Epigenetic Modifications and Neurodegenerative Disorders: A Biochemical Perspective

Abstract

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.

Why Omicron Variant of SARS‐CoV‐2 is Less Fatal?

“…Oxalic acid was indeed enriched in the serum of SARS‐CoV‐2 patients [5] . The positively charged lysine residues attract anions such as Cl − via ionic bonds which can solubilize insoluble and stiff salts [4] . The antagonism between insoluble salts and acids or strong anions is widespread in cells (Figure 1).…”

“…Glycine and valine possess long carbonyl bond lengths and weakened carbonyl bonds that prompt carbonyl oxygen atoms to bind divalent cations such as calcium [4] . The generation of insoluble and stiff calcium salts such as calcium oxalate or/and calcium phosphate is very stressful and can trigger cell senescence as demonstrated in the studies of renal stones [4] . Oxalic acid was indeed enriched in the serum of SARS‐CoV‐2 patients [5] .…”

“…These features are biochemically intriguing due to the chemical attributes of amino acids which render this variant less lethal. Glycine and valine possess long carbonyl bond lengths and weakened carbonyl bonds that prompt carbonyl oxygen atoms to bind divalent cations such as calcium [4] . The generation of insoluble and stiff calcium salts such as calcium oxalate or/and calcium phosphate is very stressful and can trigger cell senescence as demonstrated in the studies of renal stones [4] .…”

“…Interestingly, glycine supplement displayed anticancer effects [15] which can be credited to its calcium binding property allowing the neutralization of mutagenic strong acids such as HCl, as single stranded DNA can draw protons via hydrogen bonding for the formation of acids. [4] Non-polar amino acid mutations in the proteins of a viral variant can be detrimental as they increase the insolubility of aggregates formed among glycine and valine residues in proteins and calcium oxalate. [10] In a study on 5 year-olds and under which excludes the compounding of vaccination and past infections, the symptoms of Omicron infected patients were substantially less severe than those infected with the Delta variant.…”

Extremely lethal viruses share sequence features

“…15 Interestingly, numerous proteins of moderate virulent viruses such as SARS or SARS-CoV-2 also possess high valine and glycine content. 13,[16][17][18]…”