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Peer-reviewedCC BY-NC-ND 4.0Chem & Bio Engineering

Chemo-Enzymatic Synthesis of Purine 3′-O-Amino-Deoxyribonucleoside Triphosphates

  • Qin He1,2,3
  • Shuai Cheng1,2
  • Jianqing Yue2
  • Shu Zong4
  • Congyu Li2
  • Xuerong Qi2
  • Lipei Liu2
  • Zhidan Zhang5
  • Jun Sun2
  • Jian Cheng6
  • Xiaoyun Lu2
  • Huifeng Jiang6
6 affiliations
  1. 1School of Life Science and Technology, Wuhan Polytechnic University, Wuhan 430023, China
  2. 2Zhonghe Gene Technology Co., Ltd., Tianjin 300308, China
  3. 3Haihe Laboratory of Synthetic Biology, Tianjin 300308, China
  4. 4College of Life Sciences, Nankai University, Tianjin 300071, P. R. China
  5. 5Key Laboratory of Engineering Biology for Low-Carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, National Center of Technology Innovation for Synthetic Biology, Tianjin 300308, China
  6. 6College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China
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Abstract

3′-O-amino-deoxyribonucleoside triphosphates (3′-ONH2-dNTPs) are crucial reversible terminators for template-independent DNA synthesis. Owing to the structural complexity of purine bases, here we propose a chemo-enzymatic process for the synthesis of purine-type 3′-ONH2-dNTPs. First, the aminoalkoxyl group was introduced into commercially available dA and dG via a chemical catalytic process, affording yields of 24.9% and 27.3%, respectively. Subsequently, to establish a green and scalable enzymatic cascade for phosphorylation of the substrates, we engineered two key phosphorylation enzymes (Dm-dNK and MrPPK2), improving the rate-limiting monophosphorylation of 3′-ONH2-dG from 26% to 97.8% and achieving 59.9% conversion to the corresponding triphosphate. Lastly, the produced nucleotides exhibit performance equivalent to commercial counterparts in terminal deoxynucleotidyl transferase (TdT)-mediated DNA synthesis, supporting the construction of 120-nt strands with ∼99.7% stepwise accuracy. This work establishes an efficient and generalizable catalytic platform for producing modified dNTPs, advancing the practical application of enzymatic DNA synthesis technologies.

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Cite

BibTeXRIS
BibTeX
@article{he2026chemoenzymatic,
  title = {{Chemo-Enzymatic Synthesis of Purine 3′-O-Amino-Deoxyribonucleoside Triphosphates}},
  author = {Qin He and Shuai Cheng and Jianqing Yue and Shu Zong and Congyu Li and Xuerong Qi and Lipei Liu and Zhidan Zhang and Jun Sun and Jian Cheng and Xiaoyun Lu and Huifeng Jiang},
  journal = {Chem \& Bio Engineering},
  year = {2026},
  month = aug,
  doi = {10.1021/cbe.6c00032},
  url = {https://doi.org/10.1021/cbe.6c00032},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Chemo-Enzymatic Synthesis of Purine 3′-O-Amino-Deoxyribonucleoside Triphosphates
AU  - Qin He
AU  - Shuai Cheng
AU  - Jianqing Yue
AU  - Shu Zong
AU  - Congyu Li
AU  - Xuerong Qi
AU  - Lipei Liu
AU  - Zhidan Zhang
AU  - Jun Sun
AU  - Jian Cheng
AU  - Xiaoyun Lu
AU  - Huifeng Jiang
PY  - 2026
DA  - 2026/08/09
JO  - Chem & Bio Engineering
DO  - 10.1021/cbe.6c00032
UR  - https://doi.org/10.1021/cbe.6c00032
AB  - 3′-O-amino-deoxyribonucleoside triphosphates (3′-ONH2-dNTPs) are crucial reversible terminators for template-independent DNA synthesis. Owing to the structural complexity of purine bases, here we propose a chemo-enzymatic process for the synthesis of purine-type 3′-ONH2-dNTPs. First, the aminoalkoxyl group was introduced into commercially available dA and dG via a chemical catalytic process, affording yields of 24.9% and 27.3%, respectively. Subsequently, to establish a green and scalable enzymatic cascade for phosphorylation of the substrates, we engineered two key phosphorylation enzymes (Dm-dNK and MrPPK2), improving the rate-limiting monophosphorylation of 3′-ONH2-dG from 26% to 97.8% and achieving 59.9% conversion to the corresponding triphosphate. Lastly, the produced nucleotides exhibit performance equivalent to commercial counterparts in terminal deoxynucleotidyl transferase (TdT)-mediated DNA synthesis, supporting the construction of 120-nt strands with ∼99.7% stepwise accuracy. This work establishes an efficient and generalizable catalytic platform for producing modified dNTPs, advancing the practical application of enzymatic DNA synthesis technologies.
SN  - 2836-967X
ER  -