A new reaction for DNA: DNA is shown to catalyze Ni2+‐dependent reductive amination involving the N2‐amine of a guanosine nucleobase (see picture). This finding expands the repertoire of nucleic acid catalysis to include reductive amination, an important natural biosynthetic reaction that has practical synthetic utility.

Keywordsdeoxyribozymes; DNA; in vitro selection; reductive amination Deoxyribozymes are particular DNA sequences that have catalytic ability, analogous to protein enzymes as functional amino acid sequences. [1,2] The discovery of natural RNA enzymes (ribozymes) spurred the search for artificial deoxyribozymes, [3] which are identified by in vitro selection. [4] Most deoxyribozyme-catalyzed reactions involve phosphodiester bond cleavage or ligation, [5][6][7] although other reactions such as Diels-Alder reaction [8] and thymine dimer photoreversion [9] have also been reported.We have initiated a comprehensive effort to identify deoxyribozymes that catalyze reactions of amino acid side chains, initially focusing on small peptide substrates and with the longerterm goal of covalently modifying large proteins. [10] Towards this goal, as part of a recent study we examined the ability of several new deoxyribozymes to modify tyrosine (or serine) side chains of tripeptide substrates that are not covalently tethered to the deoxyribozyme, although the tether was required to enable the selection process. [11] Deoxyribozymes identified using tethered peptide substrates were also active with untethered peptide substrates, but with substantially lower rate and yield. Therefore, in new experiments, here we performed in vitro selection directly using untethered peptide substrates. This effort required a modified selection procedure that was intended to involve reductive amination as a step merely to "capture" catalytically active DNA sequences. Surprisingly, this selection process provided deoxyribozymes that operate entirely independently of the tripeptide substrate and instead catalyze a Ni 2+ -dependent reductive amination involving the N 2 -amine of a guanosine nucleobase on an RNA substrate, which reacts with an oligonucleotidedialdehyde substrate. Reductive amination is a key biochemical process, e.g. for amino acid biosynthesis and catabolism using amino acid dehydrogenases (oxidases) [12] and transaminases (aminotransferases). [13] In vitro, enzymatic reductive amination is important in both laboratory-scale [14] and industrial-scale organic synthesis. [15] Reductive amination may also have been important in RNA World scenarios. [16,17] Our unexpected discovery of DNA-catalyzed reductive amination suggests further exploration of the abilities of nucleic acid enzymes to catalyze this interesting and potentially useful class of reaction.For any in vitro selection strategy that does not involve physical compartmentalization or segregation of individual candidate sequences, [18] the selection design must include a mechanism by which individual, functional sequences become separable from the vast excess of nonfunctional sequences. Importantly, this mechanism must operate in parallel fashion without requiring independent interrogation (i.e., screening) of each candidate [5] A key advantage of the gel-shift approach is that functional sequences are separated largely on the basis of oligonucleotide length (size), which has incr...