Designing human Sphingosine-1-phosphate lyases using a temporal Dirichlet variational autoencoder
Designing human Sphingosine-1-phosphate lyases using a temporal Dirichlet variational autoencoder
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DOI：
10.1101/2022.02.14.480330
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发表时间：
2022-02
期刊：
影响因子：
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通讯作者：
E. Lobzaev;M. A. Herrera;D. Campopiano;Giovanni Stracquadanio
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文献类型：
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作者：
E. Lobzaev;M. A. Herrera;D. Campopiano;Giovanni Stracquadanio
酶缺乏会导致细胞内底物毒性水平的积累，并与危及生命的病理相关。通过注射缺陷酶的重组版本来恢复生理酶水平可以提供可行的治疗选择。然而，这些酶替代疗法的成功有限，因为重组酶的催化活性较低，会引起免疫反应并且难以制造。此外，巨大的序列设计空间使得寻找具有所需治疗特性的酶变得极具挑战性。在这里，我们提出了一种新的酶工程框架，该框架基于深度学习、变分微积分和自然语言处理的最新进展，设计具有与野生型蛋白质相当的生化特征的人类酶变体，作为快速构建用于下游筛选的目标库的方法。我们应用我们的方法设计了人 1-磷酸鞘氨醇裂解酶 (HsS1PL) 的变体，作为 14 型肾病综合征 (NPHS14) 的潜在治疗方法，并通过广泛的序列和分子动力学分析表征了其生化特性。
Enzymatic deficiencies cause the accumulation of toxic levels of substrates in a cell and are associated with life-threatening pathologies. Restoring physiological enzymes levels by injecting a recombinant version of the defective enzyme could provide a viable therapeutic option. However, these enzyme replacement therapies have had limited success, as the recombinant enzymes are less catalytically active, cause immune response and are difficult to manufacture. Moreover, the vast sequence design space makes finding enzymes with desired therapeutic properties extremely challenging. Here, we present a new enzyme engineering framework, which builds on recent advances in deep learning, variational calculus and natural language processing, to design variants of human enzymes with biochemical features comparable to the wild type protein as a way to rapidly build targeted libraries for downstream screening. We applied our method to design variants of human Sphyngosine-1-phosphate lyase (HsS1PL) as potential therapeutic treatments for nephrotic syndrome type 14 (NPHS14), and characterized their biochemical properties through extensive sequence and molecular dynamics analyses.