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Analyses of the Idiotypes and Ligand Binding Characteristics of Human Monoclonal Autoantibodies to Dna: Do We Better Understand Systemic Lupus Erythematosus?
Published in Irun R. Cohen, Perspectives on Autoimmunity, 2020
Several groups have reported the results of their studies of murine monoclonal anti-DNA antibodies,3,4 and they will not be reiterated here. Instead, I will deal with analyses of human monoclonal anti-DNA autoantibodies, mainly because they have direct application to the human disease. We have analyzed the nucleic acid-binding specificities of 60 monoclonal antibodies derived from seven unrelated patients with SLE.6 The results demonstrated that a single lupus autoantibody can bind to multiple nucleic acid antigens of widely different base compositions. A reasonable explanation for this seeming multiplicity of binding reactions is that the various ligands possess cross-reacting epitopes. The logical candidate for these epitopes is a structure in the sugar-phosphate backbone that is common to all nucleic acids. An important feature of the sugar-phosphate backbone is the presence of phosphate groups in phosphodiester linkage with carbon atoms of adjacent sugar molecules. We believe, for reasons to be given below, that these phosphate groups on the exterior of the helical nucleic acids constitute one of the important epitopes for lupus autoantibodies. Moreover, individual variations in binding specificities among monoclonal anti-DNA antibodies may reasonably be accounted for by structural differences in polynucleotide backbone that stem from variations in helical configuration and interphosphate distances.
Genetics
Published in Rachel U Sidwell, Mike A Thomson, Concise Paediatrics, 2020
Rachel U Sidwell, Mike A Thomson
DNA is a double helix composed of: Sugar-phosphate backbone (the pentose sugar deoxyribose and a phosphate group)Nitrogenous base The sugar-phosphate backbone has a 5′ and a 3′ endA nucleotide = a unit of one base, one deoxyribose and one phosphate groupThe DNA is coiled tightly to make up chromosomesThe gene sequence is made of exons (code for proteins) interspaced with intronsThree bases make up a codon, which codes for one amino acid (via the genetic code)The sequence of amino acids determines the protein product
The Mannitol Enzyme II of the Bacterial Phosphotransferase System: A Functionally Chimaeric Protein with Receptor, Transport, Kinase, and Regulatory Activities
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
Milton H. Saier, John E. Leonard
In subsequent studies42 60 mtlA mutants, defectie for the mannitol Enzyme II, were isolated by this procedure, and they were characterized by assays which measured the various activities catalyzed by this enzyme. The mutants fell into six classes as summarized in Table 3.42 Class I mutants lacked all activities associated with the Enzyme IIMtl (mannitol Chemotaxis, transport, PEP-dependent mannitol phosphorylation, and mannitol-1-phosphate-dependent transphosphorylation). These mutants presumably included nonsense and deletion mutants and may therefore lack the Enzyme IIMtl protein altogether. Class II mutants lacked each of the four activities assayed with the exception of transphosphorylation which was near the wild type level. The sugar and sugar phosphate binding sites of the Enzyme II had to be intact in these mutants. Class III and IV mutants showed depressed levels of all activities with the exception of Chemotaxis. While Class III mutants showed elevated chemotactic responses to mannitol, Class IV mutants showed no detectable response.42 In these mutants the chemotactic function of the Enzyme II was dissected from the other activities. Class V mutants showed an elevation of all activities except for phosphoenolpyruvate-dependent phosphorylation which was substantially depressed. Finally, in Class VI mutants, all activities of the Enzyme II were depressed. This class is the trivial class of “leaky” mutants where the genetic defect did not have a selective effect on any one activity of the enzyme.
Repurposing drugs for the treatment of galactosemia
Published in Expert Opinion on Orphan Drugs, 2019
Deletion of the gene encoding GALT in budding yeast Saccharomyces cerevisiae (GAL7) resulted in depletion in cellular inorganic phosphate levels [84]. Similar effects have been observed in the serum of patients with galactosemia and hereditary frustose intolerance (OMIM #229600), another disease which results in the accumulation of a sugar phosphate [85]. In the yeast model, this phosphate depletion resulted in altered glycogen metabolism, presumably because phosphate ions are required for the enzymatic breaking of α(1→4) glycosidic bonds in this polysaccharide. Reversal of phosphate depletion either by deletion of the galactokinase gene (GAL1) or supplementation of the media with phosphate ions prevented the reduction of cellular phosphate levels and restored normal glycogen metabolism [84]. This suggests that phosphate supplementation in galactosemia patients would be worth investigating.
siRNA drug development against hepatitis B virus infection
Published in Expert Opinion on Biological Therapy, 2018
Robert Flisiak, Jerzy Jaroszewicz, Mariusz Łucejko
Another technique is chemical modification of siRNA with a specific chemical group capable of reacting with the hepatocyte receptor. Advantages of this kind of modification are: increased bioavailability, enhanced effectiveness at lower doses and specificity, reduced dosing frequency, and weak innate immune activation during the treatment [43]. Novel examples of such modification are phosphorothiolation, substitution of the 2′-OH group with 2′-O-methyl or 2′-F-nucleotides on the sugar phosphate backbone, and locked nucleic acid [47]. All of these technologies cause the passage of RNA molecules through endocytosis. In some cases, siRNA must be chemically modified to prevent degradation by intracellular endonuclease. From a technological point of view, release from endosomes of dsRNA molecules into the cytoplasm and renal elimination are an important challenge [24,48–52].
Calculation of the initial DNA damage induced by alpha particles in comparison with protons and electrons using Geant4-DNA
Published in International Journal of Radiation Biology, 2020
Hossein Moeini, Mojtaba Mokari, Mohammad Hassan Alamatsaz, Reza Taleei
A protein data bank file was used to extract the atomic coordinates of a 216 bp long double helix B-DNA (432 nucleotides in total). Each nucleotide consists of sugar-phosphate groups and a base group. DNA molecules were then sampled within the volume of a water sphere, at which the center of the isotropic point source of alphas was located and with a radius sufficiently large to cover the particle range at each energy. The choice of the radius of the sphere depends on the energy of the initial alpha particles and their range in water. Hence, the sampling of DNAs within the water medium (see Figure 1 and Mokari, Alamatsaz, Moeini, Taleei 2018; Mokari, Alamatsaz, Moeini, Babaei-Brojeny, et al. 2018) was performed based on the µ-randomness method (Kellerer 1975) and using 20,000–100,000 samples in accordance with the alpha energy. An optimized number of DNAs was then found to satisfy the two criteria for sampling accuracy that were defined by Nikjoo et al. (1989, 1991), Mokari, Alamatsaz, Moeini, Taleei (2018) and Mokari, Alamatsaz, Moeini, Babaei-Brojeny, et al. (2018). The accuracy of sampling was checked with the help of two criteria. The first check was on the ratio of the deposited energy in the water sphere, which must be comparable within 5% with the ratio of the deposited energy in all DNAs to the sum of their volumes. The second check was on the frequency-mean specific energy (1983) of DNAs, which must be comparable within 5% with the reciprocal of the frequency of hits with non-zero energy deposition ƒ(>0). In case any of the above conditions were not satisfied, the sampling process would be repeated with a larger number of DNAs (Nikjoo et al. 1991).