Vitamin C in Immune Cell Function
Qi Chen, Margreet C.M. Vissers in Vitamin C, 2020
In mammals, one of the most widespread epigenetic modifications is DNA cytosine methylation, a modification that generally results in silencing of gene expression [138,139]. This modification can be actively reversed by the Tet enzymes that catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), potentially a stable epigenetic mark in itself [138], or initiate the generation of 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which results in active regeneration of unmarked cytosine by excision-repair mechanisms [140]. Ascorbate availability has been shown to markedly enhance Tet activity [141,142] through its cofactor function, likely maintaining the active site Fe2+ of these dioxygenases [143]. Although other reducing agents could reduce Fe3+ and promote TET activity in a cell free system, ascorbate was shown to be the most efficient [143], and glutathione was incapable of increasing murine embryonic TET activity compared to equimolar ascorbate [141,142]. The Jumonji C domain-containing histone demethylases (JHDMs) are also members of the Fe- and 2-oxoglutarate dependent dioxygenase family, and similarly to TETs, full enzyme activity of JHDMs occurs when ascorbate is present [144,145]. The JHDMs are the third and largest class of demethylase enzymes, capable of removing all three histone lysine-methylation states through oxidative reactions [145].
Lipids of Candida Albicans
Rajendra Prasad, Mahmoud A. Ghannoum in Lipids of Pathogenic Fungi, 2017
C-14 demethylase is another enzyme that has been widely studied in C. albicans because it is the main target of azoles.59 These antifungals inhibit cytochrome P450-dependent 14α-demethylase, a key enzyme in ergosterol and cholesterol biosynthesis.59-63 The accumulation of methylated sterols as a result of azole action is known to disrupt membrane structure and function. In order to understand the molecular basis of interaction between azoles and C-14 demethylase, it was recently purified from C. albicans.64 The molecular weight of the purified enzyme is estimated to be 51 kDa. Its reconstitution in a model membrane system of dilauroylphosphatidylcholine with NADH and O2 catalyzed the complete 14a-demethylation of lanosterol, which was inhibited by carbon monoxide. The enzyme demonstrates a high degree of specificity towards oxidation of lanosterol.64 A wide array of compounds, including azoles, pyridine, pyrimidine and piperazine derivatives, are known inhibitors of C-14 demethylase.65
Mammalian CYP2D Members A Comparison of Structure, Function, and Regulation
Shufeng Zhou in Cytochrome P450 2D6, 2018
Imipramine and its N-demethylated metabolite desipramine are inactivators of rat Cyp2ds (Lorenc-Koci et al. 2004; Topletz et al. 2013). Preincubation of microsomes from male Wistar rats with imipramine in the presence of NADPH causes a time-dependent inhibition of bunitrolol 4-hydroxylase activity, which has also been observed after in vivo administration of imipramine to rats (Topletz et al. 2013). Incubation of rat liver microsomes with CH]imipramine in the presence of NADPH results in covalent binding of a H-labeled substance to liver microsomal protein. Formation rates of the reactive metabolites covalently bound to protein follow Michaelis-Menten kinetics, and the Km value (1.1 μM) is close to that for imipramine 2-hydroxylation in rat liver microsomes (Topletz et al. 2013). The metabolism-dependent covalent binding of [H]imipramine is lower in DA rats than in Wistar rats. The binding is inhibited by propranolol, quinidine, and an antibody against Cyp2d. Similar strain difference (DA < Wistar rats) and inhibitory effects by the compounds and the antibody are observed in imipramine 2-hydroxylase but not in N-demethylase activity. The proteins to which [H]imipramine metabolites covalently bound are immunoprecipitated with the anti-Cyp2d antibody (Topletz et al. 2013). These results suggest that imipramine is converted by rat Cyp2d into a chemically reactive metabolite (probably arene-oxide) through its 2-hydroxylation, and the metabolite binds covalently to the enzyme itself and inactivates it.
Visfatin and global histone H3K9me levels in colon cancer
Published in Annals of Medicine, 2021
Eman A. Al Abdulsalam, Rowyda N. Al Harithy
Identifying the NAD-consuming enzymes and their processes helped to understand histone methylation and the complex nature of chromatin regulation. A well-known example of these enzymes is a histone demethylase (LSD1), also known as KDM1A is a lysine-specific demethylase dedicated to removing mono, di-methylation of histone H3 at lysine 4 [35]. Overexpression of LSD1 was found to contribute to human carcinogenesis in various cancers, including colorectal carcinomas [36] and the proliferation and metastasis of colon cancer [37]. This can explain our finding where the expression of H3K9me in cancerous colon tissue is significantly higher than the corresponding adjacent non-cancerous tissue. Our study implies the existence of additional isoforms of histone demethylases that favour mono demethylation at H3K9. While research in the field has provided and revealed many aspects of histone demethylase biology, interesting questions remain to be answered: question one is, whether unidentified LSD1 isoform exist? Another open question is whether the unidentified isoform of histone demethylases regulate colon cancerous tissue differentiation through H3K9me? The central question is whether the unidentified isoform of histone demethylases at H3K9me will be therapeutic targets in the future of “epigenetic medicines.”
Chronic social defeat stress differentially regulates the expression of BDNF transcripts and epigenetic modifying enzymes in susceptible and resilient mice
Published in The World Journal of Biological Psychiatry, 2019
Alessandra Mallei, Alessandro Ieraci, Maurizio Popoli
Increasing recent evidence suggests that epigenetic mechanisms, such as histone post-translational modifications and DNA methylation, play an important role in mediating the gene expression changes induced by stressful experiences and the subsequent behavioural responses (Tardito et al. 2013; Bagot et al. 2014; Klengel and Binder 2015; McEwen et al. 2015). The best-characterized histone modifications are acetylation and methylation. Histone acetylation levels are controlled by the opposite activity of two classes of enzymes, histone acetyltransferases and histone deacetylases (HDACs), and acetylation is generally associated with active transcription. Histone methylation levels can increase or decrease genes expression, depending on the amino acids methylated and the number of methylated groups added. Methylation changes are regulated by histone methyltransferase and histone demethylase. On the contrary, DNA methylation normally represses gene transcription and is carried out by DNA methyl transferase proteins (Szyf 2009; Peter and Akbarian 2011; Sun et al. 2013; Tardito et al. 2013). However, it is still not well known whether CSD stress differentially modulates these enzymes in the HPC and PFC of resilient and susceptible mice.
The molecular structure and biological functions of RNA methylation, with special emphasis on the roles of RNA methylation in autoimmune diseases
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Wanwan Zhou, Xiao Wang, Jun Chang, Chenglong Cheng, Chenggui Miao
In the past few years, a series of pioneering articles have described the mechanisms involved in RNA methylation. For example, methyltransferases modify adenine on RNA molecules, resulting in m6A modifications. The modified RNAs are demethylated by demethylase. After being recognized by methylated reading proteins, RNAs modified by m6A perform a series of functions including miRNA processing and mRNA transfer, translation, and splicing [27]. RNA methylation needs "writers” for methyl transfer, "erasers" for removing methyl groups, and "readers” for recognizing methyl markers [28]. With the clarification of the mechanisms of RNA methylation, the importance and universality of RNA methylation are gradually being recognized. RNA methylation affects RNA splicing and mRNA stability, localization, translation, and translocation [29]. Some well-known RNA methylation types and molecular structures (Figure 1) are discussed below.
Related Knowledge Centers
- Enzyme
- Epigenetics
- Genome
- Histone
- Methyl Group
- Methylation
- Nucleic Acid
- Chromatin
- Transcriptional Regulation
- Gene