DOCSLIB.ORG

Anticancer Agents

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Anticancer Agents Anticancer agents ANTIMETABOLITES Antimetabolites The chemical structure of antimetabolites is similar to that of metabolites which participate in biochemical processes observed in the body. This similarity enables the body to use them in biosynthesis instead of normal metabolites. This replacement leads to the incorporation of antimetabolites into DNA or RNA and causes misreading. 2 The term antimetabolites is applied to two groups of drugs. The first group comprises drugs which are built as nucleotide analogs into the biopolymers of cells (DNA, RNA). This group consists mainly of pyrimidine and purine analogs and their nucleosides. These analogs are incorporated into DNA and make its replication impossible or inhibit competitively the incorporation of deoxyribonucleoside trisphosphate into DNA. 3 The second group involves drugs inhibiting the synthesis of metabolites, necessary for cell life. Their competetive action does not depend on their participation in the building of cellular biopolymers. Inhibitors of mureine synthesis, nucleoside precursors, folic acid antagonists and tetrahydrofolic acid are classified into this group. 4 Many antimetabolite antineoplastics are categorized by the class of nucleotide they inhibit. Purine antagonists inhibit the synthesis of the purine-based nucleotides adenosine monophosphate (AMP) and guanosine monophosphate (GMP), and the pyrimidine antagonists stop the production of the pyrimidine-based nucleotides, primarily deoxythymidine monophosphate (dTMP). Three groups of antagonists are distinguished: . Tetrahydrofolic acid . Pyrimidine analogs . Purine analogs 5 OH 9 10 O N CH N COOH 4 5 2 Folic acid N 3 6 H COOH 2 N 1 8 7 H H2N N N CH O NH2 3 _ _ Methotrexate N CH C Glu N 2 N H2N N N 6 Antimetabolites of folic acid CH3 O NH2 _ _ As antagonists of N CH CH C Glu CHN O 2 dihydrofolic acid NwhichH2 3 _H N _ N CH 2 N N C Glu block the enzymeN 2 N Edatrexate dihydrofolateH N reductaseN N 2 OCH3 CH (DHFR) are classified NH2 3 H CH2 N OCH3 some anticancer agents N H N OCH3 and immunosupressants: 2 N Trimetrexate H C N CH 3 3 O COOH HN N S N COOH H O Methotrexate, METHOTREXAT, TREXAN Raltitrexed, TOMUDEX 7 Methotrexate binds competitively with dihydrofolate reductase irreversibly. This bond is 10, 000 times stronger than with a CH O normal metabolite.NH 2 3 _ _ Glu N CH2 N C The biological Nhalf-time of methotrexate is 3.5 h. H2N N N Methotrexate is used mainly in the treatment of leukemia, breast, head and neck carcinomas, pulmonary carcinoma. It permeates into the cerebrospinal fluid. 8 Methotrexate • Is given orally • The sodium salt form is marketed for intravenous, intramuscular, intra-arterial, or intrathecal injection • It dergoes intracellular folyl polyglutamate synthase, (FPGS)- catalysed polyglutamation, which adds several anionic carboxylate groups to the molecule and traps the drug at the site of action • Polyglutamation is more efficient in tumor cells than in healty cells, which promotes the selective toxicity of this drug • The polyglutamated drug will be hydrolized back to the parent structure before renal elimination • Up to 90% of an administered dose of M. is excreted unchanged in the urine within 24 hours 9 Methotrexate is a potent but very toxic drug. CH O NH2 3 _ _ N CH C Glu Unwanted actionN affects the 2hematopoietic N system, gastrointestinal tract and kidneys.H2N N N Nephrotoxicity is caused by a methotrexate metabolite – 2,4-diamino-N-methylpteroinic acid. It is created under the influence of bacterial peptidases present in the stomach. They cleave the glutamic acid rest from the parent compound. 