Translation
Paul Pumpens in Single-Stranded RNA Phages, 2020
Furthermore, the crystal structures of two complexes between recombinant MS2 capsids and RNA operator fragments have been determined at the 2.7 Å resolution (Valegård et al. 1997). The three-dimensional studies clearly confirmed the intrinsic role of the adenines A−10, A−7, A−4 and a pyrimidine at position −5. The RNA stem-loop, as bound to the protein, formed a crescent-like structure and interacted with the surface of the β-sheet of a coat protein dimer (for more detail, see Chapter 21). It made protein contacts with seven phosphate groups on the 5′ side of the stem-loop, with a pyrimidine base at position −5, which stacked onto a tyrosine, and with two exposed adenine bases, one in the loop and one at a bulge in the stem. The replacement of the wild-type uridine with a cytosine at position −5 increased the affinity of the RNA to the dimer significantly. The complex with RNA stem-loop having cytosine at this position differed from that of the wild-type complex mainly by having one extra intramolecular RNA interaction and one extra water-mediated hydrogen bond (Valegård et al. 1997). Figure 16.7 presents the actual secondary structures of the two RNA operators within the complex I.
Power and power endurance: the explosive sports
Nick Draper, Helen Marshall in Exercise Physiology, 2014
Each of the five bases bonds with a sugar, either deoxyribose or ribose, to form a nucleoside. As already mentioned, adenine bonds with ribose to form adenosine, the basic unit for ATP, which is an example of a nucleoside. Just as adenosine bonds with phosphoryl groups to form AMP (adenosine monophosphate), ADP and ATP, so each of the other four nucleosides can bond with phosphoryl groups to create a nucleotide. As with ATP, the addition of the final two phosphates to a nucleoside provides an energy store that can be used to fuel cellular activity. If ATP is the petrol for our bodies, then the other nucleotides represent diesel or liquefied petroleum gas (LPG), alternative fuels for the cells of the body. For example, guanosine triphosphate (GTP) is used as an energy source for protein synthesis and one molecule of GTP is produced during the Krebs cycle (which is discussed further in Chapter 12). Uridine triphosphate (UTP), by way of a further example, is used by the liver and muscles to provide the energy necessary for the synthesis of glycogen. Adenosine triphosphate, however, is the main source of energy for the cellular activity within the body including the muscular contractions that are necessary for sports performance.
Analysis of Small RNA Species: Phylogenetic Trends
S. K. Dutta in DNA Systematics, 2019
Participation of small RNAs and/or oligoribonucleotides in the translation of mRNAs into proteins has been postulated 141,150 and thereafter confirmed by experimental data.143,151,152 Oligoribonucleotides have been found attached to initiation factors involved in protein biosynthesis. Such an RNA molecule called “i-RNA”143 is rich in adenine (46%) and poor in guanine (7%).153 This “i-RNA” found in reticulocytes is present in ribosomes from various sources. Although it participates in translation of mRNAs, it lacks specificity for an mRNA from a given species. A small “translating control RNA” rich in uridine, inhibits in vitro the translation of mRNA.152 Small RNAs, isolated from newborn rats, alter the translation of mRNA in a system of wheat germ.143 Such an RNA, containing poly U stretches, inhibits the translation of homologous or hererologous mRNA.154 RNA without poly U appears to activate the translation.
Uridine triacetate - an antidote in the treatment of 5-fluorouracil or capecitabine poisoning
Published in Expert Opinion on Orphan Drugs, 2019
Muhammad Wasif Saif
Because of the association between the incorporation of 5-FU into RNA and dose-limiting toxicities, uridine has previously been examined for potential reduction of host toxicity [14]. Preclinical and clinical studies have revealed that sustained uridine concentrations of at least 50 µmol/L are required to confer protection to normal tissues from the toxic effects of 5-FU. Differences in uptake and utilization of uridine between tumor and normal tissues underlie uridine’s ability to reduce the toxicities of 5-FU without proportionally reducing antitumor activity [14–17]. Both hematopoietic and gastrointestinal mucosal progenitors efficiently incorporate exogenous uridine (via the ‘salvage pathway’), whereas most other tissues, including malignant tumors, favor the ‘de novo pathway’ of uridine nucleotide biosynthesis, in which free uridine is not an intermediate. Thus, exogenous uridine is more effective at competing with fluorouridine triphosphate (FUTP) for incorporation into RNA in normal tissues versus all solid tumors tested to date in murine systems [18].
Advances in prodrug design for Alzheimer’s disease: the state of the art
Published in Expert Opinion on Drug Discovery, 2022
Valentin Travers--Lesage, Serge M. Mignani, Patrick Dallemagne, Christophe Rochais
The preparation of a glycosylated prodrug 14 of the anti-neuroinflammatory acetyl-p-phenylenediamine, both increased BBB permeation and water solubility (Table 2). The prodrug demonstrated promising properties in vivo alleviating both amyloid deposition and neuroinflammation associated with procognitive effect in transgenic models [32]. A glycosylation strategy was also followed to increase the solubility of Silybin, a natural compound that demonstrated neuroprotective properties in vivo. A trehalose moiety was conjugated to Silybin with a phosphate linker 15 and improved both its stability and by 3-fold its solubility. The resulted prodrug demonstrated its ability to reduce amyloid growth and toxicity [33]. Already developed in oncology field, glycosylation of bases has been also applied to neurodegenerative diseases and more specifically AD. In this context, the uridine prodrug PN401 16 has demonstrated some neuroprotective effects in animal models [34]. In addition, another glycosylated catecholamine prodrug 17 [35] or other types have been patented in the recent years [36–38].
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
DHODH is a necessary enzyme in the cellular pathway of de novo pyrimidine synthesis [126,128,129]. This mitochondrial membrane enzyme mediates the fourth step in the pyrimidine synthetic pathway, catalyzing the conversion of dihydroorotate to orotate [126,128]. The final product of this pathway is the generation of the pyrimidine uridine monophosphate (UMP), one of four nucleotides necessary for RNA synthesis and a precursor for synthesis of other necessary pyrimidine nucleotides [128,129]. Cells can obtain uridine by two pathways, the de novo synthetic pathway mentioned above and a secondary scavenging pathway that utilizes membrane nucleoside transporters to shuttle extracellular uridine into the cell [126,129]. Though cells at rest can likely survive primarily off the uridine scavenging pathway, actively dividing cells have much higher nucleic acid synthetic needs and largely depend on intracellular pyrimidine biosynthesis [129,130]. Increased DHODH activity in myeloid leukemias has been known for over 60 years, with an initial study in the late 1950s demonstrating that leukocytes from patients with AML had significantly increased DHODH enzymatic activity [131]. Interestingly, increased DHODH enzymatic activity does not appear to be a driver of leukemogenesis but rather a necessary cellular response to increased replication demands. DHODH is not known to be mutated or amplified in AML, though it is a target of the oncogenic transcription factor c-Myc [129,130].