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Artificial intelligence uncovers carcinogenic human metabolites
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2022-08-11 , DOI: 10.1038/s41589-022-01110-7
Aayushi Mittal 1 , Sanjay Kumar Mohanty 1 , Vishakha Gautam 1 , Sakshi Arora 1 , Sheetanshu Saproo 2 , Ria Gupta 1 , Roshan Sivakumar 1 , Prakriti Garg 1 , Anmol Aggarwal 1 , Padmasini Raghavachary 1 , Nilesh Kumar Dixit 1 , Vijay Pal Singh 3 , Anurag Mehta 4 , Juhi Tayal 4 , Srivatsava Naidu 2 , Debarka Sengupta 1 , Gaurav Ahuja 1
Affiliation  

The genome of a eukaryotic cell is often vulnerable to both intrinsic and extrinsic threats owing to its constant exposure to a myriad of heterogeneous compounds. Despite the availability of innate DNA damage responses, some genomic lesions trigger malignant transformation of cells. Accurate prediction of carcinogens is an ever-challenging task owing to the limited information about bona fide (non-)carcinogens. We developed Metabokiller, an ensemble classifier that accurately recognizes carcinogens by quantitatively assessing their electrophilicity, their potential to induce proliferation, oxidative stress, genomic instability, epigenome alterations, and anti-apoptotic response. Concomitant with the carcinogenicity prediction, Metabokiller is fully interpretable and outperforms existing best-practice methods for carcinogenicity prediction. Metabokiller unraveled potential carcinogenic human metabolites. To cross-validate Metabokiller predictions, we performed multiple functional assays using Saccharomyces cerevisiae and human cells with two Metabokiller-flagged human metabolites, namely 4-nitrocatechol and 3,4-dihydroxyphenylacetic acid, and observed high synergy between Metabokiller predictions and experimental validations.



中文翻译:

人工智能揭示致癌的人类代谢物

真核细胞的基因组由于不断暴露于无数异质化合物中,往往容易受到内在和外在威胁。尽管存在先天 DNA 损伤反应,但一些基因组损伤会引发细胞的恶性转化。由于关于真正(非)致癌物的信息有限,准确预测致癌物是一项极具挑战性的任务。我们开发了 Metabokiller,这是一种集成分类器,可通过定量评估致癌物的亲电性、诱导增殖的潜力、氧化应激、基因组不稳定性、表观基因组改变和抗细胞凋亡反应来准确识别致癌物。伴随致癌性预测,Metabokiller 是完全可解释的,并且优于现有的致癌性预测最佳实践方法。Metabokiller 揭示了潜在的致癌人类代谢物。为了交叉验证 Metabokiller 预测,我们使用酿酒酵母和具有两种 Metabokiller 标记的人类代谢物(即 4-硝基儿茶酚和 3,4-二羟基苯乙酸)的人类细胞,并观察到 ​​Metabokiller 预测和实验验证之间的高度协同作用。

更新日期:2022-08-11
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