NMR analyses on N-hydroxymethylated nucleobases - implications for formaldehyde toxicity and nucleic acid demethylases.
NMR analyses on N-hydroxymethylated nucleobases - implications for formaldehyde toxicity and nucleic acid demethylases.
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DOI：
10.1039/c8ob00734a
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发表时间：
2018-05-30
影响因子：
3.2
通讯作者：
Hopkinson RJ
中科院分区：
文献类型：
--
作者：
Shishodia S;Zhang D;El-Sagheer AH;Brown T;Claridge TDW;Schofield CJ;Hopkinson RJ
核磁共振研究表明，甲醛是一种有毒污染物和代谢物，与核苷酸反应形成不同稳定性的n -羟甲基化加合物。甲醛在细胞中通过酶催化的去甲基化反应产生，包括那些发生在n -甲基化核酸上的反应。甲醛与核碱基反应形成n -羟甲基化加合物，当外源添加时，这些加合物可能有助于其毒性/致癌性，但这些反应的化学性质尚未完全确定。我们报道了甲醛与规范/修饰核碱基反应的核磁共振研究。结果表明，胸腺嘧啶和单磷酸尿嘧啶上的羟甲基半氨基化合物比外环氮上的同等半氨基化合物形成得更快；然而，与腺嘌呤、鸟嘌呤和胞嘧啶形成的外环加合物在溶液中更稳定。核酸去甲基酶（FTO）催化（6-甲基）腺苷的羟基化反应生成（6-羟甲基）腺苷作为主要观察产物；相比之下，fto催化的（3-甲基）胸腺嘧啶氧化没有产生稳定的3-羟甲基加合物的证据。总的来说，我们的结果表明，通过与甲醛反应或通过去甲基酶催化形成的核酸碱基的n -羟甲基化加合物具有本质上不同的稳定性，其中一些足够稳定，在疾病或核酸/核碱基活性调节中具有功能作用。
NMR studies reveal that formaldehyde, a toxic pollutant and metabolite, reacts with nucleotides to form N-hydroxymethylated adducts of varying stabilities. Formaldehyde is produced in cells by enzyme-catalysed demethylation reactions, including those occurring on N-methylated nucleic acids. Formaldehyde reacts with nucleobases to form N-hydroxymethylated adducts that may contribute to its toxicity/carcinogenicity when added exogenously, but the chemistry of these reactions has been incompletely defined. We report NMR studies on the reactions of formaldehyde with canonical/modified nucleobases. The results reveal that hydroxymethyl hemiaminals on endocyclic nitrogens, as observed with thymidine and uridine monophosphates, are faster to form than equivalent hemiaminals on exocyclic nitrogens; however, the exocyclic adducts, as formed with adenine, guanine and cytosine, are more stable in solution. Nucleic acid demethylase (FTO)-catalysed hydroxylation of (6-methyl)adenosine results in (6-hydroxymethyl)adenosine as the major observed product; by contrast no evidence for a stable 3-hydroxymethyl adduct was accrued with FTO-catalysed oxidation of (3-methyl)thymidine. Collectively, our results imply N-hydroxymethyled adducts of nucleic acid bases, formed either by reactions with formaldehyde or via demethylase catalysis, have substantially different stabilities, with some being sufficiently stable to have functional roles in disease or the regulation of nucleic acid/nucleobase activity.
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RNA 假尿苷化：对旧修饰的新见解。
影响因子：
13.8
作者：
Ge, Junhui;Yu, Yi-Tao
通讯作者：
Yu, Yi-Tao
影响因子：
4
作者：
Alseth, Ingrun;Dalhus, Bjorn;Bjoras, Magnar
通讯作者：
Bjoras, Magnar
DOI：
10.1080/15298668591394275
发表时间：
1985-01-01
期刊：
AMERICAN INDUSTRIAL HYGIENE ASSOCIATION JOURNAL
影响因子：
--
作者：
HECK, HD;CASANOVASCHMITZ, M;TOSUN, T
通讯作者：
TOSUN, T
影响因子：
3.2
作者：
Hopkinson, Richard J.;Barlow, Philippa S.;Claridge, Timothy D. W.
通讯作者：
Claridge, Timothy D. W.
DOI：
10.1126/science.1151710
发表时间：
2007-11-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gerken T;Girard CA;Tung YC;Webby CJ;Saudek V;Hewitson KS;Yeo GS;McDonough MA;Cunliffe S;McNeill LA;Galvanovskis J;Rorsman P;Robins P;Prieur X;Coll AP;Ma M;Jovanovic Z;Farooqi IS;Sedgwick B;Barroso I;Lindahl T;Ponting CP;Ashcroft FM;O'Rahilly S;Schofield CJ
通讯作者：
Schofield CJ