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A Guardian of the Development of Diabetic Retinopathy
Diabetes Volume 67, April 2018 745 Sirt1: A Guardian of the Development of Diabetic Retinopathy Manish Mishra, Arul J. Duraisamy, and Renu A. Kowluru Diabetes 2018;67:745–754 | https://doi.org/10.2337/db17-0996 Diabetic retinopathy is a multifactorial disease, and the molecular mechanism of the development of diabetic reti- exact mechanism of its pathogenesis remains obscure. nopathy remains to be established. Sirtuin 1 (Sirt1), a multifunctional deacetylase, is impli- Sirtuin 1 (Sirt1), a member of the silent information cated in the regulation of many cellular functions and in regulator 2 family, is a class III histone deacetylase that gene transcription, and retinal Sirt1 is inhibited in di- interacts with target proteins and regulates many cellular abetes. Our aim was to determine the role of Sirt1 in the functions including cell proliferation, apoptosis, and inflam- development of diabetic retinopathy and to elucidate the matory responses (6–8). Sirt1 is mainly a nuclear protein, Sirt1 molecular mechanism of its downregulation. Using - and its activity depends on cellular NAD availability (9). It is overexpressing mice that were diabetic for 8 months, Sirt1 expressed throughout the retina, and upregulation of COMPLICATIONS structural, functional, and metabolic abnormalities were protects against various ocular diseases including retinal investigated in vascular and neuronal retina. The role of degeneration, cataract, and optic neuritis (10). Our previous epigenetics in Sirt1 transcriptional suppression was inves- work has shown that Sirt1 expression and activity are de- tigated in retinal microvessels. Compared with diabetic wild-type mice, retinal vasculature from diabetic Sirt1 mice creased in the retina and its capillary cells in diabetes (11). -
Cytosine-Rich
Proc. Natl. Acad. Sci. USA Vol. 93, pp. 12116-12121, October 1996 Chemistry Inter-strand C-H 0 hydrogen bonds stabilizing four-stranded intercalated molecules: Stereoelectronic effects of 04' in cytosine-rich DNA (base-ribose stacking/sugar pucker/x-ray crystallography) IMRE BERGERt, MARTIN EGLIt, AND ALEXANDER RICHt tDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and tDepartment of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, IL 60611-3008 Contributed by Alexander Rich, August 19, 1996 ABSTRACT DNA fragments with stretches of cytosine matic cytosine ring systems from intercalated duplexes (Fig. 1A). residues can fold into four-stranded structures in which two Second, unusually close intermolecular contacts between sugar- parallel duplexes, held together by hemiprotonated phosphate backbones in the narrow grooves are observed, with cytosine-cytosine+ (C C+) base pairs, intercalate into each inter-strand phosphorus-phosphorus distances as close as 5.9 A other with opposite polarity. The structural details of this (5), presumably resulting in unfavorable electrostatic repulsion if intercalated DNA quadruplex have been assessed by solution not shielded by cations or bridging water molecules. NMR and single crystal x-ray diffraction studies of cytosine- The close contacts between pairs of antiparallel sugar- rich sequences, including those present in metazoan telo- phosphate backbones from the two interdigitated duplexes are meres. A conserved feature of these structures is the absence a unique characteristic of four-stranded intercalated DNA. of stabilizing stacking interactions between the aromatic ring Indeed, the unusually strong nuclear overhauser effect signals systems of adjacent C-C+ base pairs from intercalated du- between inter-strand sugar Hi' protons and Hi' and H4' plexes. -
Chapter 23 Nucleic Acids
