G-四链体DNA/血红素诱导对映选择性分子内环丙烷化反应

doi:10.1016/S1872-2067(25)64797-8

催化学报 ›› 2025, Vol. 78: 138-143.DOI: 10.1016/S1872-2067(25)64797-8

G-四链体DNA/血红素诱导对映选择性分子内环丙烷化反应

苗文慧^a^,^b^,¹, 郝静雅^a^,^b^,¹, 周文琴^a, 贾国卿^a^,^*(), 李灿^a^,^b^,^*()

^a中国科学院大连化学物理研究所, 能源催化转化全国重点实验室, 辽宁大连 116023
^b中国科学院大学, 北京 100049

收稿日期:2025-06-30 接受日期:2025-07-29 出版日期:2025-11-18 发布日期:2025-10-14
通讯作者: *电子信箱: gqjia@dicp.ac.cn (贾国卿), canli@dicp.ac.cn (李灿).
作者简介:¹共同第一作者.
基金资助:
国家重点研发计划(2022YFA0911900)

Enantioselective induction by G-quadruplex DNA/hemin in intramolecular cyclopropanation

Wenhui Miao^a^,^b^,¹, Jingya Hao^a^,^b^,¹, Wenqin Zhou^a, Guoqing Jia^a^,^*(), Can Li^a^,^b^,^*()

^aState Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, Liaoning, China
^bUniversity of Chinese Academy of Sciences, Beijing 100049, China

Received:2025-06-30 Accepted:2025-07-29 Online:2025-11-18 Published:2025-10-14
Contact: *E-mail: gqjia@dicp.ac.cn (G. Jia), canli@dicp.ac.cn (C. Li).
About author:¹Contributed equally to this work.
Supported by:
National Key Research and Development Program of China(2022YFA0911900)

摘要/Abstract

摘要：

G-四链体DNA(G4)因其独特的结构多样性及与金属配合物的结合能力, 在构建人工DNA金属酶的领域备受关注. 血红素(Fe(III)-原卟啉IX, hemin)是一种生物内源性的含铁配合物, 已有研究表明, G4可结合hemin构筑G4/hemin核酸生物催化剂, 并表现出类血红素蛋白酶的催化活性. 然而, 如何实现基于G4/hemin催化的立体选择性一直面临挑战. 本文以分子内环丙烷化为探针反应, 基于G4的结构多样性, 成功实现了对映选择性的诱导.

本研究选取了49种具有明确二级结构(涵盖平行、杂化和反平行构型)的G4序列, 通过非共价相互作用与hemin结合, 构建G4/hemin复合物. 以反式-4-苯基丁烯-2-重氮乙酸酯(1a)的分子内环丙烷化为探针反应, 考察了不同G4二级结构对该反应对映选择性的影响. 结果表明,平行构型G4中, 有75%的序列展现出显著的对映选择性诱导能力(对映体过量值ee>5%), 杂化构型中46%的序列表现出对映选择性诱导能力, 而反平行结构G4几乎无对映选择性诱导能力. 因此, 对于探针分子内环丙烷化反应, 产物对映体选择性高度依赖于G4的构型, 其构效关系排序如下: 平行>杂化>反平行. 在平行构型的G4中, 由PW17(5’-GGGTAGGGCGGGTTGGG-3’)构筑的PW17/hemin表现出最优异的对映选择性. 为阐明其结构基础, 综合运用圆二色光谱、紫外-可见吸收光谱、紫外熔点分析和非变性聚丙烯酰胺凝胶电泳等手段进行表征. 结果表明,PW17形成二聚体结构, 并以1:1的化学计量比与hemin结合. 通过碱基位点突变实验探究影响反应对映选择性的关键结构元素, 发现PW17的5’端和3’端在催化过程中发挥不同作用, 3’端对碱基的变化更为敏感, 在催化过程中起关键作用, 而5’端则主要起结构支撑作用. 此外, G-四平面的层数对反应对映选择性也至关重要. 基于上述结果, 我们提出PW17/hemin的二聚体结构模型: 两个相同的具有平行构型的G4单体通过其5’端堆叠形成二聚体, 两个hemin分子分别结合在单体的3’端, 共同构筑催化活性位点.

