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一个基板许多酶 虚拟查揭示了人类和小鼠中缺失的卡尼丁生物合成基因
Marco Malatesta1, Emanuele Fornasier2, Martino Luigi Di Salvo3
1Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.
Nature communications
|April 13, 2024
概括
我们开发了一种计算方法,使用蛋白质结构来预测酶功能. 这种方法确定了卡尼丁生物合成中的关键酶,揭示了人类潜在的基因损失.
科学领域:
- 生物化学和结构生物学
- 计算生物学和生物信息学
背景情况:
- 越来越多的蛋白质结构有助于预测酶功能的可用性.
- 需要自动化方法来识别参与代谢途径的酶.
研究的目的:
- 开发一种自动化的计算程序,以基质对接和活性位子构成为基础,用于识别酶.
- 应用这种方法来预测维生素B6依赖酶的功能,并识别新型酶在代谢途径.
主要方法:
- 使用基质对接方法对AlphaFold模拟的维生素B6依赖酶进行选.
- 基于对酶功能预测的催化有利的构造的指标的开发.
- 预测酶活动的实验验证,包括确定晶体结构.
主要成果:
- 开发的指标在识别与已知的代谢反应相关的基因时获得了0.84的AUROC得分.
- 鉴定了对氧三甲氨酸阿尔多酶 (HTMLA) 的哺乳动物基因,该基因对卡尼丁生物合成至关重要.
- 发现血清基甲基转移酶 (SHMT) 1和2可催化HTMLA反应,而小鼠的三氨酸阿尔多酶 (Tha1) 显示出更高的效率,在使用其实验晶体结构时其排名得到改善.
结论:
- 计算程序有效地预测了酶功能,并识别了关键的代谢酶.
- 人类可能已经丢失了一种参与卡尼丁生物合成的基因,SHMT部分补偿了这一损失.
- 与单独的模型相比,实验结构可以提高计算酶功能预测的准确性.
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