10 CH3 O Edatrexate demonstrates greater anticancerNH2 activity against cancers _ _ N CH CH C Glu of various organs and lower toxicityN than methotrexate.2 H2N N N Its greater activity is caused by the intensive intracellular metabolism of cancerous cells to polyglutamated forms. Edatrexate is the most effective in the treatment of pulmonary microcellular carcinoma. 11 Trimetrexate - the analog of methotrexate - acts also in the S phase of the cell cycle. It differs from the precursor only in the lack of a glutamic acid rest. It acts synergistically together with fluorouracil and calcium folate. OCH3 CH NH2 3 H CH N OCH It is effective in the treatment ofN colorectal2 carcinoma,3 breast OCH carcinoma, head and stomachH2N carcinomasN and soft3 tissue sarcoma. 12 Pemetrexed Disodium • a new multitarget antifolate administered by the intravenous route for the treatment non-small cell lung cancer and in combination with cisplatin in melignant pleural mesothelioma • Patients on P. must take folic acid and vitamin B12 to reduce the risk of bon marrow suppression and use-limiting GI side effects like mucositis and stomatitis • Pretreatment with corticosteroids can reduce the risk of drug- induced skin rash 13 Pralatrexate • Also more extensively polyglutamated than mothotrexate. • Used in the treatment of non-small cel lung cancer and in combination with the DNA polymerase inhibitor gemcitabine, in NHL. • When used in combination with gemcytabine, the synergistic apoptotic effect is maximized when the antifolate is administered before polymerase inhibitor. 14 Raltitrexed is a new analogue of folates, inhibitors of thymidylate synthetase, which is necessary in the synthesis and repair process of DNA. In the body it undergoes a rapid transformation to polyglutamated forms which act 100 times more strongly than the parent compound. Polyglutamated forms act toxically on the normal cells. Raltitrexed is effective in the treatment of colorectal and rectal carcinomas, ovarian carcinoma, breast carcinoma, pancreas H C N CH carcinoma and non-microcellular3 pulmonary3 O carcinoma.COOH HN N S N COOH H O 15 Antimetabolites of pyrimidine analogues Purine and pyrimidine analogs, the basic elements of the chemical structure of DNA and RNA, play the main role in their normal function. Cytosine, thymine and uracil are pyrimidine analogs. Those bases, bound with pentoses – D-ribose ((Ryb), 2-deoxyribose (d- Ryb) or cytosine (C) create nucleosides – cytidine, uridine, thymidine. 16 cytosine cytidine deoxycytidine 17 • Those compounds create esters with phosphoric acid and are converted into ribonucleotides: uridine monophosphate (UMP), cytidine monophosphate (CMP), thymidine monophosphate (TMP). • If the sugar fragment of those nucleotides is 2-deoxyribose, those derivatives are called deoxythymidine monophosphate (dTMP) and deoxycytidine monophosphate (dCMP). 18 Synthetic fluorine derivatives of pyrimidine analogs and their nucleotides play an important role in cancer therapy. Those antimetabolites act mainly as anticancer or antiviral agents and their activity is the strongest in the S phase. They differ in the mechanism of action and toxicity. 19 The mechanism of action depends on the size of substituents at position 5 in uracil. Analog uracylu Fluorouracyl (Fluorouracil, FLUROBLASTIN) 5-Fluorouracil derivatives (5-FdUMP) O inhibit the activity of thymidylate HN F synthetase. O N H O O Their affinity for that enzyme is several Thymidylatesyntetaza H CH3 thousand times greater than for natural HN synthetasetymidylowa HN O dUMP. O N N d-Ryb-P d-Ryb-P InIncorporationkorporacja dtoo DDNANA 5-FdUMP acts as an enzyme inhibitor and w formasi ed -dRyb-Ry-Pb--PP--PP-P similarly to the natural substrate creates a O O CF covalently bound intermediate product. HN I HN 3 O N O N This product is different from the natural Dd--RiboseRyboza D-dRibose-Ryboza substrate because of the presence of IdoIdoxuridineksyurydyna TTrifluridineriflurydyna fluorine, which is why it is not cleaved into AThyminenalogi tyanalogsminy the enzyme and the end reaction product. DNA The action mechanism of pyrimidine analogs. 