综上, 本研究实现了G4/hemin催化的对映选择性分子内环丙烷化反应, 揭示了G4构型与对映选择性之间的构效关系, 并提出了PW17/hemin的二聚平行结构模型. 未来可进一步结合多种光谱技术与理论计算, 深入解析G4/hemin的精细结构与催化机制. 本工作成功突破了G4/hemin催化中立体化学控制的瓶颈, 为开发新型G4/hemin生物催化剂提供了实验基础, 同时也为基于核酸构建人工酶的研究提供了重要参考.

关键词: G-四链体DNA, 血红素, 对映体选择性, 分子内环丙烷化, 核酸催化

Abstract:

G-quadruplex DNA (G4) can function as a kind of nucleic acid apoenzyme for constructing G4/hemin biocatalyst to mimic the catalytic function of hemoprotein. However, achieving stereoselective control with G4/hemin remains a persistent challenge. Here, we report that a PW17/hemin (PW17: 5’-GGGTAGGGCGGGTTGGG-3’), adopting the 5’-5’ stacked dimeric parallel G4 topology, can realize the enantioselective induction in intramolecular cyclopropanation of allyl diazoacetates with enantioselectivity up to 87% ee. Spectroscopic characterization and catalytic results demonstrate that the relatively open G-quartet of the 3’ terminal in dimeric PW17 contributes a catalytic pocket for hemin accommodation and plays a pivotal role in enantioselective control. This finding expands the unique repertoire of heme enzyme using biological scaffolds from proteins to nucleic acids and resolves the long-standing challenge of stereochemical control in G4/hemin catalysis.

Key words: G-quadruplex DNA, Hemin, Enantioselectivity, Intramolecular cyclopropanation, Nucleic acid catalysis

苗文慧, 郝静雅, 周文琴, 贾国卿, 李灿. G-四链体DNA/血红素诱导对映选择性分子内环丙烷化反应[J]. 催化学报, 2025, 78: 138-143.

Wenhui Miao, Jingya Hao, Wenqin Zhou, Guoqing Jia, Can Li. Enantioselective induction by G-quadruplex DNA/hemin in intramolecular cyclopropanation[J]. Chinese Journal of Catalysis, 2025, 78: 138-143.

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图/表 6

Scheme 1. Schematic representation of the non-covalent assembly of G-quadruplex (G4) and hemin into a G4/hemin complex and the benchmark reaction of G4/hemin catalyzed intramolecular cyclopropanation.

Fig. 1. The relationship between the enantioselectivity of product 2a and three types of G4s’ secondary structures (parallel, hybrid, and anti-parallel). The Y-axis lists the 49 G4s used in this study. The detailed sequence information is provided in Table S1.

Fig. 2. Characterization of PW17 and its complex with hemin. (a) CD spectra. (b) UV melting experiments. (c) Native polyacrylamide gel electrophoresis (PAGE), single-stranded dT17 and dT34, containing 17nt and 34nt dT, respectively, were used as the control of random structure. (d) UV-vis titration of hemin with PW17. For (a-c), the molar ratio of PW17 to hemin was maintained as 1:1. (e) Proposed dimeric structure of the PW17/hemin.

Fig. 3. (a) The relation between base modifications of PW17 (5’-GGG TAGGG CGGG TTGGG-3’) and the enantioselectivity of 2a. (b) Dimeric structure of PW17: 5’-terminal, 3’-terminal, Loop 1 (-TA-, L1), Loop 2 (-C-, L2), Loop 3 (-TT-, L3) are indicated.

Fig. 4. Imino proton NMR spectra of G4s and their hemin complexes: (a) PW17, 2LBY, and 2LPW G4s; (b) 2LBY and 2LBY/hemin; (c) 2LPW and 2LPW/hemin.

Table 1 Activities and enantioselectivities of PW17/hemin for the intramolecular cyclopropanation.

Entry	Product	Yield (%) ^a	ee (%)^{b, c}
1	2a	48±5	62±2
2	2b	37±2	77±3
3	2c	11±6	81±5
4	2d	19±5	87±7
5	2e	19±6	76±8
6	2f	23±10	75±5
7	2g	18±3	60±2

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G-四链体DNA/血红素诱导对映选择性分子内环丙烷化反应

Enantioselective induction by G-quadruplex DNA/hemin in intramolecular cyclopropanation

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