Structural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites.
Structural evolution of a DNA repair self-resistance mechanism targeting genotoxic secondary metabolites.
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针对遗传毒性次生代谢物的 DNA 修复自我抵抗机制的结构进化。
DOI：
10.1038/s41467-021-27284-7
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发表时间：
2021-11-26
影响因子：
16.6
通讯作者：
Eichman BF
中科院分区：
文献类型：
--
作者：
Mullins EA;Dorival J;Tang GL;Boger DL;Eichman BF
微生物产生广泛的抗生素天然产物，包括许多破坏dna的基因毒素。其中最有效的是螺旋环丙基环己二烯酮（SCPCHD）家族的DNA烷基化剂，包括多卡霉素、CC-1065、吉尔武霉素和亚他克霉素。Streptomyces sp. TP-A0356中的yatakemycin生物合成簇含有与alkd相关的DNA糖基酶YtkR2，该酶可作为抵抗yatakemycin毒性的自抗性机制。我们以前报道过，在SCPCHD生产者中不存在AlkD，仅对yatakemycin提供有限的抗性。我们现在表明，YtkR2和C10R5（在zelensis链霉菌CC-1065生物合成基因簇中发现的先前未被表征的同源物）对各自的SCPCHD天然产物具有更大的抗性。我们确定了跨基因簇的底物特异性的结构基础，并显示了体内抗性和体外酶活性之间的相关性，这表明降低的产物亲和力-而不是增强的底物识别-是选择性压力的进化结果，以提供对yatakemycin和CC-1065的自我抗性。与DNA损伤抗生素的生物合成相关的微生物DNA糖基酶已经对其同源天然产物产生了自我抗性。在这里，作者提供的证据表明，细胞自我抵抗是通过糖基酶对相应DNA病变的切除产物的亲和力降低而实现的。
Microbes produce a broad spectrum of antibiotic natural products, including many DNA-damaging genotoxins. Among the most potent of these are DNA alkylating agents in the spirocyclopropylcyclohexadienone (SCPCHD) family, which includes the duocarmycins, CC-1065, gilvusmycin, and yatakemycin. The yatakemycin biosynthesis cluster in Streptomyces sp. TP-A0356 contains an AlkD-related DNA glycosylase, YtkR2, that serves as a self-resistance mechanism against yatakemycin toxicity. We previously reported that AlkD, which is not present in an SCPCHD producer, provides only limited resistance against yatakemycin. We now show that YtkR2 and C10R5, a previously uncharacterized homolog found in the CC-1065 biosynthetic gene cluster of Streptomyces zelensis, confer far greater resistance against their respective SCPCHD natural products. We identify a structural basis for substrate specificity across gene clusters and show a correlation between in vivo resistance and in vitro enzymatic activity indicating that reduced product affinity—not enhanced substrate recognition—is the evolutionary outcome of selective pressure to provide self-resistance against yatakemycin and CC-1065. Microbial DNA glycosylases associated with the biosynthesis of DNA-damaging antibiotics have evolved self-resistance for their cognate natural products. Here, the authors provide evidence that cellular self-resistance is enabled by reduced affinity of the glycosylases for the excision products of the corresponding DNA lesions.
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影响因子：
4.8
作者：
Gunz, D;Hess, MT;Naegeli, H
通讯作者：
Naegeli, H
影响因子：
5.7
作者：
Kiakos, Konstantinos;Sato, Atsushi;Hartley, John A.
通讯作者：
Hartley, John A.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
5.6
作者：
Batty, D;Rapic'-Otrin, V;Wood, RD
通讯作者：
Wood, RD
影响因子：
14.9
作者：
Davis IW;Leaver-Fay A;Chen VB;Block JN;Kapral GJ;Wang X;Murray LW;Arendall WB 3rd;Snoeyink J;Richardson JS;Richardson DC
通讯作者：
Richardson DC