Pre-miR-675 is a microRNA expressed from the exon 1 of H19 long noncoding RNA, and the atypical expression of pre-miR-675 has been linked with several diseases and disorders including cancer. To ...execute its function inside the cell, pre-miR-675 is folded into a particular conformation, which aids in its interaction with several other biological molecules. However, the exact folding dynamics of pre-miR-675 and its protein-binding motifs are currently unknown. Moreover, how H19 lncRNA and pre-miR-675 crosstalk and modulate each other’s activities is also unclear. The detailed structural analysis of pre-miR-675 in this study determines its earlier unknown conformation and identifies novel protein-binding sites on pre-miR-675, thus making it an excellent therapeutic target against cancer. Co-folding analysis between H19 lncRNA and pre-miR-675 determine structural transformations in pre-miR-675, thus describing the earlier unknown mechanism of interaction between these two molecules. Comprehensively, this study details the conformation of pre-miR-675 and its protein-binding sites and explains its relationship with H19 lncRNA, which can be interpreted to understand the role of pre-miR-675 in the development and progression of tumorigenesis and designing new therapeutics against cancers.
Reduction of CO2 holds the key to solving two major challenges taunting the societyclean energy and clean environment. There is an urgent need for the development of efficient non-noble metal-based ...catalysts that can reduce CO2 selectively and efficiently. Unfortunately, activation and reduction of CO2 can only be achieved by highly reduced metal centers jeopardizing the energy efficiency of the process. A carbon monoxide dehydrogenase inspired Co complex bearing a dithiolato ligand can reduce CO2, in wet acetonitrile, to CO with ∼95% selectivity over a wide potential range and 1559 s–1 rate with a remarkably low overpotential of 70 mV. Unlike most of the transition-metal-based systems that require reduction of the metal to its formal zerovalent state for CO2 reduction, this catalyst can reduce CO2 in its formal +1 state making it substantially more energy efficient than any system known to show similar reactivity. While covalent donation from one thiolate increases electron density at the Co(I) center enabling it to activate CO2, protonation of the bound thiolate, in the presence of H2O as a proton source, plays a crucial role in lowering overpotential (thermodynamics) and ensuring facile proton transfer to the bound CO2 ensuring facile (kinetics) reactivity. A very covalent Co(III)–C bond in a Co(III)-COOH intermediate is at the heart of selective protonation of the oxygen atoms to result in CO as the exclusive product of the reduction.
Activation and reduction of N2 have been a major challenge to chemists and the focus since now has mostly been on the synthesis of NH3. Alternatively, reduction of N2 to hydrazine is desirable ...because hydrazine is an excellent energy vector that can release the stored energy very conveniently without the need for catalysts. To date, only one molecular catalyst has been reported to be able to reduce N2 to hydrazine chemically. A trinuclear T-shaped nickel thiolate molecular complex has been designed to activate dinitrogen. The electrochemically generated all Ni(I) state of this molecule can reduce N2 in the presence of PhOH as a proton donor. Hydrazine is detected as the only nitrogen-containing product of the reaction, along with gaseous H2. The complex reported here is selective for the 4e–/4H+ reduction of nitrogen to hydrazine with a minor overpotential of ∼300 mV.
Reactivity as well as selectivity are crucial in the activation and electrocatalytic reduction of molecular oxygen. Recent developments in the understanding of the mechanism of electrocatalytic O2 ...reduction by iron porphyrin complexes in situ using surface enhanced resonance Raman spectroscopy coupled to rotating disc electrochemistry (SERRS-RDE) in conjunction with H/D isotope effects on electrocatalytic current reveals that the rate of O2 reduction, ∼104 to 105 M–1 s–1 for simple iron porphyrins, is limited by the rate of O–O bond cleavage of an intermediate ferric peroxide species (FeIII–OOH). SERRS-RDE probes the system in operando when it is under steady state such that any intermediate species that has a greater rate of formation relative to its rate of decay, including the rate determining species, would accumulate and can be identified. This technique is particularly well suited to investigate iron porphyrin electrocatalysts as the intense symmetric ligand vibrations allow determination of the oxidation and spin states of the bound iron with high fidelity. The rate of O2 reduction could be tuned up by 3 orders of magnitude by incorporating residues in the catalyst design that can exert “push” or “pull” effects, that is, axial phenolate and thiolate ligands and distal arginine residues. Similarly the rate of O–O bond cleavage can be enhanced by several orders of magnitude upon incorporating a distal Cu site and installing the active site in a hydrophobic protein environment in synthetic models and biosynthetic protein scaffolds. The selectivity, however, is solely determined by the site of protonation of a ferric peroxide (FeIII–OOH) intermediate and can be governed by installing preorganized second sphere residues in the distal pocket. The 4e–/4H+ reduction of O2 entails protonation of the distal oxygen of the FeIII–OOH species, while 2e–/2H+ reduction requires the proximal oxygen to be protonated. Mechanistic investigations of CO2 reduction by iron porphyrins reveal that the rate-determining step is the C–O bond cleavage of a FeII–COOH species analogous to the O–O bond cleavage step of a FeIII–OOH species in O2 reduction. The selectivity, resulting in either CO or HCOOH, is determined by the site of protonation of this species. These similarities suggests that the chemical principles governing the rate and selectivity of reduction of small molecules like O2, CO2, NO x , and SO x may be quite similar in nature.