20 Derivatives with large substituents at position 5 (e.g.5-iodo- and 5- trifluoromethyl analogs of thymidine) are incorporated into DNA during biosynthesis. As a result of this process DNA functions are disturbed. The inhibition of the ability of DNA to replicate decreases or interrupts the development of cells. Idoxuridine and trifluridine, which is better soluble in water, are incorporated by viral and cellular DNA. 21 O R R = 5-Fluorouracil (5-FU) was designed in N COOH N 1957. The development of this compound N NH H O was based on the observation that some O N COOH H tumors preferentially use uracil rather than HN HN O NH2 O N N5,N10-metyleno-THF orotic acid for pyrimidine biosynthesis. P O N5,N10 –Methylene-THF HO O OH S H SyThymidylatentetaza tymidylan synthetaseowa Thymidine synthesis from uracil involves HO thymidylate synthetase and in this process dUMP a thiol group of a cysteine residue in the R enzyme (E-SH) adds to the C-6 position of O N H N NH deoxyuridylic acid and with subsequent HN 5 10 O addition of the C-5 carbon to the N ,N - O N O N P O S HN 5 10 HO O methylene of N ,N -methylenetetrahydro- NH2 folate. OH SThymidylateyntetaza tymidyla nsynthetaseowa HO The resulting intermediate product transfers the C5-hydrogen to the N10 O CH R HN 3 N position of the folate creating O H O N N NH deoxythymidylic acid, dihydrofolate, and HO P O + O O N the regenerated enzyme. OH HN NH HO 2 + The synthesis of deoxythymidylic acid from dTMP S H SThymidylateyntetaza tymidyla nsynthetaseowa deoxyuridylic acid. 22 In vivo, 5-FU must first be activated by conversion to 5- fluoro-2’- deoxyuridylic acid (5-FdUMP). In general this occurs by conversion of 5-FU to 5-fluorouracil riboside which is then transformed directly into 5-FdUMP by ribonucleotide reductase. The 5-FdUMP then binds to thymidylate synthetase to give an intermediate product that resembles the intermediate product formed with uridylic acid. 23 However, the intermediate compound has fluorine at C-5 instead of a hydrogen atom and the latter is unable to transfer the fluorine. Thus, the intermediate compound cannot break down and the enzyme is inhibited. This can lead to a deficiency of thymidine which is essential for the synthesis of DNA.
Load more

Recommended publications
  • Nucleotide Metabolism
    NUCLEOTIDE METABOLISM General Overview • Structure of Nucleotides Pentoses Purines and Pyrimidines Nucleosides Nucleotides • De Novo Purine Nucleotide Synthesis PRPP synthesis 5-Phosphoribosylamine synthesis IMP synthesis Inhibitors of purine synthesis Synthesis of AMP and GMP from IMP Synthesis of NDP and NTP from NMP • Salvage pathways for purines • Degradation of purine nucleotides • Pyrimidine synthesis Carbamoyl phosphate synthesisOrotik asit sentezi • Pirimidin nükleotitlerinin yıkımı • Ribonükleotitlerin deoksiribonükleotitlere dönüşümü Basic functions of nucleotides • They are precursors of DNA and RNA. • They are the sources of activated intermediates in lipid and protein synthesis (UDP-glucose→glycogen, S-adenosylmathionine as methyl donor) • They are structural components of coenzymes (NAD(P)+, FAD, and CoA). • They act as second messengers (cAMP, cGMP). • They play important role in carrying energy (ATP, etc). • They play regulatory roles in various pathways by activating or inhibiting key enzymes. Structures of Nucleotides • Nucleotides are composed of 1) A pentose monosaccharide (ribose or deoxyribose) 2) A nitrogenous base (purine or pyrimidine) 3) One, two or three phosphate groups. Pentoses 1.Ribose 2.Deoxyribose •Deoxyribonucleotides contain deoxyribose, while ribonucleotides contain ribose. •Ribose is produced in the pentose phosphate pathway. Ribonucleotide reductase converts ribonucleoside diphosphate deoxyribonucleotide. Nucleotide structure-Base 1.Purine 2.Pyrimidine •Adenine and guanine, which take part in the structure
