Genetics
Frank J. Dye in Human Life Before Birth, 2019
Our consideration of DNA replication has used a simple example—having to do with scale, among other things. When two deoxyribonucleotides are hydrogen-bonded together in the DNA molecule (e.g., A-T), they are referred to as a base pair. The DNA in the nucleus of a single human cell contains 3 billion base pairs. Indeed, it was the goal of the multibillion-dollar international scientific effort called the Human Genome Project to determine the sequence of all 3 billion base pairs. Why? Because the sequence is information, and one use of information is improved medical care. Note that each diploid (having two sets of chromosomes) human cell has 46 chromosomes, and each chromosome contains a single DNA molecule, and therefore each chromosome has, on average, millions of base pairs (our example of DNA replication above, with 12 base pairs, was obviously a simplification of scale).
Affinity Modification — Organic Chemistry
Dmitri G. Knorre, Valentin V. Vlassov in Affinity Modification of Biopolymers, 1989
The enhanced interest in derivatives of nucleosides and especially nucleotides originates from the outstanding significances of nucleotides for living organisms. Almost all energyconsuming processes such as endergonic chemical reactions, transmembrane transfer of ions, muscle contraction, and unidirectional movement of template nucleic acids along the information-multiplying or -transforming systems are supplied with energy by ATP or sometimes GTP molecules. Besides this, ATP serves as a nearly universal donor of phosphate in numerous phosphorylation reactions. Nucleotide coenzymes NAD and NADP participate in the hundreds of oxidation-reduction transformations of hydroxy and carbonylic groups as well as the aldehyde and carboxylic groups. Adenosine moieties are found in coenzyme A, the main acyl groups carrier, and in S-adenosylmethionine, nearly a single source of methyl groups in a great number of biochemical methylation processes. Nucleotide sugars are intermediates in the oligo- and polysaccharides biosynthesis. Ribonucleoside and deoxyribonucleoside-5′-triphosphates are substrates of nucleic acid polymerases. Nucleotides play a great role in the regulation processes. 3′,5′-Cyclophosphates of adenosine and guanosine (cAMP and cGMP) are participants of the systems transferring the signals produced by the interaction of hormones and neurotransmitters with cell surface receptors (see Chapter 1, Section I.F). Therefore, the reactive derivatives of nucleotides may be used for affinity modification of many hundreds of proteins.
Toxicity of Antineoplastic Chemotherapy in Children
Sam Kacew in Drug Toxicity and Metabolism in Pediatrics, 1990
Hydroxyurea is a water-soluble compound with the molecular weight of 76. Hydroxyurea putatively inhibits DNA synthesis by acting on ribonucleotide synthetase and blocks cell cycle progression through G,.135 This enzyme is important in the reduction of ribonucleotides to deoxyribonucleotides. Hydroxyurea apparently binds to the ribonucleotide synthetase in a nonreversible manner which thus inhibits enzymatic reductive capacity. Cells are thus unable to synthesize DNA, although RNA and protein synthesis are unimpeded at least for a limited time. Iron may reverse the effects of hydroxyurea as does the exogenous infusion of deoxyribonucleotides. Other DNA changes, such as fragmentation and template destruction, have also been reported as possible mechanisms of action for this drug. By these mechanisms, cells are synchronized between the G-l and S phases. Many cell lines show increased radiosensitivity or susceptibility in the G-l phase and this may account for the in vitro observation that the combination of radiation and hydroxyurea results in increased cell kill.
The preclinical discovery and development of molnupiravir for the treatment of SARS-CoV-2 (COVID-19)
Published in Expert Opinion on Drug Discovery, 2022
Pasquale Pagliano, Carmine Sellitto, Tiziana Ascione, Giuliana Scarpati, Veronica Folliero, Ornella Piazza, Gianluigi Franci, Amelia Filippelli, Valeria Conti
The activity of MOV against RNA viruses is due to its mutagenic activity, but great concern derives from the potential ability of MOV to induce mutations in the DNA of mammalian cells. Some investigations indicate that these highly active mutagenic ribonucleosides may hold a mutagenic risk for the host because the active form of β-d-N4-hydroxycytidine can be metabolized to 2′-deoxyribonucleotide and theoretically incorporated into the host genome. The impact of this phenomenon on carcinogenesis should receive further investigations. However, based on the analysis of lung samples taken by a hamster model of SARS-CoV-2 infection receiving MOV, there was no significant difference in absolute numbers and percentile distribution of both substitution and indel mutations, which could be related to MOV administration. Similar results were reported by producing company (Merck Pharmaceutical) through in vivo Pig-a mutation assay, and Big Blue (cII Locus) transgenic assay in rats [79–81].
Levels of Folate and Vitamin B12, and Genetic Polymorphisms Involved in One-Carbon Metabolism May Increase the Risk of Cervical Cytological Abnormalities
Published in Nutrition and Cancer, 2022
Nayara Nascimento Toledo Silva, Ana Carolina Silva Santos, Maria de Fátima Dias de Sousa Brito, Diama Bradha Andrade Peixoto do Vale, Cláudia Martins Carneiro, Angélica Alves Lima
TS enzyme catalyzes the conversion of deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP), through methylene transfer from folate, being the only de novo source of thymidine for DNA synthesis and repair. TS acts as a protein that binds to RNA for translation repression of its messenger RNA (mRNA) or other proteins, and can regulate cell cycle progression (15, 16). High levels of TS activity may to increase DNA synthesis, as well as the accumulation of genetic alterations, due to imbalance of deoxyribonucleotide triphosphates (dNTPs) pool. Therefore, TS enzyme is a potential target of several chemotherapeutic agents in treatment of cancer, besides the analysis of its levels to be useful in evaluation of tumor cell sensitivity to radiation (17). Many polymorphisms in untranslated regions (UTRs) were identified in TS gene, which is located on chromosome 18p11.32. The polymorphisms most frequently studied are double or triple 28 bp tandem repeat in 5′-untranslated enhanced region (TSER), and 6 bp deletion/insertion at nucleotide 1494 in TS 3′-untranslated region (TS3’UTR). These two genetic variations may influence the TS gene expression and the stability of its mRNA, respectively (15).
Transcriptome analysis identifies key regulators and networks in Acute myeloid leukemia
Published in Hematology, 2019
Jiaxin Ye, Daliang Luo, Jianhong Yu, Sibo Zhu
Next, we observed that the target genes of hub miRNAs were related to cell growth, proliferation, death, and survival. Pathway analysis demonstrated that the ATP enzyme was significantly affected by miRNA regulation. The ATP was involved in biosynthesis pathways which were significantly enriched. Salvage Pathways of Pyrimidine Deoxyribonucleotides was a pathway related to the biosynthesis of deoxyribonucleotides. ATP played a very important role in this biological procedure [19–23]. Deoxyribonucleotides were essential to DNA synthesis/repair. The previous study demonstrated that the biosynthesis of deoxyribonucleotides was an important target for anticancer therapy [24,25].