Methyl group, hyperconjugation and human diseases

Wang, Yuchuan; Liao, Lipeng; Lin, Yu Hsien; David, Chanyuk Lam; Ouyang, Jess Lan; Fu, Minyue; Liu, Qiuyun

doi:10.31219/osf.io/xp5eu

Cited by 1 publication

(3 citation statements)

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“…C–H in methyl groups enables σ–σ hyperconjugation with adjacent C–H or σ–π hyperconjugation with a neighboring C=C double bond. Conjugation in 5-methylcytosine (5mC) leads to the extension of C 4 =C 5 and C 4 –N 4 bond lengths in the system, , weakening the C 4 –N 4 bonding and allowing easier protonation in the N 4 atom and generation of a positive charge . The electrostatic interactions between a positively charged N 4 amino group and negatively charged phosphate groups generate compact DNA and contribute to the formation of heterochromatin, therefore repressing gene expression.…”

Section: Mechanistic Connections Of Neurodegenerative Disorders To Ep...mentioning

confidence: 99%

“…Trimethylation at this position would create a positive charge on the tail. However, the electron delocalization of three electron-donating methyl groups can effectively lessen the positive charge and stabilize lysine 4 of histone H3 (Figure ), which results in less attraction between histone H3 and the negatively charged phosphate groups on DNA and less compact chromatin, consequently activating gene expression.…”

Section: Mechanistic Connections Of Neurodegenerative Disorders To Ep...mentioning

confidence: 99%

“…Conjugation in 5methylcytosine (5mC) leads to the extension of C 4 =C 5 and C 4 − N 4 bond lengths in the system, 44,45 weakening the C 4 −N 4 bonding and allowing easier protonation in the N 4 atom and generation of a positive charge. 46 The electrostatic interactions between a positively charged N 4 amino group and negatively charged phosphate groups generate compact DNA and contribute to the formation of heterochromatin, therefore repressing gene expression. The protonated amino nitrogen N 4 of 5-methylcytosine attracts Cl − occasionally and enhances the formation of HCl and hastens C to T transition mutations and other types of mutations, which can be carcinogenic.…”

Section: And Dementia: Biochemical Balancing Between Proton Stress An...mentioning

confidence: 99%

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Epigenetic Modifications and Neurodegenerative Disorders: A Biochemical Perspective

Zhang

Wang

et al. 2022

ACS Chem. Neurosci.

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Methylations in living cells are methyl groups attached to amino acids, DNA, RNA, and so on. However, their biochemical roles have not been fully defined. A theory has been postulated that methylation leads to hyperconjugation, and the electron-donating feature weakens a nearby chemical bond, which increases the bond length of C 4 −N 4 of 5-methylcytosine, therefore weakening the C 4 −N 4 bond and resulting in stronger protonation or hydrogen bonding of the N 4 nitrogen atom. Protonation can give rise to the generation of mutagenic and carcinogenic strong acids such as HCl, which are also capable of solubilizing stressful, insoluble, and stiff salts. Insoluble and rigid salts such as calcium oxalate and/or calcium phosphate were recently proposed as a primary cause of some neurodegenerative disorders. Protonation of nitrogen atoms in 5-methylcytosine enhances the interaction with negatively charged phosphate groups and contributes to the formation of compact heterochromatin. The electronegativity of the oxygen atoms in the modifications of 5-hydroxymethylcytosine or 5-formylcytosine can shorten the lengths of adjacent bonds with no increase of cation affinity in N 4 . The carboxyl group in 5-carboxylcytosine is a weak acid capable of antagonizing mutagenic HCl and modestly helping solubilize insoluble salts. Electron delocalization of the methyl group in N4methylcytosine results in a lower affinity of N 4 to cations. The positive charge at N 3 in the resonance structure of 3-methylcytosine is lessened by the electron-donating attribute of the methyl group attached to the N 3 atom, consequently reducing acid formation. The electron delocalization of three methyl groups decreases the positive charge in the amino nitrogen in the side group of lysine 4 in histone H3, weakening interactions with phosphate groups and consequently activating gene expression. The carbonyl oxygen in 8oxo-7,8-dihydroguanine draws protons and accumulates HCl, accounting for its moderate mutation propensity and potential capacity to solubilize stiff salts. The biochemical insight will further our understanding on the crosstalk of genetics and epigenetics in the etiology of neurodegenerative diseases.

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Section: Mechanistic Connections Of Neurodegenerative Disorders To Ep...mentioning

confidence: 99%

Section: Mechanistic Connections Of Neurodegenerative Disorders To Ep...mentioning

confidence: 99%

Section: And Dementia: Biochemical Balancing Between Proton Stress An...mentioning

confidence: 99%

See 1 more Smart Citation

Epigenetic Modifications and Neurodegenerative Disorders: A Biochemical Perspective

Zhang

Wang

et al. 2022

ACS Chem. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

Methyl group, hyperconjugation and human diseases

Cited by 1 publication

References 12 publications

Epigenetic Modifications and Neurodegenerative Disorders: A Biochemical Perspective

Epigenetic Modifications and Neurodegenerative Disorders: A Biochemical Perspective

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