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Environmental Toxins and Chronic Illness
Published in Aruna Bakhru, Nutrition and Integrative Medicine, 2018
Because of the importance of COMT in reducing accumulation of potentially procarcinogenic estradiol metabolites, attention has also been focused on environmental toxins or endogenous metabolites that may interfere with its activity. Garner et al. point out that PCBs are not only substrates for COMT but can inhibit its activity, potentially leading to increased accumulation of carcinogenic estradiol metabolites (Garner et al., 2000). Concerning endogenous metabolites, Zhu points out that accumulation of S-adenosyl-L-homocysteine (SAH), which often occurs in association with elevated homocysteine, can act as a strong noncompetitive inhibitor of COMT-mediated methylation of both 2-OH-E2 and 4-OH-E2 (Zhu, 2003).
Epigenetics, Nutrition, and Infant Health
Published in Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, Klaus Kraemer, The Biology of the First 1,000 Days, 2017
Philip T. James, Matt J. Silver, Andrew M. Prentice
S-adenosyl methionine (SAM) methylates a wide variety of acceptors in reactions catalyzed by methyl transferases. Over 200 methylation reactions are required for transcription, translation, protein localization, and signaling purposes [45], but it is the methylation of cytosine bases and amino acids on histone tails that play a role in epigenetics. The donation of SAM’s methyl group forms S-adenosyl homocysteine (SAH), which is further hydrolyzed to homocysteine (Hcy), where it is maintained in an equilibrium state that thermodynamically favors SAH over Hcy [46]. A buildup of Hcy results in an increase in SAH, which in turn impedes methylation reactions since SAH competes with SAM for the active site on methyl transferase enzymes [47]. The SAM:SAH ratio is therefore often used as a proxy indicator of methylation potential [48]. In order to maintain favorable methylation conditions, Hcy has to be removed from the system. One way in which this can happen is by accepting a methyl group to form methionine, which can then in turn be condensed with ATP to form SAM and continue the cycle. Hcy can also be removed through its irreversible degradation to cystathionine and cysteine in the transsulfuration pathway requiring vitamin B6.
Choline *
Published in Judy A. Driskell, Ira Wolinsky, Sports Nutrition, 2005
Patricia A. Deuster, Jamie A. Cooper
The second pathway for choline synthesis involves the conversion of phosphatidylethanolamine to phosphatidylcholine.3 Three methylation reactions are required, with each using SAM as a methyl group donor. S-adenosyl methionine becomes S-adenosyl homocysteine after donating its methyl group and is metabolized to homocysteine, which can be converted to methionine in a reaction that requires methyl tetrahydrofolate (THF) and a vitamin B12-dependent enzyme. Thus, a close relationship exists between the synthesis of choline, methionine and folate.1
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).
Opicapone for the treatment of Parkinson’s disease: an update
Published in Expert Opinion on Pharmacotherapy, 2019
András Salamon, Dénes Zádori, László Szpisjak, Péter Klivényi, László Vécsei
Dopamine (DA) is not able to cross the blood-brain barrier (BBB), therefore we use its precursor, LD. However, LD is rapidly converted by DOPA decarboxylase (DDC) and catechol-O-methyltransferase (COMT) enzymes to its metabolites in the periphery (Figure 1; [10]). If we administer LD orally, only 1% will penetrate into the central nervous system (CNS [11];). To increase CNS availability of LD, we use DDC and COMT inhibitors. The function of the COMT enzyme is to transfer a methyl group to catecholamines. During the catalytic process S-adenosyl methionine (SAM) is converted to S-adenosyl homocysteine (SAH) [10]; the detailed metabolism is presented in Figure 1. The most common COMT inhibitors are entacapone (ENT) and tolcapone (TLC) [12]. Since 24 June 2016 a third COMT inhibitor, namely opicapone (OPC) is also available, which was approved by the European Medicine Agency for the treatment of end-of-dose motor fluctuations in adult patients whose symptoms are not controllable by LD/DOPA decarboxylase inhibitor (DDCI) combination [13]. Probably the most important advantages of OPC in comparison with second generation COMT inhibitors are the following: there is a less frequent need to administer and there is no real risk of hepatotoxicity [12].
A resurging boom in new drugs for epilepsy and brain disorders
Published in Expert Review of Clinical Pharmacology, 2018
Iyan Younus, Doodipala Samba Reddy
Adenosine influences DNA methyltransferase (DNMT) enzyme activity in the brain through the property of mass action. Increased ADK activity results in lower adenosine levels, which drives DNA methylation. In contrast, high adenosine levels shift the equilibrium and inhibit DNMTs through product inhibition. Adenosine modulates DNA methylation via the S-adenosyl methionine (SAM)-dependent pathway. SAM donates its own methyl group to DNA in a mechanism catalyzed by DNMT. This yields the compound S-adenosyl-homocysteine (SAH), which is further converted to adenosine. Due to the nature of the equilibrium constant, the reaction will only proceed in the forward direction if adenosine levels are low enough. If SAH levels rise because of adenosine buildup, DNMT activity will be inhibited [75]. Therefore, adenosine plays a critical role as an endogenous regulator of DNMT activity.