卡特鲁生物合成中的最终氧化重组步骤的分子基础
Yi Shuang Wang1, Bo Zhang1, Jiapeng Zhu2
1State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, School of Life Sciences , Nanjing University , Nanjing 210023 , China.
Journal of the American Chemical Society
|August 2, 2018
概括
研究人员发现了一种新型酶ChaP, 对于形成抗瘤化合物的复杂结构至关重要 这种二氧化酶利用黄素激活的氧气,揭示了自然产品生物合成中的氧化重组的新见解.
科学领域:
- 生物化学和天然产品生物合成
- 酶学和蛋白质结构
- 化学生物学
背景情况:
- 氧化重组对于通过II型多基合成酶 (PKS) 合成的自然产品的结构多样性和生物活性至关重要.
- 卡特鲁辛 (1) 是一种强大的抗瘤药物,具有来自II型PKS路径的独特五环芳二甲基.
研究的目的:
- 识别和描述在查特鲁辛生物合成中的最终α-皮龙环形成的酶.
- 阐明这种新型酶催化氧化重组的分子机制.
主要方法:
- 对二氧化酶ChaP及其同类的生物化学特征.
- 用X射线结晶学来确定ChaP和相关酶的三维结构.
- 计算对接研究和位点定向的突变发生,以探测酶基质相互作用和催化机制.
主要成果:
- 一种前所未有的二氧化酶,ChaP,被确定为使用flavin激活氧的终端α- pyrone环形成的催化剂.
- 结构和机制研究发现了一种新的氧化重组,涉及两个连续的C-C键裂变,随后是乳化.
- ChaP 是邻近氧酸盐 (VOC) 酶超级家族中的一个新类,它独特地利用了没有内在酸酶结合位点的酸活性氧.
结论:
- ChaP催化了一种独特的氧化重组,这对于查特的复杂结构和其可能的生物活性至关重要.
- 发现ChaP扩大了已知的二氧化酶的范围,并突出了依赖于黄素的氧化激活的新机制.
- 这项工作为了解复杂的自然产品生物合成提供了分子基础,并为酶工程开辟了道路.
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