    [Show full text]
  • Monophosphate- Binding Protein Complex with Subsequent Poly(A) RNA Synthesis in Embryonic Chick Cartilage
    Specific nuclear binding of adenosine 3',5'-monophosphate- binding protein complex with subsequent poly(A) RNA synthesis in embryonic chick cartilage. W M Burch Jr, H E Lebovitz J Clin Invest. 1980;66(3):532-542. https://doi.org/10.1172/JCI109885. Research Article We used embryonic chick pelvic cartilage as a model to study the mechanism by which cyclic AMP increases RNA synthesis. Isolated nuclei were incubated with [32P]-8-azidoadenosine 3,5'-monophosphate ([32P]N3cAMP) with no resultant specific nuclear binding. However, in the presence of cytosol proteins, nuclear binding of [32P]N3cAMP was demonstrable that was specific, time dependent, and dependent on a heat-labile cytosol factor. The possible biological significance of the nuclear binding of the cyclic AMP-protein complex was identified by incubating isolating nuclei with either cyclic AMP or cytosol cyclic AMP-binding proteins prepared by batch elution DEAE cellulose chromatography (DEAE peak cytosol protein), or both, in the presence of cold nucleotides and [3H]uridine 5'-triphosphate. Poly(A) RNA production occurred only in nuclei incubated with cyclic AMP and the DEAE peak cytosol protein preparation. Actinomycin D inhibited the incorporation of [3H]uridine 5'-monophosphate into poly(A) RNA. The newly synthesized poly(A) RNA had a sedimentation constant of 23S. Characterization of the cytosol cyclic AMP binding proteins using [32P]N3-cAMP with photoaffinity labeling three major cAMP-binding complexes (41,000, 51,000, and 55,000 daltons). The 51,000 and 55,000 dalton cyclic AMP binding proteins were further purified by DNA-cellulose chromatography. In the presence of cyclic AMP they stimulated poly(A) RNA synthesis in isolated nuclei.
    [Show full text]
  • Nucleotide Metabolism 22
    Nucleotide Metabolism 22 For additional ancillary materials related to this chapter, please visit thePoint. I. OVERVIEW Ribonucleoside and deoxyribonucleoside phosphates (nucleotides) are essential for all cells. Without them, neither ribonucleic acid (RNA) nor deoxyribonucleic acid (DNA) can be produced, and, therefore, proteins cannot be synthesized or cells proliferate. Nucleotides also serve as carriers of activated intermediates in the synthesis of some carbohydrates, lipids, and conjugated proteins (for example, uridine diphosphate [UDP]-glucose and cytidine diphosphate [CDP]- choline) and are structural components of several essential coenzymes, such as coenzyme A, flavin adenine dinucleotide (FAD[H2]), nicotinamide adenine dinucleotide (NAD[H]), and nicotinamide adenine dinucleotide phosphate (NADP[H]). Nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), serve as second messengers in signal transduction pathways. In addition, nucleotides play an important role as energy sources in the cell. Finally, nucleotides are important regulatory compounds for many of the pathways of intermediary metabolism, inhibiting or activating key enzymes. The purine and pyrimidine bases found in nucleotides can be synthesized de novo or can be obtained through salvage pathways that allow the reuse of the preformed bases resulting from normal cell turnover. [Note: Little of the purines and pyrimidines supplied by diet is utilized and is degraded instead.] II. STRUCTURE Nucleotides are composed of a nitrogenous base; a pentose monosaccharide; and one, two, or three phosphate groups. The nitrogen-containing bases belong to two families of compounds: the purines and the pyrimidines. A. Purine and pyrimidine bases Both DNA and RNA contain the same purine bases: adenine (A) and guanine (G).
