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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
HDAC1 is phosphorylated by cyclic adenosine monophosphate (cAMP)-dependent kinase PKA and protein kinase CK2 (Pflum et al., 2001). The two phosphate group acceptor sites on the carboxyl-terminal of HDAC1 are S421 and S423, which are essential for enzymatic activity and when mutated in to alanine causes a significant reduction in enzymatic activity and disrupts the complex formation. Phosphorylation of HDAC1 and HDAC2 is reversibly regulated by the protein phosphatase PP1 (Galasinski et al., 2002). Phosphorylation of HDAC3 by CK2 and DNA-PKcs significantly enhances HDAC3 activity (Zhang et al., 2005). HDAC3 can also be phosphorylated by Glycogen synthase kinase 3 (GSK-3b), and inhibition of GSK-3b protects against HDAC3-induced neurotoxicity (Bardai and D’Mello, 2011).
Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
Kinases typically are highly selective, which is based on their ability to recognise a particular amino acid motif on the phosphorylated protein. In contrast, phosphatases can usually dephosphorylate many proteins, but they target individual proteins for dephosphorylation by interacting with regulator subunits. For example, protein phosphatase-1 (PP1) interacts with the PP1 regulatory subunit 3A to specifically dephosphorylate muscle glycogen phosphorylase.
Synapses
Published in Nassir H. Sabah, Neuromuscular Fundamentals, 2020
The phosphate group is hydrolyzed back to an OH– group by enzymes referred to as phosphatases, and the process is known as dephosphorylation. Protein phosphatase 1 (PP1) dephosphorylates a variety of proteins as well as K+ and Ca2+ channels, NMDA, and AMPA glutamate receptors. Protein phosphatase 2A (PP2A) also dephosphorylates a range of proteins that overlap with those of PP1, in addition to tau protein that stabilizes microtubules of the cytoskeleton. Excessive phosphorylation of tau protein is associated with Alzheimer’s disease. Protein phosphatase 2B (PP2B), also known as calcineurin, is abundant in neurons and is activated by Ca2+. It activates T cells of the immune system and dephosphorylates AMPA receptors. Protein phosphorylation and dephosphorylation are of fundamental importance in cell functioning as it is the major molecular mechanism through which protein activity in a cell is regulated both in and outside the nervous system.
Approaches for the discovery of drugs that target K Na 1.1 channels in KCNT1-associated epilepsy
Published in Expert Opinion on Drug Discovery, 2022
Barbara Miziak, Stanisław J Czuczwar
As already mentioned, the KCNT1 gene, is responsible for encoding sodium-activated potassium channels. Known mutations, altering the function of potassium channels, lead to the development of severe epilepsy and significant intellectual impairment [7,10,12]. The research data indicate that most of the disruption is localized to the extended cytoplasmic C-terminus of KNa 1.1 channels, resulting in increased potassium current [55]. One such example is the phosphorylation of this site by protein kinase C, which results in a rapid amplitude of potassium currents [10,55]. Studies indicate that this element is responsible for binding cytoplasmic signaling proteins, including Phactr1, which, by binding actin, recruits protein phosphatase 1 (PP1) to certain phosphoprotein substrates [55]. Other proteins have also been shown to be present, for example, FMRP, PSD95, CYFIP1, and TMEM16C, but their role is not yet as well understood [26,50,56]. Selected mutations on a KNa1.1 protein are presented in Figure 1.
Inhibition of protein phosphatase-1 and -2A by ellagitannins: structure-inhibitory potency relationships and influences on cellular systems
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Zoltán Kónya, Bálint Bécsi, Andrea Kiss, Dániel Horváth, Mária Raics, Katalin E. Kövér, Beáta Lontay, Ferenc Erdődi
Proteins were purified as described in previous publications: Skeletal muscle PP1c and PP2Ac12, FLAG-tagged alpha isoform of PP1c (rPP1cα)21, Hexahistidine-tagged delta isoform of PP1c (rPP1cδ)22), Hexahistidine-tagged protein phosphatase 1 inhibitor 2 (I2)21, 32P-labelled 20 kDa light chain of turkey gizzard myosin (32P-MLC20) phosphorylated to an extent of 0.85–0.95 mol phosphate/mol MLC2023. Cells of tsA201 were transfected with FLAG-peptide (Asp-Tyr-Lys-Asp-Asp-Asp-Asp-Lys)-coupled myosin phosphatase target subunit 1 (MYPT1, PPP1R12A) plasmid and FLAG-MYPT1 as well as its associated proteins (such as PP1cδ) were isolated from cell lysates on anti-FLAG coupled resin. The resin was washed three times with Tris-buffered saline (TBS) and the FLAG-MYPT1-PP1cδ complex was eluted from the resin with 300 µg/ml FLAG-peptide in TBS.
Indirect activation of pregnane X receptor in the induction of hepatic CYP3A11 by high-dose rifampicin in mice
Published in Xenobiotica, 2018
Yuki Yamasaki, Kaoru Kobayashi, Asumi Inaba, Daisuke Uehara, Hiroki Tojima, Satoru Kakizaki, Kan Chiba
To examine the effect of RIF on CYP3A11 and CYP2C55 mRNA levels, hepatocytes were treated with either a vehicle control (DMSO) or RIF (1, 10 or 30 μM) at 20 h after changing to Medium O. GA, a benzoquinone ansamycin, binds to an ATP/ADP binding site of heat shock protein 90 (HSP90), resulting in interruption of its chaperoning function (Pratt & Toft, 1997). OA, a protein phosphatase inhibitor, inhibits the protein phosphatase 1/2 A at a low nM concentration (Timsit & Negishi, 2007). GA and OA are known to inhibit the nuclear translocation of CAR and some nuclear receptors (Kawamoto et al., 1999; Mackowiak & Wang, 2016; Yoshinari et al., 2003). To examine the effects of GA and OA on the induction of CYP3A11 and CYP2C55 by RIF, hepatocytes were pretreated with either a vehicle (DMSO), GA (20 μM) or OA (10 nM) for 1 h at 20 h after changing to Medium O, followed by treatment with RIF (10 μM) for 48 h in the presence of either the vehicle (DMSO), GA (20 μM) or OA (10 nM). All compounds were dissolved in DMSO at a final concentration of 0.1% (v/v) and added to medium S (medium O excluding dexamethasone). The medium containing a test compound was replaced every 24 h.