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Metabolism and Toxicity of Occupational Neurotoxicants: Genetic, Physiological, and Environmental Determinants
Published in Lucio G. Costa, Luigi Manzo, Occupatinal Neurotoxicology, 2020
Stefano M. Candura, Luigi Manzo, Anna F. Castoldi, Lucio G. Costa
The best characterized P450 polymorphism is that of cytochrome CYP2D6 (debrisoquine 4-hydroxylase). Its discovery followed the observation of unusual subject sensitivity to the hypotensive effect of debrisoquine,43 and of unusual neurological side effects in some patients treated with sparteine.44 It was subsequently clarified that the debrisoquine-sparteine polymorphism is caused by mutations of the CYP2D6 gene, which is part of a gene cluster on chromosome 22.45 Enzymatic activity is deficient in 7–10% of Caucasian subjects, who therefore show a slower oxidative metabolism.46,47 The frequency of poor metabolizers appears to be markedly lower in non-Caucasian populations.38 Since many therapeutic agents are oxidized by CYP2D6, the polymorphism has important clinical consequences, particularly in the use of cardiovascular and psychoactive drugs.8 With regard to neurotoxicology, CYP2D6 detoxifies 1,2,3,4-tetrahydroisoquinoline (TIQ) and MPTP. MPTP and other environmental neurotoxins with similar chemical structures have been implicated in the pathogenesis of Parkinson’s disease. Some researchers characterized the genotype that regulates 2D6 expression in Parkinson patients, suggesting that slow metabolizers have a two-three fold increased disease susceptibility.48,49
Charge and Spin Dynamics in DNA Nanomolecules: Modeling and Applications
Published in Klaus D. Sattler, st Century Nanoscience – A Handbook, 2020
Samira Fathizadeh, Sohrab Behnia
In most works on studying the charge transfer in DNA, its sequence–dependent electrical conductivity is determined [76]. However, the spin filtering efficiency in DNA segments depends on the sequence and its length [22]. We have examined the different DNA blocks from human chromosome 22’s (CH22) sequence to study the effect of DNA sequence type and length on the net spin current to determine a better sequence for information transport. Table 12.7 reports the spin currents and spin filtering for different DNA segments. It is clear that the AT-rich oligomers are a better candidate than CG-rich for creating the net spin current (Figure 12.16). Also, increasing of the AT-rich blocks has a positive impact on the ratio of the net spin current to net charge current.
Bioinformatics and Applications in Biotechnology
Published in Ram Chandra, R.C. Sobti, Microbes for Sustainable Development and Bioremediation, 2019
A major application of bioinformatics tool is drug design when structure of candidate protein is known. Various tools are used to find out the free energy of binding of various conformers of a small molecule in the active site by calculating the Van der Waal’s interactions, hydrogen bonding, solvation energy, and electrostatic interactions. A classic example is the design of the antitumor drug Gleevec. Gleevec has high specificity for the onco-protein BCR-Abl, which is a fusion protein resulting from reciprocal translocation between chromosome 9 and chromosome 22 (Philadelphia translocation), leading to a constitutively active kinase. Gleevec was approved by the FDA for clinical use in 2001 for treating chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. The DFG-loop (Asp-Phe-Gly) in the kinase structure was taken as a structural feature that differs between kinases that bind Gleevec tightly or weakly. In the structure of Abl kinase, this loop adopts a so-called out conformation in both the apo and Gleevec-bound protein, while in the closest homolog and weak binder Src kinase, it occupies an in conformation in the apo protein that would have to move into the “out” position to accommodate the drug. It was hypothesized that the preferential occupancy of the DFG-out state by Abl but not Src is the primary source of Gleevec selectivity. A variety of approaches, both experimental and computational, were taken to quantify the free energy profile of the DFG-loop dynamics (Agafonov et al., 2015).
Genetic polymorphisms of PPAR genes and human cancers: evidence for gene–environment interactions
Published in Journal of Environmental Science and Health, Part C, 2019
PPARs have been shown to be genetically polymorphic. Two different isoforms have been reported for PPAR-α in diverse species including humans: PPARα1 and PPARα2, mapped to chromosome 22, adjacent to region 22q12-q13.1.48 PPARα2 is truncated at exon 6, with no ligand-binding domain in the gene product, and hence is unable to bind any ligand. For PPARα1, The focus of the literature has mainly been on the rs1800206 (L162V) missense polymorphism, which results in a leucine to valine substitution at exon 5-codon 162 and a subsequent C > G substitution in the DNA-binding domain. Studies reported that the V162 allele encodes a higher transcription activity as compared to the L162 allele.49 The L162V heterozygous genotype (CG) prevalence was reported to be 30% in Chinese,5 10.3% in US Caucasians,50,51 and 3% among populations of African descent.50