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Epigenetic Alterations in Alzheimer’s Disease and Its Therapeutic and Dietary Interventions
Published in Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu, Phytomedicine and Alzheimer’s Disease, 2020
P. M. Aswathy, C. M. Shafeeque, Moinak Banerjee
In the one-carbon metabolism pathway, serine hydroxymethyltransferase 1 (SHMT1) is an enzyme that is involved in the reversible conversion of serine and tetrahydrofolate (THF) to glycine and 5,10-methylenetetrahydrofolate (5,10-MTHF). Methylene tetrahydrofolate reductase (MTHFR) is another enzyme in the pathway that irreversibly reduces 5,10-MTHF to 5-MTHF. 5-MTHF is the most stable and abundant form of the folate metabolites, and is the methyl donor for the pathway. Subsequently, methionine synthase (MTR) transfers a methyl group from 5-MTHF to homocysteine, forming methionine and tetrahydrofolate (THF), with the help of methionine synthase reductase (MTRR). Methionine is then converted back to SAM in a reaction catalyzed by methionine adenosyltransferase (MAT). Most of the SAM generated is used in transmethylation reactions, whereby SAM is converted to SAH by transferring the methyl group to diverse biological acceptors, including proteins and DNA. Vitamins B2 (riboflavin), B6 (pyridoxine), and B12 (cobalamin) are the cofactors of MTHFR, SHMT1, and MTRR, respectively, that are required for the maintenance of MTR in its active state (Figure 12.2).
Micronutrient Supplementation and Ergogenesis — Metabolic Intermediates
Published in Luke Bucci, Nutrients as Ergogenic Aids for Sports and Exercise, 2020
Methyl donors comprise a group of compounds found in intermediary metabolism. Interactions with cobalamins and folate are implicit in methyl donor metabolism. Choline, betaine (trimethylglycine or TMG), dimethylglycine (DMG), sarcosine (N-methylglycine), methionine, and S-adenosyl methionine (SAM) are involved in transmethylation.542 This process is essential for biosynthesis of several compounds important to muscle performance, primarily creatine and nucleic acids.542
Adenosine deaminase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
ADA inhibitors, coformycin and deoxycoformycin, produce a metabolic pattern in normal cells similar to that of ADA-deficient cells, and so does an inhibitor of nucleoside transport; neither compound had any effect on ADA-deficient cells [60]. Lymphocytes and lymphoblasts undergo apoptosis when treated with deoxyadenosine [62]. The activity of S-adenyosylhomocysteine (SAH) hydrolase is reduced in ADA deficiency, a consequence of suicide-like inactivation by deoxyadenosine [64]. Accumulation of adenosylhomocysteine could inhibit transmethylation.
Design, synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ennian Li, Kai Wang, Bei Zhang, Siqi Guo, Senhao Xiao, Qi Pan, Xiaowan Wang, Weiying Chen, Yunshan Wu, Hesong Xu, Xiangqian Kong, Cheng Luo, Shijie Chen, Bo Liu
Based on the DNMT1 Inhibition Assays data, some derivatives showed a considerable DNMT1 inhibition activity. Monocarbazole molecules that exhibited better inhibition on DNMT1 than DC_05, or dicarbazole molecules that exhibited better inhibition than DC_517 at 50 µM and 100 µM, were chosen to promote the next step. In addition to DNMT1, there are many other methyltransferases that can bind with S-adenosyl-L-methionine (SAM) to facilitate transmethylation reactions24,25. To investigate the selectivity of these potent compounds for DNMT1, we then evaluated the inhibitory activities against DNMT1 and other important methyltransferases at the concentration of 50 µM, including DNMT3A/3L, DNMT3B/3L, and other SAM-dependent enzymes1,2,26, such as EZH227, LSD128, G9a (histone H3 lysine 9 methyltransferase)29.
Modulation of SETDB1 activity by APQ ameliorates heterochromatin condensation, motor function, and neuropathology in a Huntington’s disease mouse model
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Yu Jin Hwang, Seung Jae Hyeon, Younghee Kim, Sungsu Lim, Min Young Lee, Jieun Kim, Ashwini M. Londhe, Lizaveta Gotina, Yunha Kim, Ae Nim Pae, Yong Seo Cho, Jihye Seong, Hyemyung Seo, Yun Kyung Kim, Hyunah Choo, Hoon Ryu, Sun-Joon Min
SETDB1 enzyme activity was analysed using commercially available SETBD1 chemiluminescent assay kit (BPS Bioscience, San Diego, CA, #51056) according to the manufacturer’s instructions. All analyses were performed in duplicates and all reagents used are supplied in the kit. S-adenosyl-l-homocysteine (SAH) as a product of S-adenosyl-l-methionine (SAM)-dependent transmethylation reaction was used as a non-selective inhibitor of SETDB1. Briefly, SAH and test compound APQ were diluted serially in DMSO and added at a final concentration of 1–100 µM in threefold increment. Total 50 µL mixture of histone methylation transfer buffer (50 mM Tris–HCl, pH 9.0, 1 mM phenylmethylsulfonyl fluoride, and 0.5 mM dithiothreitol) containing 20 µM SAM, each concentration of inhibitors and 1.25 ng/µL SETDB1 enzyme was added to each well of a 96-well plate. The wells were pre-coated with histone H3 peptide substrate. Reactions were allowed to proceed for 1 h 30 min at room temperature. Methylated K9 residue of H3 peptide was detected with anti-methylated H3K9 primary antibody and HRP-conjugated secondary antibody. Chemiluminescence resulting from the reaction between the HRP-conjugated secondary antibody and the added HRP substrate was measured using a SpectraMax M2 plate reader (Molecular Devices, Sunnyvale, CA).
In silico, in ovo and in vitro antiviral efficacy of phosphorylated derivatives of abacavir: an experimental approach
Published in Journal of Receptors and Signal Transduction, 2020
Kuruva Chandra Sekhar, Chintha Venkataramaiah, Chamarthi Naga Raju
Phosphorylated followed by aminated nucleoside drugs were proved to be NDV inhibitors in our previous work [3]. Charles et al. established the analogs of S-Adenosylhomocysteine (AdoHcy) derivatives inhibit the NDV messenger RNA (guanine-7)-methyltransferase. AdoHcy sulfoxide, AdoHcy sulfone and N6-methyl-AdoHcy exhibited potent and selective inhibitory activities on this RNA transmethylation, suggesting the possibility of designing specific inhibitors of this methyltransferase for in vivo use [4]. It has been reported that amino acid ester pro-drug of nucleoside analog especially, L-valine could be transported across the intestine mediated by the intestinal proton-coupled peptide transporter for increasing oral absorption [5,6], such as Acyclovir and Ganciclovir [7–9]. Mc Guigan et al. reported the first application of pronucleotide (Pro Tide) technology to the antiviral abacavir (Ziagen), used for the treatment of HIV infection. The phenyl methoxy alaninyl phosphoramidate of abacavir was prepared in one-step. The antiviral profile of the parent nucleoside was compared to that of the phosphoramidate Pro Tides. A significant (28-to-60-fold) increase in anti-HIV potency was noted for the ProTide of abacavir. The anti-HBV potency of abacavir was improved (10-fold) by Pro Tide formation [10].