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Introduction to Cells, DNA, and Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
Since viruses are using our cellular machinery for reproduction, that means that they are operating with our genetic code. Watson and Crick first published the structure of DNA, consisting of nucleotide subunits of four varieties: adenine, guanine, cytosine, and thymine (Watson and Crick 1953). In their work, Watson and Crick detailed the double-helical structure of the DNA molecule, requiring two strands of DNA in opposite orientations. Each nucleotide building block of DNA contains a nitrogenous base that would pair with a base in the opposite strand to make a “rung” of the DNA ladder, with the sugar and phosphate components of the nucleotides making up the “sides” of the ladder. Because of work done by Rosalind Franklin, Erwin Chargaff, and others, Watson and Crick were confident that the bases were turned inward as the rungs, rather than studding the sides on the outside, of the helical structure. In addition, a purine (guanine or adenine) and a pyrimidine (cytosine or thymine) aligned on each rung to create a uniform length to the ladder rung throughout the helix (Alberts et al. 2019). Rosalind Franklin made significant contributions to Watson and Crick’s discovery through her X-ray crystallography work on DNA structure (Maddox 2002).
Antiviral Agents and Rational Drug Design
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Acyclovir, shown in Figure 4.1, is in fact a pro-drug; the active agent is generated by phosphorylation in three stages to from a triphosphate within the infected cell. Nucleotide trisphosphates are the constituent building blocks of DNA, which assemble together along a template strand through the action of enzymes during DNA replication. Namely, DNA polymerase is responsible for this process and acyclovir works as an inhibitor of viral DNA polymerase and prevents DNA replication in two ways: either by inhibiting DNA polymerase, or as a chain terminator. DNA polymerase can catalyse the attachment of acyclovir into the growing DNA chain because it has a sufficiently similar structure to deoxy guanosine. Since the sugar ring is incomplete, and lacks the required hydroxyl group on position 3’ of the sugar ring, the nucleic acid chain cannot extend further and DNA replication ceases.
Role of Genetic Variability in Breast Cancer Treatment Outcomes
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Kandace L. Amend, Ji-Yeob Choi, Christine B. Ambrosone
The agents 5FU and MTX are involved in folate metabolism, in the conversion of homocysteine to methionine, and in purine and pyrimidine synthesis. The activated metabolites of 5FU, similar to pyrimidine nucleotides, competitively and reversibly bind fluoropyrimidine thymidylase synthase (TS) inhibitors, forming covalently bound complexes with the TS enzyme, thus inhibiting the enzyme’s activity (48). Folate antagonists, such as MTX, are structurally similar to folate and inhibit the action of various enzymes such as dihydrofolate reductase (DHFR) (49). Their action is accomplished through incorporation as false precursors in DNA or RNA or through inhibition of proteins involved in nucleotide metabolism.
Emergence of varicella-zoster virus resistance to acyclovir: epidemiology, prevention, and treatment
Published in Expert Review of Anti-infective Therapy, 2021
Kimiyasu Shiraki, Masaya Takemoto, Tohru Daikoku
VZV encodes viral thymidine kinase (TK), ribonucleotide reductase (RR), thymidylate synthase (TS), helicase-primase (HP), and DNA polymerase (DNApol). Figure 2 illustrates the role of each of the abovementioned enzymes in nucleotide metabolism. RR and TS supply deoxyribonucleotide diphosphates (dNDP)s with the ribonucleotides of RNA metabolism and facilitate viral DNA synthesis in the early phase of infection. Acyclovir and penciclovir are phosphorylated by viral TK and are further phosphorylated into their triphosphate (TP) forms, which compete with deoxyguanosine TP (dGTP) for incorporation into viral DNA and terminate chain elongation when incorporated. Chain termination by acyclovir occurs at the incorporated site, and penciclovir stops elongation after its incorporation, followed by some nucleotides [19].
Coronavirus helicases: attractive and unique targets of antiviral drug-development and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2021
Austin N. Spratt, Fabio Gallazzi, Thomas P. Quinn, Christian L. Lorson, Anders Sönnerborg, Kamal Singh
Helicases are ubiquitous nucleic acid unwinding enzymes. These biological motors couple the chemical energy of nucleotide triphosphate hydrolysis (NTPase) to mechanical energy that translocates through nucleic acids, unwinding the helical structure as it progresses, thus the term ‘helicase.’ Efficient genome replication, recombination and repair require single stranded DNA (ssDNA) or single stranded RNA (ssRNA) as a template that is largely devoid of secondary structures [1]. Helicases in situ generate ssDNA or ssRNA, and due to this crucial role during genome replication, repair and recombination, defects in helicase function can lead to many genetic disorders. Notable examples of helicase-associated disorders include Bloom’s syndrome, Werner’s syndrome, and X-chromosome-linked α-thalassemia [2–9].
Chromosome aberration in typical biological systems under exposure to low- and high-intensity magnetic fields
Published in Electromagnetic Biology and Medicine, 2020
Emanuele Calabrò, Hit Kishore Goswami, Salvatore Magazù
Chromosomes are molecules composed of the deoxyribonucleic acid (DNA) that represents the genetic material of a living being. In human beings, there are 22 pairs of chromosomes and 2 sex chromosomes for a total of 46. DNA is an organic polymer composed of monomers that are called nucleotides. They consist of a phosphate group and a nitrogenous base linked to deoxyribose by the so-called N-glycoside bond. The nitrogenous bases that can be used in nucleotide formation are adenine, cytosine, guanine and thymine disposed in base pairs of adenine-thymine (A-T) and guanine-cytosine (G-C) that in aqueous solutions are linked one each other by hydrogen bonds forming a double helix structure because of the repulsions between the negative charge of phosphate groups. This double helix structure is bound to proteins (the histones) that have positively charged amino acids in order to bind the DNA which is negatively charged and is wrapped around the core of histone of eight protein subunits forming the nucleosome. About 200 base pairs of DNA are coiled around each histone. This coil is untwisted generating a negative superturn per nucleosome that is the active chromatin.