7-9/99 Neuman Chapter 23 Chapter 23 Nucleic Acids from Organic Chemistry by Robert C. Neuman, Jr. Professor of Chemistry, emeritus University of California, Riverside [email protected] <http://web.chem.ucsb.edu/~neuman/orgchembyneuman/> Chapter Outline of the Book ************************************************************************************** I. Foundations 1. Organic Molecules and Chemical Bonding 2. Alkanes and Cycloalkanes 3. Haloalkanes, Alcohols, Ethers, and Amines 4. Stereochemistry 5. Organic Spectrometry II. Reactions, Mechanisms, Multiple Bonds 6. Organic Reactions *(Not yet Posted) 7. Reactions of Haloalkanes, Alcohols, and Amines. Nucleophilic Substitution 8. Alkenes and Alkynes 9. Formation of Alkenes and Alkynes. Elimination Reactions 10. Alkenes and Alkynes. Addition Reactions 11. Free Radical Addition and Substitution Reactions III. Conjugation, Electronic Effects, Carbonyl Groups 12. Conjugated and Aromatic Molecules 13. Carbonyl Compounds. Ketones, Aldehydes, and Carboxylic Acids 14. Substituent Effects 15. Carbonyl Compounds. Esters, Amides, and Related Molecules IV. Carbonyl and Pericyclic Reactions and Mechanisms 16. Carbonyl Compounds. Addition and Substitution Reactions 17. Oxidation and Reduction Reactions 18. Reactions of Enolate Ions and Enols 19. Cyclization and Pericyclic Reactions *(Not yet Posted) V. Bioorganic Compounds 20. Carbohydrates 21. Lipids 22. Peptides, Proteins, and α−Amino Acids 23. Nucleic Acids ************************************************************************************** -
Inhibition by Cyclic Guanosine 3':5'-Monophosphate of the Soluble DNA Polymerase Activity, and of Partially Purified DNA Polymer
Inhibition by Cyclic Guanosine 3':5'-Monophosphate of the Soluble DNA Polymerase Activity, and of Partially Purified DNA Polymerase A (DNA Polymerase I) from the Yeast Saccharomyces cere visiae Hans Eckstein Institut für Physiologische Chemie der Universität, Martinistr. 52-UKE, D-2000 Hamburg 20 Z. Naturforsch. 36 c, 813-819 (1981); received April 16/July 2, 1981 Dedicated to Professor Dr. Joachim Kühnauon the Occasion of His 80th Birthday cGMP, DNA Polymerase Activity, DNA Polymerase A, DNA Polymerase I, Baker’s Yeast DNA polymerase activity from extracts of growing yeast cells is inhibited by cGMP. Experiments with partially purified yeast DNA polymerases show, that cGMP inhibits DNA polymerase A (DNA polymerase I from Chang), which is the main component of the soluble DNA polymerase activity in yeast extracts, by competing for the enzyme with the primer- template DNA. Since the enzyme is not only inhibited by 3',5'-cGMP, but also by 3',5'-cAMP, the 3': 5'-phosphodiester seems to be crucial for the competition between cGMP and primer. This would be inconsistent with the concept of a 3'-OH primer binding site in the enzyme. The existence of such a site in the yeast DNA polymerase A is indicated from studies with various purine nucleoside monophosphates. When various DNA polymerases are compared, inhibition by cGMP seems to be restricted to those enzymes, which are involved in DNA replication. DNA polymerases with an associated nuclease activity are not inhibited, DNA polymerase B from yeast is even activated by cGMP. Though some relations between the cGMP effect and the presumed function of the enzymes in the living cell are apparent, the biological meaning of the observations in general remains open. -
A Previously Undescribed Pathway for Pyrimidine Catabolism
A previously undescribed pathway for pyrimidine catabolism Kevin D. Loh*†, Prasad Gyaneshwar*‡, Eirene Markenscoff Papadimitriou*§, Rebecca Fong*, Kwang-Seo Kim*, Rebecca Parales¶, Zhongrui Zhouʈ, William Inwood*, and Sydney Kustu*,** *Department of Plant and Microbial Biology, 111 Koshland Hall, University of California, Berkeley, CA 94720-3102; ¶Section of Microbiology, 1 Shields Avenue, University of California, Davis, CA 95616; and ʈCollege of Chemistry, 8 Lewis Hall, University of California, Berkeley, CA 94720-1460 Contributed by Sydney Kustu, January 19, 2006 The b1012 operon of Escherichia coli K-12, which is composed of tive N sources. Here we present evidence that the b1012 operon seven unidentified ORFs, is one of the most highly expressed codes for proteins that constitute a previously undescribed operons under control of nitrogen regulatory protein C. Examina- pathway for pyrimidine degradation and thereby confirm the tion of strains with lesions in this operon on Biolog Phenotype view of Simaga and Kos (8, 9) that E. coli K-12 does not use either MicroArray (PM3) plates and subsequent growth tests indicated of the known pathways. that they failed to use uridine or uracil as the sole nitrogen source and that the parental strain could use them at room temperature Results but not at 37°C. A strain carrying an ntrB(Con) mutation, which Behavior on Biolog Phenotype MicroArray Plates. We tested our elevates transcription of genes under nitrogen regulatory protein parental strain NCM3722 and strains with mini Tn5 insertions in C control, could also grow on thymidine as the sole nitrogen several genes of the b1012 operon on Biolog (Hayward, CA) source, whereas strains with lesions in the b1012 operon could not. -
