结构特征分析显示，异胞嘧啶特异性脱氨酶VCZ的应用潜力在抗癌疗法中。
Structural characterization of an isocytosine-specific deaminase VCZ reveals its application potential in the anti-cancer therapy.
发表日期：2023 Sep 15
作者：
Wenting Guo, Xiaojia Li, Jingyu Fan, Hongwei Li, Yan Wen, Chunyan Meng, Haitao Chen, Zhipeng Zhao, Yuling Zhang, Yushen Du, Baixing Wu
来源：
Epigenetics & Chromatin
摘要：
非天然核碱基异胞嘧啶（IC）是胞嘧啶的异构体；化学衍生物5-氟异胞嘧啶（5-FIC）与异胞嘧啶特异脱氨酶（ICD）VCZ一起被认为是潜在的癌症治疗酶/前药对，通过基因导向的酶/前药疗法（GDEPT）方法。在本研究中，我们确定了apo-VCZ和其与5-FU复合物的晶体结构。我们确定了底物结合和催化反应的关键氨基酸残基。我们还捕获了底物诱导的VCZ构象变化，然后提出了VCZ将IC转化为尿嘧啶的假设反应过程。此外，我们评估了野生型或突变型VCZ蛋白在结直肠癌细胞系中的治疗效果。我们的研究将通过根据结构观察来优化ICD/5-FIC配对，从而改善将ICD/5-FIC配对应用于临床试验的可能性。© 2023作者。
Non-natural nucleobase isocytosine (IC) is the isomer of cytosine; its chemical derivate 5-fluoroisocytosine (5-FIC) together with the isocytosine-specific deaminase (ICD) VCZ was suggested to be potential practical enzyme/prodrug pair for cancer therapy through gene-directed enzyme-prodrug therapy (GDEPT) method. In this study, we have determined the crystal structures of apo-VCZ and its complex with 5-FU. We identified the critical residues for substrate binding and catalytic reaction. We also captured the substrate-induced conformational changes of VCZ, then proposed the conjectural reaction procedures of VCZ for converting the IC into the uracil. Moreover, we evaluated the therapeutic effect of wildtype or the mutated VCZ protein in the colorectal cancer cell lines. Our studies will shed light on optimizing the ICD/5-FIC pairs by modifying either the enzyme or the prodrug based on the structural observations, thereby improving the possibility of applying the ICD/5-FIC pair in clinical trials.© 2023 The Author(s).