Characterization of Heme–DNA Complexes Composed of Some Chemically Modified Hemes and Parallel G-Quadruplex DNAs

Abstract

Heme {Fe(II)- or Fe(III)-protoporphyrin IX complex [heme(Fe(2+)) or heme(Fe(3+)), respectively]} binds selectively to the 3'-terminal G-quartet of a parallel G-quadruplex DNA formed from a single repeat sequence of the human telomere, d(TTAGGG), through a π-π stacking interaction between the porphyrin moiety of the heme and the G-quartet. The binding affinities of some chemically modified hemes(Fe(3+)) for DNA and the structures of complexes between the modified hemes(Fe(2+)) and DNA, with carbon monoxide (CO) coordinated to the heme Fe atom on the side of the heme opposite the G6 G-quartet, have been characterized to elucidate the interaction between the heme and G-quartet in the complexes through analysis of the effects of the heme modification on the structural properties of the complex. The study revealed that the binding affinities and structures of the complexes were barely affected by the heme modification performed in the study. Such plasticity in the binding of heme to the G-quartet is useful for the versatile design of the complex through heme chemical modification and DNA sequence alteration. Furthermore, exchangeable proton signals exhibiting two-proton intensity were observed at approximately -3.5 ppm in the (1)H nuclear magnetic resonance (NMR) spectra of the CO adducts of the complexes. Through analysis of the NMR results, together with theoretical consideration, we concluded that the heme(Fe(2+)) axial ligand trans to CO in the complex is a water molecule (H2O). Identification of the Fe-bound H2O accommodated between the heme and G-quartet planes in the complex provides new insights into the structure-function relationship of the complex.

G-quadruplexes Sequester Free Heme in Living Cells

“…Parallel quadruplexes have more accessible ends, and a number of studies have shown that heme preferentially binds to parallel rather than antiparallel quadruplexes (Cheng et al, 2009;Kong et al, 2010;Kosman and Juskowiak, 2011). In vitro studies have shown that heme, like other porphyrins, binds to external guanines in a quadruplex, stacking like a slightly mismatched dinner plate on the planar ring of a terminal G-quartet (e.g., Yamamoto et al, 2015). PhenDC3 is also an end-binding quadruplex ligand and may therefore be well suited for heme displacement.…”

Applications of guanine quartets in nanotechnology and chemical biology

“…Upon addition of a sto ichiometric oxidant (hydrogen peroxide, H 2 O 2 ), the complex was found to accelerate 250fold the oxida tion of the chromogenic substrate ABTS 78 ]) and the K + dependency of its catalytic activ ity, the authors wisely mused about its quadruplex struc ture 79 , which offers a defined binding site to hemin that becomes catalytically competent once nestled within this site only. It is intriguing that, more than three decades after its discovery, the precise mechanism of quadruplex DNAzyme remains unclear [80][81][82] , despite hundreds of new applications reported each year (for relevant reviews, see reFs [83][84][85]. Inspired by Sintim's work, Spinelli and col leagues further exploited the intramolecular assembly of TASQ to provide versatile catalytic systems (TASQzyme) that could be applied with a variety of precatalysts, cofactors and substrates 86 .…”

The heme biosynthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of mitochondrial dynamics and ER contact sites, regulate heme mobilization to the nucleus

“…Indeed, as an iron containing, redox active, hydrophobic molecule, heme may catalyze spurious redox reactions that promote oxidative damage in the nucleus (Hanna et al, 2017; Reddi and Hamza, 2016). Alternatively, heme may act as an anti-proliferation signal through its ability to act as a transcriptional regulator by binding G-quadruplexes in DNA (Shinomiya et al, 2018; Shumayrikh et al, 2015; Yamamoto et al, 2015) or controlling transcription via Hap1 and the HAP complex (Buschlen et al, 2003; Hon et al, 2005; Zhang et al, 1993; Zhang and Hach, 1999; Zhang et al, 1998). Taken together, our results indicate that the relatively fast rate of nuclear heme acquisition may serve an important role in mitochondrial-nuclear retrograde signaling.…”