Wang, Binju published the artcileComputations Reveal a Rich Mechanistic Variation of Demethylation of N-Methylated DNA/RNA Nucleotides by FTO, HPLC of Formula: 608-34-4, the publication is ACS Catalysis (2015), 5(12), 7077-7090, database is CAplus.
The fat-mass and obesity-associated (FTO) protein employs an iron(IV) oxo species to demethylate N-methylated nucleic acids. Herein, we use atomistic-theor. calculations to study the demethylation of the N-methylated DNA/RNA bases 6-methylated adenine (m6A), 3-methylated thymine (m3T), and 3-methylated uracil (m3U). The mechanisms involve in-enzyme hydroxylation of the Me group, followed by hydrolysis of the oxidized intermediates in aqueous solution to demethylate the bases. The in-enzyme reactions have been studied using quantum mech./mol. mech. (QM/MM) calculations, while the hydrolytic reactions occurring outside the enzyme have been explored with hybrid cluster-continuum (HCC) calculations When the results obtained with these different methods are combined, the calculated barrier for the overall transformation is consistent with the exptl. free energy barrier for the major route of m6A demethylation: in this pathway, adenine’s N1 site acts as an internal base catalyst in the rate-determining hydrolysis of the hydroxylated hemiaminal intermediate hm6A to a demethylated A and formaldehyde. This N1-catalyzed mechanism makes m6A the most reactive substrate in comparison to other bases we tested. In the minor, slower, route, two oxidation steps by FTO generate an amide intermediate (f6A) that undergoes in-water hydrolysis, producing A and formic acid, as found exptl. In contrast, since m3T and m3U lack internal basic catalytic sites, their hemiaminals decompose with high barriers. The mechanism instead involves two sequential oxidations, leading to demethylated bases and formic acid. Thus, our results, obtained using a holistic approach combining modeling the enzyme and the surrounding aqueous solution, suggest revisions of the exptl. mechanisms for m3T and m3U demethylation.
ACS Catalysis published new progress about 608-34-4. 608-34-4 belongs to pyrimidines, auxiliary class Pyrimidine,Amide, name is 3-Methylpyrimidine-2,4(1H,3H)-dione, and the molecular formula is C50H65O4P, HPLC of Formula: 608-34-4.
Referemce:
https://pubchem.ncbi.nlm.nih.gov/compound/Pyrimidine,
Pyrimidine – Wikipedia