The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, United States.
Department of Chemistry, Texas A&M University, P.O. Box 30012, College Station, Texas 77842, United States.
J Am Chem Soc. 2020 Sep 9;142(36):15331-15339. doi: 10.1021/jacs.0c05635. Epub 2020 Aug 26.
Biology relies almost exclusively on homochiral building blocks to drive the processes of life. Yet cross-chiral interactions can occur between macromolecules of the opposite handedness, including a previously described polymerase ribozyme that catalyzes the template-directed synthesis of enantio-RNA. The present study sought to optimize and generalize this activity, employing evolution to select cross-chiral polymerases that use either mono- or trinucleotide substrates that are activated as the 5'-triphosphate. There was only modest improvement of the former activity, but dramatic improvement of the latter, which enables the trinucleotide polymerase to react 10-10-fold faster than its ancestor and to accept substrates with all possible sequence combinations. The evolved ribozyme can assemble long RNAs from a mixture of trinucleotide building blocks, including a two-fragment form of the ancestral polymerase ribozyme. Further improvement of this activity could enable the generalized cross-chiral replication of RNA, which would establish a new paradigm for the chemical basis of Darwinian evolution.
生物学几乎完全依赖手性构建块来驱动生命过程。然而，具有相反手性的大分子之间可以发生交叉手性相互作用，包括先前描述的一种聚合酶核酶，它可以催化对映体-RNA 的模板指导合成。本研究试图优化和推广这种活性，通过进化选择使用单核苷酸或三核苷酸底物的交叉手性聚合酶，这些底物被激活为 5'-三磷酸。前者的活性只有适度的提高，但后者的活性有了显著的提高，这使得三核苷酸聚合酶的反应速度比其前身快 10-10 倍，并能接受具有所有可能序列组合的底物。进化而来的核酶可以从三核苷酸构建块的混合物中组装长 RNA，包括前体聚合酶核酶的两片段形式。进一步提高这种活性可以实现 RNA 的广义交叉手性复制，这将为达尔文进化的化学基础建立一个新的范例。