    [Show full text]
  • Mechanisms of Synthesis of Purine Nucleotides in Heart Muscle Extracts
    Mechanisms of Synthesis of Purine Nucleotides in Heart Muscle Extracts David A. Goldthwait J Clin Invest. 1957;36(11):1572-1578. https://doi.org/10.1172/JCI103555. Research Article Find the latest version: https://jci.me/103555/pdf MECHANISMS OF SYNTHESIS OF PURINE NUCLEOTIDES IN HEART MUSCLE EXTRACTS1 BY DAVID A. GOLDTHWAIT2 (From the Departments of Biochemistry and Medicine, Western Reserve University, Cleveland, Ohio) (Submitted for publication February 18, 1957; accepted July 18, 1957) The key role of ATP, a purine nucleotide, in 4. Adenine or Hypoxanthine + PRPP -> AMP the conversion of chemical energy into mechanical or Inosinic Acid (IMP) + P-P. work by myocardial tissue is well established (1, The third mechanism of synthesis is through the 2). The requirement for purine nucleotides has phosphorylation of a purine nucleoside (8, 9): also been demonstrated in the multiple synthetic 5. Adenosine + ATP -, AMP + ADP. reactions which maintain all animal cells in the Several enzymatic mechanisms are known which steady state. Since the question immediately arises result in the degradation of purine nucleotides and whether the purine nucleotides are themselves in nucleosides. The deamination of adenylic acid is a steady state, in which their rates of synthesis well known (10): equal their rates of degradation, it seems reason- 6. AMP -* IMP + NH8. able to investigate first what mechanisms of syn- Non-specific phosphatases (11) as well as spe- thesis and degradation may be operative. cific 5'-nucleotidases (12) have been described At present, there are three known pathways for which result in dephosphorylation: the synthesis of purine nucleotides. The first is 7.
    [Show full text]
  • Calcium 5'-Ribonucleotides
    CALCIUM 5'-RIBONUCLEOTIDES Prepared at the 18th JECFA (1974), published in NMRS 54B (1975) and in FNP 52 (1992). Metals and arsenic specifications revised at the 57th JECFA (2001). An ADI ‘not specified’ was established at the 18th JECFA (1974). SYNONYMS Calcium ribonucleotides, INS No. 634 DEFINITION Chemical names (Mixture of) calcium inosine-5'-monophosphate and calcium guanosine-5'- monophosphate Chemical formula C10H11CaN4O8P · x H2O and C10H12CaN5O8P · x H2O Structural formula Calcium 5’-guanylate Calcium 5’-inosinate Assay Not less than 97% and not more than the equivalent of 102% of C10H11CaN4O8P and C10H12CaN5O8P, calculated on the anhydrous basis. The proportion of C10H11CaN4O8P or C10H12CaN5O8P to the sum of them is between 47% and 53%. DESCRIPTION Odourless, white or off-white crystals or powder FUNCTIONAL USES Flavour enhancer CHARACTERISTICS IDENTIFICATION Solubility (Vol. 4) Sparingly soluble in water Test for ribose (Vol. 4) Passes test Test for organic phosphate Passes test (Vol. 4) Test 5 ml of a 1 in 2,000 solution Test for inosinic acid To 2 ml of a 1 in 2,000 solution add 2 ml of 10% hydrochloric acid and 0.1 g of zinc powder, heat in a water bath for 10 min, and filter. Cool the filtrate in ice water, add 1 ml of a 3 in 1,000 sodium nitrite solution, shake well, and allow to stand for 10 min. Add 1 ml of a 1 in 200 ammonium sulfamate solution, shake well, and allow to stand for 5 min. Add 1 ml of a 1 in 500 N-(1- naphthyl)-ethylenediamine dihydrochloride solution.