Questions with Answers- Nucleotides & Nucleic Acids A. the Components
Questions with Answers- Nucleotides & Nucleic Acids A. The components and structures of common nucleotides are compared. (Questions 1-5) 1._____ Which structural feature is shared by both uracil and thymine? a) Both contain two keto groups. b) Both contain one methyl group. c) Both contain a five-membered ring. d) Both contain three nitrogen atoms. 2._____ Which component is found in both adenosine and deoxycytidine? a) Both contain a pyranose. b) Both contain a 1,1’-N-glycosidic bond. c) Both contain a pyrimidine. d) Both contain a 3’-OH group. 3._____ Which property is shared by both GDP and AMP? a) Both contain the same charge at neutral pH. b) Both contain the same number of phosphate groups. c) Both contain the same purine. d) Both contain the same furanose. 4._____ Which characteristic is shared by purines and pyrimidines? a) Both contain two heterocyclic rings with aromatic character. b) Both can form multiple non-covalent hydrogen bonds. c) Both exist in planar configurations with a hemiacetal linkage. d) Both exist as neutral zwitterions under cellular conditions. 5._____ Which property is found in nucleosides and nucleotides? a) Both contain a nitrogenous base, a pentose, and at least one phosphate group. b) Both contain a covalent phosphodister bond that is broken in strong acid. c) Both contain an anomeric carbon atom that is part of a β-N-glycosidic bond. d) Both contain an aldose with hydroxyl groups that can tautomerize. ___________________________________________________________________________ B. The structures of nucleotides and their components are studied. (Questions 6-10) 6._____ Which characteristic is shared by both adenine and cytosine? a) Both contain one methyl group. -
Xanthine/Hypoxanthine Assay Kit
Product Manual Xanthine/Hypoxanthine Assay Kit Catalog Number MET-5150 100 assays FOR RESEARCH USE ONLY Not for use in diagnostic procedures Introduction Xanthine and hypoxanthine are naturally occurring purine derivatives. Xanthine is created from guanine by guanine deaminase, from hypoxanthine by xanthine oxidoreductase, and from xanthosine by purine nucleoside phosphorylase. Xanthine is used as a building block for human and animal drug medications, and is an ingredient in pesticides. In vitro, xanthine and related derivatives act as competitive nonselective phosphodiesterase inhibitors, raising intracellular cAMP, activating Protein Kinase A (PKA), inhibiting tumor necrosis factor alpha (TNF-α) as well as and leukotriene synthesis. Furthermore, xanthines can reduce levels of inflammation and act as nonselective adenosine receptor antagonists. Hypoxanthine is sometimes found in nucleic acids such as in the anticodon of tRNA in the form of its nucleoside inosine. Hypoxanthine is a necessary part of certain cell, bacteria, and parasitic cultures as a substrate and source of nitrogen. For example, hypoxanthine is often a necessary component in malaria parasite cultures, since Plasmodium falciparum needs hypoxanthine to make nucleic acids as well as to support energy metabolism. Recently NASA studies with meteorites found on Earth supported the idea that hypoxanthine and related organic molecules can be formed extraterrestrially. Hypoxanthine can form as a spontaneous deamination product of adenine. Because of its similar structure to guanine, the resulting hypoxanthine base can lead to an error in DNA transcription/replication, as it base pairs with cytosine. Hypoxanthine is typically removed from DNA by base excision repair and is initiated by N- methylpurine glycosylase (MPG). -
Chem 109 C Bioorganic Compounds
