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc HER2/Neu: mechanisms of dimerization/oligomerization Patrick J Brennan1, Toru Kumogai1, Alan Berezov1, Ramachandran Murali1 and Mark I Greene*,1 1Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA Oncogene (2000) 19, 6093 ± 6101. principles involved remain to be de®ned. Key studies which have led to our current understanding of the Keywords: erbB; kinase; growth factor; signaling; mechanism and function of the oligomerization process tumor in erbB receptors will be outlined below, as will the outstanding questions raised by these studies. Introduction Mechanisms of dimerization/oligomerization Within a multi-celled organism, regulation and organ- Though dimerization/oligomerization has been recog- ization require that biological signals be transmitted nized as an integral component of signaling by erbB from one cell to another, across cell membranes. Such family receptors since shortly after the discovery of is the case with growth factors, which originate from neu, the mechanism by which these receptors aggregate one site in an organism, yet need to be distributed is still not fully understood. Extracellular, transmem- throughout the organism to many cell types in order to brane, and intracellular domains of the protein have all exert their pleiotropic eects. Systems have evolved to been implicated in dimerization/oligomerization; the allow a soluble signal, a growth factor for example, to potential contribution of each of these domains to be conveyed from the extracellular space to the receptor aggregation will be discussed below.