    [Show full text]
  • Unless Otherwise Noted, the Content of This Course Material Is Licensed Under a Creative Commons Attribution – Share Alike 3.0 License
    Unless otherwise noted, the content of this course material is licensed under a Creative Commons Attribution – Share Alike 3.0 License. Copyright 2007, Robert Lyons. The following information is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. You should speak to your physician or make an appointment to be seen if you have questions or concerns about this information or your medical condition. You assume all responsibility for use and potential liability associated with any use of the material. Material contains copyrighted content, used in accordance with U.S. law. Copyright holders of content included in this material should contact [email protected] with any questions, corrections, or clarifications regarding the use of content. The Regents of the University of Michigan do not license the use of third party content posted to this site unless such a license is specifically granted in connection with particular content objects. Users of content are responsible for their compliance with applicable law. Mention of specific products in this recording solely represents the opinion of the speaker and does not represent an endorsement by the University of Michigan. Viewer discretion advised: Material may contain medical images that may be disturbing to some viewers. Formation of PRPP: Phosphoribose pyrophosphate PRPP Use in Purine Biosynthesis: The First Purine: Inosine Monophosphate (folates are involved in this synthesis) Conversion to Adenosine: Conversion to Guanosine: Nucleoside Monophosphate Kinases AMP + ATP <--> 2ADP (adenylate kinase) GMP + ATP <---> GDP + ADP (guanylate kinase) • similar enzymes specific for each nucleotide • no specificity for ribonucleotide vs.
    [Show full text]
  • Effects of Allopurinol and Oxipurinol on Purine Synthesis in Cultured Human Cells
    Effects of allopurinol and oxipurinol on purine synthesis in cultured human cells William N. Kelley, James B. Wyngaarden J Clin Invest. 1970;49(3):602-609. https://doi.org/10.1172/JCI106271. Research Article In the present study we have examined the effects of allopurinol and oxipurinol on thed e novo synthesis of purines in cultured human fibroblasts. Allopurinol inhibits de novo purine synthesis in the absence of xanthine oxidase. Inhibition at lower concentrations of the drug requires the presence of hypoxanthine-guanine phosphoribosyltransferase as it does in vivo. Although this suggests that the inhibitory effect of allopurinol at least at the lower concentrations tested is a consequence of its conversion to the ribonucleotide form in human cells, the nucleotide derivative could not be demonstrated. Several possible indirect consequences of such a conversion were also sought. There was no evidence that allopurinol was further utilized in the synthesis of nucleic acids in these cultured human cells and no effect of either allopurinol or oxipurinol on the long-term survival of human cells in vitro could be demonstrated. At higher concentrations, both allopurinol and oxipurinol inhibit the early steps ofd e novo purine synthesis in the absence of either xanthine oxidase or hypoxanthine-guanine phosphoribosyltransferase. This indicates that at higher drug concentrations, inhibition is occurring by some mechanism other than those previously postulated. Find the latest version: https://jci.me/106271/pdf Effects of Allopurinol and Oxipurinol on Purine Synthesis in Cultured Human Cells WILLIAM N. KELLEY and JAMES B. WYNGAARDEN From the Division of Metabolic and Genetic Diseases, Departments of Medicine and Biochemistry, Duke University Medical Center, Durham, North Carolina 27706 A B S TR A C T In the present study we have examined the de novo synthesis of purines in many patients.
