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首页> 外文期刊>Physical chemistry chemical physics: PCCP >Hydrolysis of the damaged deoxythymidine glycol nucleoside and comparison to canonical DNA
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Hydrolysis of the damaged deoxythymidine glycol nucleoside and comparison to canonical DNA

机译：受损脱氧乙二醇核苷的水解并与典型DNA的比较

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摘要

Genomic integrity is continually under attack by both endogenous and exogenous sources. One of the most common forms of damage is oxidation of the thymine nucleobase to form (5R,6S)-dihydroxy-5,6-dihydro-thymine (thymine glycol or Tg), which stops DNA polymerases and is thus cytotoxic. Thymine glycol damage is repaired through a variety of mechanisms, including the multi-step base excision repair (BER) pathway. In the first BER step, the glycosidic bond of the dTg nucleotide is hydrolyzed by a DNA glycosylase. In order to understand the catalytic effect of the glycosylases, the corresponding uncatalyzed mechanisms and barriers are required, as well as an appreciation of the relative reactivity of the glycosidic bond with respect to the corresponding canonical nucleoside. To this end, the PCM-B3LYP/6-31+G(d) reaction potential energy surfaces (PES) for deoxythymidine (dT) and dTg hydrolysis are characterized in the present study using solvent-phase optimizations and a model containing three explicit water molecules. The surfaces are comparable to those generated using functional that account for dispersion interactions (B3LYP-D3 and M06-2X). Mapping the PES as a function of the glycosidic bond length and nucleophile-sugar distance reveals a synchronous SN2 mechanism as the lowest energy pathway for damaged dTg hydrolysis, which contrasts the preferred dissociative S_N1 mechanism isolated for the deglycosylation of natural dT. As proposed for other enzymes, the difference in excision pathway may at least in part help the enzyme selectively target the damaged base and discriminate against the natural counterpart. Interestingly, the barrier to dTg deglycosylation (ΔG = 138.0 kJ mol~(-1)) is much higher than for dT deglycosylation (ΔG = 112.7 kJ mol~(-1)), which supports the stability of this lesion and clarifies the catalytic feat presented to DNA repair enzymes that remove this detrimental damage from the genome. Although nucleotide excision repair (NER) typically targets bulky DNA lesions, the large calculated barrier for dTg deglycosylation rationalizes why the NER mechanism also excises this non-bulky lesion from cellular DNA.
机译：内源性和外源性源不断受到基因组完整性。最常见的损伤形式之一是胸腺嘧啶核酸酶的氧化，以形成（5R，6S）-DiHydroxy-5,6-二氢胸腺嘧啶（胸腺嘧啶乙二醇或Tg），其停止DNA聚合酶，因此是细胞毒性的。通过各种机制修复胸腺嘧啶乙二醇损伤，包括多步基本切除修复（BER）途径。在第一BER步骤中，DTG核苷酸的糖苷键通过DNA糖基糖酶水解。为了理解糖基酶的催化作用，需要相应的未催化机制和屏障，以及甘油粘键相对于相应的规范核苷的相对反应性的理解。为此，用于脱氧瘤（DT）和DTG水解的PCM-B3LYP / 6-31 + G（D）反应电位能表面（PES），其特征在本研究中，使用溶剂相优化和含有三种显式水的模型分子。表面与使用用于分散相互作用的功能（B3LYP-D3和M06-2x）产生的表面相当。作为糖苷键长度的函数映射PE，核官 - 糖距离显示出同步SN2机制作为受损DTG水解的最低能量通路，这对比自然DT的脱糖基化的优选的离归S_N1机制形成对比。如所提出的其他酶，切除途径的差异至少可以部分地帮助酶选择性地靶向受损底座并鉴别自然对应物。有趣的是，DTG脱糖基化的屏障（ΔG= 138.0kJmol〜（-1））远高于DT脱糖基化（Δg= 112.7kJ mol〜（-1）），其支持该病变的稳定性并阐明催化剂壮举呈现给DNA修复酶，以消除基因组的这种有害损伤。虽然核苷酸切除修复（NER）通常靶向庞大的DNA病变，但DTG脱糖基化的大计算屏障合理化了NER机制也从细胞DNA促进这种非庞大的病变。

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    Lex Navarro-Whyte; Jennifer L. Kellie; Stefan A. P. Lenz;

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    Department of Chemistry and Biochemistry University of Lethbridge 4401 University Drive Lethbridge Alberta T1K 3M4 Canada.;

    Department of Chemistry and Biochemistry University of Lethbridge 4401 University Drive Lethbridge Alberta T1K 3M4 Canada.;

    Department of Chemistry and Biochemistry University of Lethbridge 4401 University Drive Lethbridge Alberta T1K 3M4 Canada.;

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  • 正文语种 eng
  • 中图分类 物理学;化学;
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