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Exercise, Metabolism and Oxidative Stress in the Epigenetic Landscape
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Gareth W. Davison, Colum P. Walsh
Histone demethylation can have a repressive or activating role, depending on context, and occurs through lysine-specific demethylases (LSD) and the JumonjiC (JmjC) domain proteins (Lu and Thompson, 2012). LSD1 incorporates the co-factor flavin adenine dinucleotide (FAD+), which is reduced to FADH2 (Miranda-Goncalves et al., 2018) following demethylation of H3K4me1, H3K4me2, H3K9me1 and H3K9me2 (Etchegaray and Mostoslavsky, 2016). The paralog LSD2 also utilises FAD+ to demethylate H3K4me1 and H3K4me2 (Karytinos et al., 2009). Similar to the workings of the TET isoenzymes, the circa 30 JmjC domain-contain histone demethylases rely on Fe2+ and α-KG co-factors to aid the removal of methyl groups from arginine and trimethylated lysine (H3K4, H3K9, H3K27, H3K36 and H4K20) in an oxidative-style reaction producing hydroxymethyl lysine. JmjC is also known to be inhibited by the TCA intermediates fumarate and succinate (Wang et al., 2018; Rodriguez et al., 2017; Etchegaray and Mostoslavsky, 2016; Davison et al., 2021).
Proteinase Inhibitors: An Overview of their Structure and Possible Function in the Acute Phase
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Rat T-kininogens appear not to be substrates for kinin excision by kallikreins due to the replacement of residues flanking the kinin segment. Although it is possible that the kinin sequence (which is identical to that of H- and L-kininogens) may be released by other proteinases, it is not clear whether this is physiologic. More likely, T-kininogens have lost their ability to act as kinin substrates and are now just proteinase inhibitors. The two rat T-kininogens are encoded by distinct genes126 that separated recently, though at distinct times, from the rodent H/L-kininogen gene124 and are therefore paralogs of Rat H- and L-kininogen. T-kininogens, therefore, probably do not exist in mammals other than rodents.
TRPML Subfamily of Endolysosomal Channels
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Nicholas E. Karagas, Morgan A. Rousseau, Kartik Venkatachalam
Evolutionarily, TRPMLs are highly conserved proteins with homologs identified in diverse lineages. Vertebrates encode multiple paralogs of TRPML – the mammalian and zebrafish genomes are marked by the expression of three and five TRPML encoding genes, respectively (Benini et al., 2013; Li et al., 2017). Two independently generated mouse models with Mcoln1 deletions have been described (Chandra et al., 2011; Venugopal et al., 2007). Both models faithfully recapitulate various aspects of MLIV including neurodevelopmental and psychomotor defects, ophthalmological abnormalities and retinal degeneration, achlorhydria and elevated serum gastrin levels, and of course, diminished endolysosomal Ca2+ release. The neurological phenotypes of the Mcoln1-/- mice include diminished strength, shorter gait, and eventual paralysis of the hindlimbs. Remarkably, these mice also demonstrated MLIV phenotypes on the cellular level including ubiquitous presence of endolysosomal inclusions. Zebrafish express two orthologs of human TRPML1, and their deletions elicit many of the features of MLIV including retinal and neuromuscular defects (Benini et al., 2013; Li et al., 2017).
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
Published in Expert Opinion on Drug Discovery, 2022
Riccardo Rozza, Pavel Janoš, Angelo Spinello, Alessandra Magistrato
Regarding the RNA components of the SPL, mutations of U1 and U2 snRNA are implicated in cancer (hepatocellular carcinoma, CCL, and medulloblastoma). These mutations are responsible for 5’ cryptic splicing and intron retention events. Additionally, mutations of U1 snRNA at the 5’SS induce spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease and the leading genetic cause of newborn lethality [26,27,71–73]. The mechanism underlying SMA onset is rather complex. SMA is caused by a homozygous deletion of the survival of motor neuron-1 gene (SMN1) in chromosome 5 encoding for the SMN protein, which plays a critical role in snRNP assembly [72–74]. In humans, two paralog SMN genes exist: SMN1 and SMN2 [75]. The SMN protein produced by the SMN2 gene cannot fully compensate for the loss of SMN1 in SMA patients.
Serpina3n: Potential drug and challenges, mini review
Published in Journal of Drug Targeting, 2020
Mehwish Saba Aslam, Liudi Yuan
Serpins, a large superfamily of structurally conserved serine protease inhibitors, distributed among eukaryotes, some prokaryotes and viruses [18,19] characterised in more than 1000 types which in turn subclassified into 16 clades (clade A-clade P) based on their evolutionary conserved amino acids and functions. Among these subgroups clade 9 (A1 to A13) comprises of 36 genes in humans and 60 genes in murine. Among 60 genes of murine some have evolved their multiple paralogs through duplication [5,20]. Human serpin genes are located on 10 different chromosomes in cluster forms and within each cluster all serpins belong to the same clade. 25/36 human serpin genes are mapped on chromosome 6, 14, and 18. Others are located on chromosome 1, 3, 9, 11, 22, and X. Most of the murine serpins are mapped on chromosome 1, 12, and 13 while others on chromosome 1, 2, 3, 5, 7, 8, and 11. There is another group of serpins not yet classified into any clade termed as “orphans” [5,9]. Serpina3n is a ∼48–55 KD secretory serine protease inhibitor sharing 61% homology with human SERPINA3 (α1-antichymotrypsin).SERPINA3 encoded by a single gene in humans is mapped on 14q32.1 while Serpina3n 1/14 multigene cluster in mice is mapped on 12F1 [1] (Table 1).
Novel strain of Pseudoruminococcus massiliensis possesses traits important in gut adaptation and host-microbe interactions
Published in Gut Microbes, 2022
Kaisa Hiippala, Imran Khan, Aki Ronkainen, Fredrik Boulund, Helena Vähä-Mäkilä, Maiju Suutarinen, Maike Seifert, Lars Engstrand, Reetta Satokari
OrthoVenn2 (https://orthovenn2.bioinfotoolkits.net/home) was used to generate clusters of proteins, orthologs or paralogs, between the type strain of P. massiliensis and the isolate P. massiliensis E10-96H. An overlapping cluster indicates that the cluster contains proteins shared between the different strains. The type strain of P. massiliensis and isolate P. massiliensis E10-96H formed 1792 clusters and 1744 single-copy gene clusters. Overall, there were 1758 common clusters shared between the two strains, 20 unique clusters in P. massiliensis E10-96H and 14 in the type strain of P. massiliensis (Figure 1d).