    [Show full text]
  • Metabolomics Identifies Pyrimidine Starvation As the Mechanism of 5-Aminoimidazole-4-Carboxamide-1- Β-Riboside-Induced Apoptosis in Multiple Myeloma Cells
    Published OnlineFirst April 12, 2013; DOI: 10.1158/1535-7163.MCT-12-1042 Molecular Cancer Cancer Therapeutics Insights Therapeutics Metabolomics Identifies Pyrimidine Starvation as the Mechanism of 5-Aminoimidazole-4-Carboxamide-1- b-Riboside-Induced Apoptosis in Multiple Myeloma Cells Carolyne Bardeleben1, Sanjai Sharma1, Joseph R. Reeve3, Sara Bassilian3, Patrick Frost1, Bao Hoang1, Yijiang Shi1, and Alan Lichtenstein1,2 Abstract To investigate the mechanism by which 5-aminoimidazole-4-carboxamide-1-b-riboside (AICAr) induces apoptosis in multiple myeloma cells, we conducted an unbiased metabolomics screen. AICAr had selective effects on nucleotide metabolism, resulting in an increase in purine metabolites and a decrease in pyrimidine metabolites. The most striking abnormality was a 26-fold increase in orotate associated with a decrease in uridine monophosphate (UMP) levels, indicating an inhibition of UMP synthetase (UMPS), the last enzyme in the de novo pyrimidine biosynthetic pathway, which produces UMP from orotate and 5-phosphoribosyl- a-pyrophosphate (PRPP). As all pyrimidine nucleotides can be synthesized from UMP, this suggested that the decrease in UMP would lead to pyrimidine starvation as a possible cause of AICAr-induced apoptosis. Exogenous pyrimidines uridine, cytidine, and thymidine, but not purines adenosine or guanosine, rescued multiple myeloma cells from AICAr-induced apoptosis, supporting this notion. In contrast, exogenous uridine had no protective effect on apoptosis resulting from bortezomib, melphalan, or metformin. Rescue resulting from thymidine add-back indicated apoptosis was induced by limiting DNA synthesis rather than RNA synthesis. DNA replicative stress was identified by associated H2A.X phosphorylation in AICAr-treated cells, which was also prevented by uridine add-back.
    [Show full text]
  • UC San Diego UC San Diego Electronic Theses and Dissertations
    UC San Diego UC San Diego Electronic Theses and Dissertations Title On the origin of the canonical nucleobases : selection pressures and hydrolytic stabilities of N-glycosyl bonds Permalink https://escholarship.org/uc/item/0bx9p84v Author Rios, Andro C. Publication Date 2012 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO On the origin of the canonical nucleobases: selection pressures and hydrolytic stabilities of N-glycosyl bonds A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Chemistry by Andro C. Rios Committee in Charge: Professor Yitzhak Tor, Chair Professor Jeffrey Bada Professor Stanley Opella Professor Emmanuel Theodorakis Professor Jerry Yang 2012 Copyright Andro C. Rios, 2012 All rights reserved. The Dissertation of Andro C. Rios is approved, and it is acceptable in quality and form for publication on microfilm and electronically: Chair University of California, San Diego 2012 iii DEDICATION To the memories of Leslie E. Orgel (1927–2007) and Stanley L. Miller (1930–2007). It is because of their work in the field of prebiotic and origin of life chemistry that I was inspired to pursue a career in chemistry. And especially to Professor Orgel, thank you for your inspiration and encouragement . iv TABLE OF CONTENTS Signature Page .......................................................................................................... iii Dedication .................................................................................................................
    [Show full text]
  • Purine and Pyrimidine Biosynthesis
    Biosynthesis of Purine & Pyrimidi ne Introduction Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined together to form macromolecules. This process often consists of metabolic pathways. The purines are built upon a pre-existing ribose 5- phosphate. Liver is the major site for purine nucleotide synthesis. Erythrocytes, polymorphonuclear leukocytes & brain cannot produce purines. Pathways • There are Two pathways for the synthesis of nucleotides: 1. De-novo synthesis: Biochemical pathway where nucleotides are synthesized from new simple precursor molecules 2. Salvage pathway: Used to recover bases and nucleotides formed during the degradation of RNA and DNA. Step involved in purine biosynthesis (Adenine & Guanine) • Ribose-5-phosphate, of carbohydrate metabolism is the starting material for purine nucleotide synthesis. • It reacts with ATP to form phosphoribosyl pyrophosphate (PRPP). • Glutamine transfers its amide nitrogen to PRPP to replace pyrophosphate & produce 5- phosphoribosylamine. Catalysed by PRPP glutamyl amidotransferase. • This reaction is the committed. • Phosphoribosylamine reacts with glycine in the presence of ATP to form glycinamide ribosyl 5- phosphate or glycinamide ribotide (GAR).Catalyzed by synthetase. • N10-Formyl tetrahydrofolate donates the formyl group & the product formed is formylglycinamide ribosyl 5-phosphate. Catalyzed by formyltransferase. • Glutamine transfers the second amido amino group to produce formylglycinamidine ribosyl 5- phosphate. Catalyzed by synthetase. • The imidazole ring of the purine is closed in an ATP dependent reaction to yield 5- aminoimidazole ribosyl 5-phosphate. Catalyzed by synthetase. • Incorporation of CO2 (carboxylation) occurs to yield aminoimidazole carboxylate ribosyl 5- phosphate.
