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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Homology models guide discovery of diverse enzyme specificities among dipeptide epimerases in the enolase superfamily
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Homology models guide discovery of diverse enzyme specificities among dipeptide epimerases in the enolase superfamily

机译：同源性模型指导发现烯醇酶超家族中二肽差向异构酶之间不同的酶特异性

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摘要

The rapid advance in genome sequencing presents substantial challenges for protein functional assignment, with half or more of new protein sequences inferred from these genomes having uncertain assignments. The assignment of enzyme function in functionally diverse superfamilies represents a particular challenge, which we address through a combination of computational predictions,enzymology, and structural biology. Here we describe the results of a focused investigation of a group of enzymes in the enolase superfamily that are involved in epimerizing dipeptides. The first members of this group to be functionally characterized were Ala-Glu epimerases in Eschericiha coli and Bacillus subtilis, based on the operon context and enzymological studies; these enzymes are presumed to be involved in peptidoglycan recycling. We have subsequently studied more than 65 related enzymes by computational methods, including homology modeling and metabolite docking, which suggested that many would have divergent specificities;, i.e., they are likely to have different (unknown) biological roles. In addition to the Ala-Phe epimerase specificity reported previously, we describe the prediction and experimental verification of: (i) a new group of presumed Ala-Glu epimerases; (ii) several enzymes with specificity for hydrophobic dipeptides, including one from Cytophaga hutchinsonii that epimerizes D-Ala-D-Ala; and(iii) a small group of enzymes that epimerize cationic dipeptides.Crystal structures for certain of these enzymes further elucidate the structural basis of the specificities. The results highlight the potential of computational methods to guide experimental characterization of enzymes in an automated, large-scale fashion.
机译：基因组测序的快速发展对蛋白质功能分配提出了严峻的挑战，从这些基因组推断出的新蛋白质序列中有一半或更多具有不确定的分配。在功能多样的超家族中酶功能的分配代表了一个特殊的挑战，我们通过计算预测，酶学和结构生物学的结合来解决。在这里我们描述了集中研究烯醇化酶超家族中涉及差向异构二肽的一组酶的结果。根据操纵子的背景和酶学研究，该组的第一批具有功能特征的是大肠杆菌和枯草芽孢杆菌中的Ala-Glu差向异构酶；推测这些酶参与肽聚糖的再循环。随后，我们通过计算方法研究了65种以上相关酶，包括同源性建模和代谢物对接，这表明许多酶具有不同的特异性;即它们可能具有不同的（未知的）生物学作用。除了先前报道的Ala-Phe差向异构酶特异性之外，我们还描述了以下方面的预测和实验验证：（i）一组新的推定的Ala-Glu差向异构酶； （ii）几种对疏水性二肽具有特异性的酶，包括一种来自Cytophaga hutchinsonii的酶，其差向异构化D-Ala-D-Ala；这些阳离子中某些酶的晶体结构进一步阐明了特异性的结构基础。结果突出了计算方法的潜力，以自动化，大规模的方式指导酶的实验表征。

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    Tiit Lukk; Ayano Sakai; Chakrapani Kalyanaraman; Shoshana D. Brown; Heidi J. linker; Ling Song; Alexander A.Fedorov; Elena V. Fedorov; Rafael Toro; Brandan Hillerich; Ronald Seidel; Yury Patskovsky; Matthew W. Vetting; Satish K. Nair; Patricia C. Babbitt; Steven C. Almo; John A. Gerlt; Matthew P. Jacobson;

  • 作者单位

    Departments of Biochemistry and Chemistry, University of Illinois at Urbana Champaign, Urbana, IL 61801;

    Departments of Biochemistry and Chemistry, University of Illinois at Urbana Champaign, Urbana, IL 61801;

    Department of Pharmaceutical Chemistry,School of Pharmacy and California Institute for Quantitative Biomedical Research, University of California, 1700 4th Street, San Francisco, CA 94158;

    Department of Pharmaceutical Chemistry,School of Pharmacy and California Institute for Quantitative Biomedical Research, University of California, 1700 4th Street, San Francisco, CA 94158,Department of Bioengineering and Therapeutic Sciences, School of Pharmacy and California Institute for Quantitative Biomedical Research, University of California, 1700 4th Street, San Francisco, CA 94158;

    Departments of Biochemistry and Chemistry, University of Illinois at Urbana Champaign, Urbana, IL 61801;

    Departments of Biochemistry and Chemistry, University of Illinois at Urbana Champaign, Urbana, IL 61801;

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;

    Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;

    Departments of Biochemistry and Chemistry, University of Illinois at Urbana Champaign, Urbana, IL 61801;

    Department of Pharmaceutical Chemistry,School of Pharmacy and California Institute for Quantitative Biomedical Research, University of California, 1700 4th Street, San Francisco, CA 94158,Department of Bioengineering and Therapeutic Sciences, School of Pharmacy and California Institute for Quantitative Biomedical Research, University of California, 1700 4th Street, San Francisco, CA 94158;

    Departments of Biochemistry and Chemistry, University of Illinois at Urbana Champaign, Urbana, IL 61801,Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461;

    Departments of Biochemistry and Chemistry, University of Illinois at Urbana Champaign, Urbana, IL 61801;

    Department of Pharmaceutical Chemistry,School of Pharmacy and California Institute for Quantitative Biomedical Research, University of California, 1700 4th Street, San Francisco, CA 94158;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    computational biology; enzymology; protein function;

    机译：计算生物学;酶学蛋白质功能;

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