Chem 109 C Bioorganic Compounds Fall 2019 HFH1104 Armen Zakarian Office: Chemistry Bldn 2217 http://labs.chem.ucsb.edu/~zakariangroup/courses.html CLAS Instructor: Dhillon Bhavan [email protected] Midterm 3 stats Average 49.1 St Dev 14.1 Max 87.5 Min 15 test are available outside room 2135 (Chemistry, 2nd floor) in a box, sorted in alphabetical order, by color Final Course Grading Each test will be curved individually to 75% average Lowest midterm will be dropped Scores from 2 best M and the Final will be added Grades will be assigned according to the syllabus 22. Draw all reactions required to convert hexanoic acid to 3 molecules of acetyl CoA through 11 pt the β-oxidation cycles. Name all necessary coenzymes and enzymes. How many molecules of ATP and CO2 will be produced from hexanoic acid after its entire metabolism through all 4 stages ? O O hexanoic acid (hexanoate) Overview OVERVIEW o structures of DNA vs. RNA - ribose o structures of bases: Adenine, Uracil/Thymine, Guanine, Cytosine. “Enol forms” o hydrogen bonding between A-T(U) and G-C. H-donors/acceptors o Base complementarity o RNA strand cleavage assisted by the 2’-OH group in the ribose unit (cyclic PDE) o Deamination: RNA genetic instability o DNA replication o RNA synthesis: transcription. Template strand (read 3’ to 5’). Sense strand and the RNA primary structure (T −> U). o Protein synthesis: translation. mRNA determines the amino acid sequence. tRNAs are amino acid carriers. rRNA - part of ribosomes o no section 26.12, 26.13 DNA, RNA, etc. -
Modeling of the Hydration Shell of Uracil and Thymine
Int. J. Mol. Sci. 2000, 1, 17-27 International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.org/ijms/ Modeling of the Hydration Shell of Uracil and Thymine Oleg V. Shishkin1,2, Leonid Gorb2 and Jerzy Leszczynski2* 1Department of Alkali Halide Crystals, Institute for Single Crystals, National Academy of Sciences of Ukraine, 60 Lenina Avenue., Kharkiv 310001, Ukraine 2Computational Center for Molecular Structure and Interactions, Department of Chemistry, Jackson State University, P.O. Box 17910, 1325 Lynch Street, Jackson, MS 39217, USA E-mail: [email protected] *Author to whom correspondence should be addressed. Received: 4 January 2000 / Accepted: 30 March 2000 / Published: 4 March 2000 Abstract: The molecular geometry of complexes of uracil and thymine with 11 water mole- cules was calculated using the density functional theory with the B3LYP functional. The standard 6-31G(d) basis set has been employed. It was found that the arrangement of water molecules forming a locked chain around the nucleobases significantly differs for uracil and thymine. The presence of a methyl group in thymine results in strong non-planarity of the hydrated shell. The existence of C-H...O hydrogen bonds between the water molecules and the hydrophobic part of the nucleobases is established. Interactions with water molecules cause some changes in the geometry of uracil and thymine which can be explained by the contribution of a zwitter-ionic dihydroxy resonance form into the total structure of the molecules. Keywords: Uracil, Thymine, Hydration, Molecular structure, Hydrogen bonds, Density functional theory. Introduction Since Franklin and Gosling [1] examined the first fibers of DNA it has been known that DNA oc- curs in vivo in the hydrated form. -
Non-Utilization of Radioactive Lodinated Uracil, Uridine, and Orotic Acid by Animal Tissues in Vivo W
Non-utilization of Radioactive lodinated Uracil, Uridine, and Orotic Acid by Animal Tissues in Vivo W. H. PRUSOFF,WL. HOLMES,tANDA. D. WELCH Department of Pharmacology, School of Medicine, Western Reserve University, Cleveland, Ohio) Adenine (1, 6), guanine (1, 3, 5), cytidine (13), lometric localization of brain tumors. Further desoxycytidine (18), thymidine (18), and orotic more, an I'3-labeled oxazine dye had a significant acid (2), can be utilized by certain mammalian or effect in prolonging the life of mice bearing trans ganisms for the synthesis of nucleic acids ; and the planted tumors (19). If an effective and easily syn rate of incorporation of many of these compounds thesized radioactive iodine-labeled compound into the nucleic acids of rapidly growing tissues, could be found, the possibility might be afforded of such as regenerating liver or neoplastic tissues, is the comparable use of compounds labeled with greater than into those of resting