Mining cancer genomes for change-of-metabolic-function mutations.
Mining cancer genomes for change-of-metabolic-function mutations.
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挖掘癌症基因组代谢功能突变的变化。
DOI：
10.1038/s42003-023-05475-w
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发表时间：
2023-11-10
影响因子：
5.9
通讯作者：
Reitman, Zachary J.
中科院分区：
文献类型：
--
作者：
Tu, Kevin J.;Diplas, Bill H.;Regal, Joshua A.;Waitkus, Matthew S.;Pirozzi, Christopher J.;Reitman, Zachary J.
需要具有新功能的酶来实现新的有机合成技术。从功能性改变蛋白质并影响细胞代谢的功能获得性癌症突变中汲取灵感，我们开发了METIS（来自肿瘤的突变酶）。METIS使用突变复发率和蛋白质结构识别改变代谢的癌症突变。我们使用METIS筛选了298，517个癌症突变，并确定了48个候选突变，包括先前确定的改变酶功能的突变。外源表达候选突变体（OGDHLp.A400T）的细胞的无偏代谢组学分析支持改变的表型，该表型促进体外生产黄嘌呤，黄嘌呤是一种非常有用的化学物质，目前使用不可持续的水密集型方法生产。然后，我们将METIS应用于4900万个癌症突变，产生了一组精细的候选物，这些候选物可能赋予新的酶功能或有助于肿瘤进展。因此，METIS可用于鉴定和分类潜在有用的癌症突变，用于绿色化学和治疗应用。METIS的发展：一种计算方法来识别赋予酶新的催化功能的癌症突变，然后将这些突变应用于绿色化学或治疗开发。
Enzymes with novel functions are needed to enable new organic synthesis techniques. Drawing inspiration from gain-of-function cancer mutations that functionally alter proteins and affect cellular metabolism, we developed METIS (Mutated Enzymes from Tumors In silico Screen). METIS identifies metabolism-altering cancer mutations using mutation recurrence rates and protein structure. We used METIS to screen 298,517 cancer mutations and identify 48 candidate mutations, including those previously identified to alter enzymatic function. Unbiased metabolomic profiling of cells exogenously expressing a candidate mutant (OGDHLp.A400T) supports an altered phenotype that boosts in vitro production of xanthosine, a pharmacologically useful chemical that is currently produced using unsustainable, water-intensive methods. We then applied METIS to 49 million cancer mutations, yielding a refined set of candidates that may impart novel enzymatic functions or contribute to tumor progression. Thus, METIS can be used to identify and catalog potentially-useful cancer mutations for green chemistry and therapeutic applications. The development of METIS: a computational approach to identify cancer mutations that confer novel catalytic functions upon enzymes, then apply these mutations towards green chemistry or therapeutic development.
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影响因子：
3.7
作者：
Jin G;Reitman ZJ;Spasojevic I;Batinic-Haberle I;Yang J;Schmidt-Kittler O;Bigner DD;Yan H
通讯作者：
Yan H
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.9
作者：
Shihab, Hashem A.;Gough, Julian;Cooper, David N.;Stenson, Peter D.;Barker, Gary L. A.;Edwards, Keith J.;Day, Ian N. M.;Gaunt, Tom R.
通讯作者：
Gaunt, Tom R.
影响因子：
9.8
作者：
Coban-Akdemir, Zeynep;White, Janson J.;Carvalho, Claudia M. B.
通讯作者：
Carvalho, Claudia M. B.
影响因子：
14.8
作者：
Leonard, Effendi;Runguphan, Weerawat;Prather, Kristala Jones
通讯作者：
Prather, Kristala Jones