The reduction of CO2 by an iron porphyrin complex with a hydrogen bonding distal pocket involves at least two intermediates. The resonance Raman data of intermediate I, which could only be stabilized ...at −95 °C, indicates that it is a Fe(II)–CO2 2– adduct and is followed by an another intermediate II at −80 °C where the bound CO2 in intermediate I is protonated to form a Fe(II)–COOH species. While the initial protonation can be achieved using weak proton sources like MeOH and PhOH, the facile heterolytic cleavage of the C–OH bond in intermediate II requires strong acids.
Iron porphyrin complexes with second-sphere distal triazole residues show a hydrogen evolution reaction (HER) catalyzed by the Fe(I) state in both organic and aqueous media, whereas an analogous ...iron porphyrin complex without the distal residues catalyzes the HER in the formal Fe(0) state. This activation of the Fe(I) state by the second-sphere residues lowers the overpotential of the HER by these iron porphyrin complexes by 50%. Experimental data and theoretical calculations indicate that the distal triazole residues, once protonated, enhance the proton affinity of the iron center via formation of a dihydrogen bond with an Fe(III)–H– intermediate.
Oxygen reduction reaction (ORR) is a complex 4e–/4H+ multistep process, and factors that determine the rate and selectivity of this reaction are a matter of contemporary interest. Synthetic iron ...porphyrin model complexes mimicking the active site of horseradish peroxidase (HRP) are shown to enhance the rate of ORR and 4H+/4e– selectivity irrespective of the rate of electron transfer from the electrode relative to unfunctionalized iron porphyrins. In operando spectroscopic analysis over self-assembled monolayer-modified electrodes allows characterization of reactive intermediates involved in ORR. Two key intermediate species of ORR, FeIII–OOH and FeIVO, are identified using 18O2 labeling depending on the nature of the pendant residue of these HRP mimics. The results indicate that the nature of the pendant distal moiety in the distal superstructure of iron porphyrin changes the distribution of the intermediate species under steady state relative to simple mononuclear porphyrins. Density functional theory calculations indicate that not only the presence of hydrogen bonding from the pendant groups but also its relative spatial orientation with respect to the proximal and distal oxygen atom of a FeIII–OOH intermediate species controls the selectivity of ORR.
The past decade has seen considerable growth in the development of materials for fuel cell electrodes, and there is a desire for active electrocatalysts derived from base metals instead of noble ...metals. Fuels cells that consume H2 and O2 require catalysts to cleave these reactants, with the oxygen reduction reaction (ORR) — either 4H+/4e− reduction to 2H2O or 2H+/2e− reduction to H2O2 — being particularly challenging. The ORR is efficiently performed by certain metalloenzymes, and understanding the links between their structure and function aids the design of molecular ORR electrocatalysts. These bio-inspired catalysts exhibit good activity relative to previous synthetic systems and, furthermore, have provided mechanistic insights relevant to synthetic and enzymatic catalysts. This Review covers recent developments in homogeneous and heterogeneous molecular ORR catalysis, placing emphasis on reaction mechanisms and the factors governing rates and selectivities.Electrocatalysts for the oxygen reduction reaction are important components of energy technologies such as fuel cells. The study of molecular catalysts affords mechanistic insights that further the development of robust, active and energy-efficient systems. This Review describes state-of-the-art metal complexes that operate either in solution or immobilized on an electrode.
Catalytic oxidation of organic substrates, using a green oxidant like O2, has been a long-term goal of the scientific community. In nature, these oxidations are performed by metalloenzymes that ...generate highly oxidizing species from O2, which, in turn, can oxidize very stable organic substrates, e.g., mono-/dioxygenases. The same oxidants are produced during O2 reduction/respiration in the mitochondria but are reduced by electron transfer, i.e., reductases. Iron porphyrin mimics of the active site of cytochrome P450 (Cyt P450) are created atop a self-assembled monolayer covered electrode. The rate of electron transfer from the electrode to the iron porphyrin site is attenuated to derive monooxygenase reactivity from these constructs that otherwise show O2 reductase activity. Catalytic hydroxylation of strong C–H bonds to alcohol and epoxidation of alkenes, using molecular O2 (with 18O2 incorporation), is demonstrated with turnover numbers >104. Uniquely, one of the two iron porphyrin catalysts used shows preferential oxidation of 2° C–H bonds of cycloalkanes to alcohols over 3° C-H bonds without overoxidation to ketones. Mechanistic investigations with labeled substrates indicate that a compound I (FeIVO bound to a porphyrin cation radical) analogue, formed during O2 reduction, is the primary oxidant. The selectivity is determined by the shape of the distal pocket of the catalyst, which, in turn, is determined by the substituents on the periphery of the porphyrin macrocycle.
Replicative capacity of a cell is strongly correlated with telomere length regulation. Aberrant lengthening or reduction in the length of telomeres can lead to health anomalies, such as cancer or ...premature aging. Telomerase is a master regulator for maintaining replicative potential in most eukaryotic cells. It does so by controlling telomere length at chromosome ends. Akin to cancer cells, most single-cell eukaryotic pathogens are highly proliferative and require persistent telomerase activity to maintain constant length of telomere and propagation within their host. Although telomerase is key to unlimited cellular proliferation in both cases, not much was known about the role of telomerase in human parasites (malaria,
, etc.) until recently. Since telomerase regulation is mediated via its own structural components, interactions with catalytic reverse transcriptase and several factors that can recruit and assemble telomerase to telomeres in a cell cycle-dependent manner, we compare and discuss here recent findings in telomerase biology in cancer, aging and parasitic diseases to give a broader perspective of telomerase function in human diseases.
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