China
Africa
Explore chapters and articles related to this topic
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 deacetylation, on the other hand, leads to a closed chromatin configuration and gene silencing. Deacetylation reactions are metabolically responsive (Wang et al., 2018; Miranda-Goncalves et al., 2018), where the glycolytic substrate nicotinamide adenine dinucleotide (NAD) acts as a redox cofactor in the deacetylation activity of sirtuins (HDAC enzymes). There are seven sirtuins in mammalian cells, with SIRT1, 2, 6 and 7 localised to the nucleus (Miranda-Goncalves et al., 2018; Imai et al., 2000). As NAD is subject to oxidation in normal cellular metabolism, it yields NAD+ and NADH, and any adjustment in the NAD+/NADH ratio can subsequently change sirtuin activity (Figure 17.2). For instance, when cells have net positive charged (e.g. due to an increased glucose flux), the NAD+/NADH ratio drops, and this metabolic sensor inhibits sirtuin activity to regulate gene expression (Wong et al., 2017). In contrast, when cell NAD+ concentration is elevated (increased NAD+/NADH ratio), sirtuin activation occurs. So, when cells are deprived of ATP and other metabolic substrates, NAD+ levels become elevated and SIRT1, in particular, is upregulated leading to histone (H3K9ac and H3K14ac) deacetylation and a potential up-regulation of metabolic enzymes (Canto et al., 2009; Davison et al., 2021; Etchegaray and Mostoslavsky, 2016).
Developments in drug design strategies for bromodomain protein inhibitors to target Plasmodium falciparum parasites
Published in Expert Opinion on Drug Discovery, 2020
Hanh H. T. Nguyen, Lee M. Yeoh, Scott A. Chisholm, Michael F. Duffy
PfGCN5 is an orthologue of the GCN5 protein in S. cerevisiae. PfGCN5 is the only P. falciparum BRD with a human ortholog; however, they are divergent (Figure 2). Both S. cerevisiae and P. falciparum GCN5 proteins possess a lysine acetyltransferase (KAT) domain. PfGCN5 preferentially acetylates lysine residues on the histone H3 tail, including H3K9 and H3K14 [39]. In a recent study, PfGCN5 was localized upstream of the open reading frame of a gene, which resulted in activation of the epigenetically silenced gene via increased local H3 acetylation [40]. Treatment with curcumin kills P. falciparum, inhibits KAT activity of recombinant PfGCN5 and decreases P. falciparum H3 acetylation [41] in vitro. However, curcumin treatment also generates harmful reactive oxygen species in the parasite [41] and inhibits many other proteins in mammalian cells [42–44] so its effects on P. falciparum could be unrelated to PfGCN5 inhibition. The function of the bromodomain (BRD) in PfGCN5 has not been characterized.