DNA G-Quadruplexes Activate Heme for Robust Catalysis of Carbene Transfer Reactions

Abstract

Guanine-rich single-stranded DNAs and RNAs that fold into G-quadruplexes (GQs) are known to complex tightly with Fe II -heme and Fe III -heme (hemin), ubiquitous cellular cofactors. Heme− GQ (DNA) complexes, known as heme•DNAzymes, are able to utilize hydrogen peroxide as an oxidant to vigorously catalyze a variety of one-electron (peroxidase) and two-electron (peroxygenase) oxidation reactions. Herein, we show that complexes of Fe II -heme with GQs also robustly catalyze a mechanistically distinct reaction, carbene transfer to an alkene substrate. Significant enhancements were seen in both reaction kinetics and product turnover (∼180) relative to disaggregated Fe II -heme in the absence of DNA or in the presence of other DNA folds, such as single-stranded or double-stranded DNA. Heme binds to GQs by end-stacking. Simple, intramolecularly folded GQs are unable to provide a complexly structured "distal side" environment to the bound heme; therefore, such DNAzymes do not display significant product stereoselectivity. However, intermolecular GQs with multiple pendant nucleotides show increasing stereoselectivity in addition to their enhanced catalytic rates. These results recapitulate the unique functional synergy and highlight the surprising catalytic versatility of complexes formed between heme and DNA/RNA GQs. Our findings suggest that heme•DNAzymes and heme•ribozymes may prove to be useful reagents for carbon−carbon bond forming "green" reactions carried out in vitro and likely within living cells.

Iron catalysts with N-ligands for carbene transfer of diazo reagents

“…The DNA-acceleration effect was also observed by D. Sen and co-authors who studied the catalytic activity of heme in presence of different folds of DNA (single-stranded, doublestranded and G-quadruplex). 123 In the model cyclopropanation of styrene by EDA, only the GQs (GQ = G-quadruplex) derivatives efficiently activated the heme towards the carbene transfer reaction. The formation of the trans isomer of 3d occurred in good yields and high rates but no reaction enantiocontrol was observed.…”

The noncovalent dimerization of a G-quadruplex/hemin DNAzyme improves its biocatalytic properties

“…[1][2][3][4][5][6][7][8][9][10][11] Catalytic DNA usually comprises a sequence in which a tertiary structure is encoded which, upon interaction with a metal cofactor, 12 accelerates chemical reactions. [13][14][15][16][17][18][19][20][21] An interesting tertiary structure is the G-quadruplex (GQ) that folds from guanine-rich sequences through the stacking of G-quartets, i.e., arrays of four guanines associated via Hoogsteen hydrogen bonds. [22][23][24][25][26] A GQ exhibits enticing catalytic properties notably upon interaction with hemin (Fe(III)-protoporphyrin IX), a well-known cofactor of hemoproteins.…”

An oxidatively damaged G-quadruplex/hemin DNAzyme

“…G4s have been instrumental in the development of a new class of functional nucleic acids, chiefly the G4-DNAzymes (Fig. 2) [5][6][7][8] . The exquisite interaction between G4s and hemin (iron (III)-protoporphyrin IX) results in peroxidasemimicking G4-DNAzyme systems 9 , which have been used as biosensors 10,11 and biodevices 5,12,13 .…”