tissues (10, 21). eka-iodine (astatine2@), a potent emitter of alpha Although 8-azaguanine is not a naturally occur particles, although this element is prepared with ring compound, evidence that it can be incorpo difficulty and has the inconveniently short half rated to a small extent into mammalian nucleic life of 7.5 hours (12). acids has been presented (16). This analog of gua Three P3-labeled pyrimidines, iodouridine-5- nine markedly inhibited the growth of Tetrahy I'S', iodouracil-5-I'31, and iodoorotic acid-5-P31, mena geleii, a guanine-requiring protozoan, and of were synthesized, and their incorporation into nor certain experimental tumors. Kidder et al. -
Abiotic Synthesis of Purine and Pyrimidine Ribonucleosides in Aqueous Microdroplets
Abiotic synthesis of purine and pyrimidine ribonucleosides in aqueous microdroplets Inho Nama,b, Hong Gil Nama,c,1, and Richard N. Zareb,1 aCenter for Plant Aging Research, Institute for Basic Science, Daegu 42988, Republic of Korea; bDepartment of Chemistry, Stanford University, Stanford, CA 94305; and cDepartment of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea Contributed by Richard N. Zare, November 27, 2017 (sent for review October 24, 2017; reviewed by Bengt J. F. Nordén and Veronica Vaida) Aqueous microdroplets (<1.3 μm in diameter on average) containing In a recent study, we showed a synthetic pathway for the 15 mM D-ribose, 15 mM phosphoric acid, and 5 mM of a nucleobase formation of Rib-1-P using aqueous, high–surface-area micro- (uracil, adenine, cytosine, or hypoxanthine) are electrosprayed from a droplets. This surface or near-surface reaction circumvents the capillary at +5 kV into a mass spectrometer at room temperature and fundamental thermodynamic problem of the condensation re- 2+ 1 atm pressure with 3 mM divalent magnesium ion (Mg )asacat- action (12). It has been suggested that the air–water interface alyst. Mass spectra show the formation of ribonucleosides that com- provides a favorable environment for the prebiotic synthesis of prise a four-letter alphabet of RNA with a yield of 2.5% of uridine (U), biomolecules (12–17). Using the Rib-1-P made in the above 2.5% of adenosine (A), 0.7% of cytidine (C), and 1.7% of inosine (I) during the flight time of ∼50 μs. -
Deoxyadenosine Triphosphate As a Mediator of Deoxyguanosine Toxicity in Cultured T Lymphoblasts
Deoxyadenosine triphosphate as a mediator of deoxyguanosine toxicity in cultured T lymphoblasts. G J Mann, R M Fox J Clin Invest. 1986;78(5):1261-1269. https://doi.org/10.1172/JCI112710. Research Article The mechanism by which 2'-deoxyguanosine is toxic for lymphoid cells is relevant both to the severe cellular immune defect of inherited purine nucleoside phosphorylase (PNP) deficiency and to attempts to exploit PNP inhibitors therapeutically. We have studied the cell cycle and biochemical effects of 2'-deoxyguanosine in human lymphoblasts using the PNP inhibitor 8-aminoguanosine. We show that cytostatic 2'-deoxyguanosine concentrations cause G1-phase arrest in PNP-inhibited T lymphoblasts, regardless of their hypoxanthine guanine phosphoribosyltransferase status. This effect is identical to that produced by 2'-deoxyadenosine in adenosine deaminase-inhibited T cells. 2'-Deoxyguanosine elevates both the 2'-deoxyguanosine-5'-triphosphate (dGTP) and 2'-deoxyadenosine-5'-triphosphate (dATP) pools; subsequently pyrimidine deoxyribonucleotide pools are depleted. The time course of these biochemical changes indicates that the onset of G1-phase arrest is related to increase of the dATP rather than the dGTP pool. When dGTP elevation is dissociated from dATP elevation by coincubation with 2'-deoxycytidine, dGTP does not by itself interrupt transit from the G1 to the S phase. It is proposed that dATP can mediate both 2'-deoxyguanosine and 2'-deoxyadenosine toxicity in T lymphoblasts. Find the latest version: https://jci.me/112710/pdf Deoxyadenosine Triphosphate as a Mediator of Deoxyguanosine Toxicity in Cultured T Lymphoblasts G. J. Mann and R. M. Fox Ludwig Institute for Cancer Research (Sydney Branch), University ofSydney, Sydney, New South Wales 2006, Australia Abstract urine of PNP-deficient individuals, with elevation of plasma inosine and guanosine and mild hypouricemia (3).