    [Show full text]
  • Alternative Pathways of Glucose Metabolism II. Nucleotides from The
    Alternative Pathways of Glucose Metabolism II . Nucleotides from the Acid-soluble Fraction of Normal and Tumor Tissues and Studies on Nucleic Acid Synthesis in Tumors*t HANNS SCHMITZ4 VAN R. POTTER, ROBERT B. HTJRLBERT,@ AND DWAIN M. WHITE (McArdie Memovial Laboratory, the Medical School, University of Wisconain, Madison, WI..) The first paper (18) in this series on the alterna MATERIALS AND METHODS tive pathways of glucose metabolism established The present study has involved the measure the fact that radioactivity from glucose-i-C'4 was ment of the specific activities of the free 5' mono-, readily incorporated into the pentose moiety of the di-, and triphosphates of adenosine, guanosine, ribonucleic and desoxyribonucleic acids of Flexner cytidine, and uridine from the acid-soluble extract Jobling tumors in rats, and described the over-all of tumor tissue in relation to the specific activities distribution of radioactivity in the acid-soluble of the corresponding nucleotides that were oh and acid-insoluble fractions of tumor and liver tis tamed by chemical or enzymatic hydrolysis of the sue at various time periods. The acid-soluble frac nucleic acids from the same tissue samples, at tion of tissue contains an appreciable amount of specified time intervals after the injection of glu free nucleotides which are possible intermediary cose-1-C'4. The experimental plan corresponds compounds in the synthesis of the nucleic acids exactly to that described in the preceding paper; (6, 7, 8, 9, 13, 16). It was noted (18) that as the C'4 many of
    [Show full text]
  • Induced Alterations in the Urine Metabolome in Cardiac Surgery
    www.nature.com/scientificreports OPEN Bretschneider solution- induced alterations in the urine metabolome in cardiac surgery Received: 16 August 2018 Accepted: 1 November 2018 patients Published: xx xx xxxx Cheng-Chia Lee1,3, Ya-Ju Hsieh 2, Shao-Wei Chen3,4, Shu-Hsuan Fu2, Chia-Wei Hsu 2, Chih-Ching Wu 2,5,6, Wei Han7, Yunong Li7, Tao Huan7, Yu-Sun Chang2,6,8, Jau-Song Yu2,9,10, Liang Li7, Chih-Hsiang Chang1,3 & Yi-Ting Chen 1,2,11,12 The development of Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) cardioplegia solution represented a major advancement in cardiac surgery, ofering signifcant myocardial protection. However, metabolic changes induced by this additive in the whole body have not been systematically investigated. Using an untargeted mass spectrometry-based method to deeply explore the urine metabolome, we sought to provide a holistic and systematic view of metabolic perturbations occurred in patients receiving HTK. Prospective urine samples were collected from 100 patients who had undergone cardiac surgery, and metabolomic changes were profled using a high-performance chemical isotope labeling liquid chromatography-mass spectrometry (LC-MS) method. A total of 14,642 peak pairs or metabolites were quantifed using diferential 13C-/12C-dansyl labeling LC-MS, which targets the amine/phenol submetabolome from urine specimens. We identifed 223 metabolites that showed signifcant concentration change (fold change > 5) and assembled several potential metabolic pathway maps derived from these dysregulated metabolites. Our data indicated upregulated histidine metabolism with subsequently increased glutamine/glutamate metabolism, altered purine and pyrimidine metabolism, and enhanced vitamin B6 metabolism in patients receiving HTK.
    [Show full text]