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Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Histone acetylation involves addition of an acetyl group to lysine residues. Acetyl-CoA is an intermediary metabolite at the crossroad of glucose and lipid catabolism. Acetyl-CoA functions as a cofactor for enzymes that require the transfer of an acetyl group, including HATs. Cellular acetyl-CoA levels could substantially fluctuate (^-10-fold), which directly impacts the activities of HATs as it normally falls within their Km range. Moreover, the ratio of acetyl-CoA to coenzyme A has also been shown to regulate histone acetylation. Oncogenic KRASG12D or c-Myc has been shown to up-regulate glycolysis flux (Ying et al., 2012; Osthus et al., 2000; Shim et al., 1997), leading to increased production of acetyl-CoA. As a consequence, a pronounced increase in global histone acetylation can be detected upon transformation with these oncogenes, suggesting that oncogenic signaling drives histone acetylation in tumors (Lee et al., 2014). Recent work has also provided evidence that acetyl-CoA is compartmentalized into cytosolic and nuclear fractions with limited exchange. Nuclear acetyl-CoA can be biosynthesized via acetyl-CoA synthetase short-chain family (ACSS1/2) or converted from citrate through ATP citrate lyase (ACL).
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The above-mentioned hypomethylation promotes the malignant degeneration of cells due to favoring a reorganization of chromosomal sections. The most important mechanism of epigenetic regulation is the methylation of DNA by DNA-methyltransferases. It has been found that hypermethylation (methylation of cytosine residues of DNA) of gene-promoter regions, leading to transcriptional repression of tumor suppressor genes the protein products of which such as CDK-inhibitor 2A and RB1 (retinoblastoma protein) decelerate tumor progression, is a common feature of many cancers (Baylin and Jones, 2011). This also holds for global deacetylation. Histone deacetylases (HDACs) class I, II, and IV are Zn2+-dependent amidohydrolases removing an acetyl moiety from a lysine residue at the N-terminus of histone. Class III HDACs (sirturins) are NAD+-dependent. The catalytic action of HDACs enables the histones to wrap the DNA more tightly whereas acetylation of histones by acetyl transferases (HATs) transferring an acetyl group from acetyl-CoA to form ε-N-acetyl lysine normally results in an increase in gene expression, e.g., that of the tumor suppressor p53. Various HAT families are known that differ from each other in their reaction mechanism. The equilibrium of histone acetylation and deacetylation is important for a proper modulation of chromatin topology and regulation of gene transcription. For an excellent review of exploiting the epigenome to control cancer-promoting gene-expression programs, see Brien et al. (2016).
List of Chemical Substances
Published in T.S.S. Dikshith, and Safety, 2016
Acetyl bromide is a colorless fuming liquid, with a pungent odor, combustible and turns yellow on exposure to air. It is used as an acetylating agent in the synthesis of fine chemicals, agrochemicals, and pharmaceuticals. It is also used as an intermediate for dyes. Acetylation, a case of acylation, is an organic synthesis process whereby the acetyl group is incorporated into a molecule by substitution for protecting -OH groups.
Modelling of acetaldehyde and acetic acid combustion
Published in Combustion Theory and Modelling, 2023
Fekadu Mosisa Wako, Gianmaria Pio, Ernesto Salzano
The oxidation chemistry of acetaldehyde is mainly affected by a unimolecular decomposition reaction via C–C fission (R9) forming methyl and formyl radicals. Besides, acetaldehyde can undergo H atom abstraction reactions either at methyl group forming methylene radical (CH2CHO) via R10 or at acetyl group resulting in acetyl radical (CH3CO) via R11. The rate parameters for the hydrogen abstraction of CH3CHO by H atoms (R10) are taken from Harding et al. [66] and R11 from Hashemi et al. [42]. The rate coefficients considered in the present study are in good agreement with experimental and theoretical rate constants under the studied conditions. Besides, to elucidate the effect of specific rate constants that contributed to the differences between the model and experiments, a sensitivity analysis was performed for both acetic acid and acetaldehyde species as shown in Figure 6.
Adsorption of graphene oxide with cellulose acetate: insights from DFT
Published in Molecular Physics, 2022
Haowen Zhang, Liyun Ding, Yumei Zhang, Tian Wu, Qin Li
As observed, the adsorption energy of all five models exhibits negative values, which imply that the adsorption of CA with GO is an exothermic process and that this process is energetically favourable. Classically, the greater the value of the adsorption energy, the greater the adsorption capacity, the adsorption capacities of the five adsorption models are in order of M2 > M1 > M5 > M3 > M4. It can be found in the electron density of the five models that the intersection of the electron clouds of CA and GO is observed in M1, M2, and M5. In the M1 model, the O(13) and H(14) atoms of CA overlap with the electron clouds of the H(1) and O(4) atoms of GO, respectively, and in M2 the H(14) atom from the hydroxyl group in CA produces a similar electron cloud overlap region with the O(1) atom of the epoxide group in GO. The electron cloud overlap also occurs in M5, where the O18 atom of the acetyl group interacts with the H(2) atom of the hydroxyl group. We found that the overlapping electron clouds occurring at M1, M2, and M5 all involve hydroxyl groups, and the adsorption processes of CA and GO are driven by nonphysical adsorption forces. The nonphysical adsorption forces lead to much higher adsorption energies for the M1, M2, and M5 models than for the M3 and M4 models.
The theoretical investigation on properties of paeonol and its isomers
Published in Molecular Physics, 2021
Min Zhang, Yuye Li, Tingting Zhu
Regarding the chemical shift value of the H atom, it was found that the H atom is distributed in the peripheral area of the entire atom and the molecule is small and light, it is easily affected by the intermolecular interaction. The chemical shift values of hydrogen atoms on methyl groups are from 2 to 4 ppm, and the chemical shift values of hydrogen atoms on benzene rings are from 5 to 9 ppm. The NMR spectrum signal of H13 contained in the hydroxyl group is different from the H atom mentioned above. The chemical shift values of H13 are from 4 to 6 ppm for a, c, and d. The chemical shift values of H13 of 1b and 2b are 12.99 and 11.28 ppm, respectively, which are significantly different from the H atoms in other positions in the spectrum. This is due to the hydroxyl hydrogen atoms participating in the formation of IMHB in 1b and 2b. The electronegativity of the O11 atom of the acetyl group is relatively large, which reduces the electron cloud density around the hydroxyl hydrogen atom and increases the chemical shift. In the presence of water, 1H and 13C isotropic chemical shifts did not change significantly, and it has a changing trend consistent with the gas phase value. The study reveals that the NMR data of the eight compounds did not show significant differences. The 1H NMR spectrum can well prove the existence of IMHB, distinguishing 1b and 2b from other isomers.