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FEBS Open Bio Jun 2024Metal-tetrapyrrole cofactors are involved in multiple cellular functions, and chelatases are key enzymes for the biosynthesis of these cofactors. CfbA is an ancestral,...
Metal-tetrapyrrole cofactors are involved in multiple cellular functions, and chelatases are key enzymes for the biosynthesis of these cofactors. CfbA is an ancestral, homodimeric-type class II chelatase which is able to use not only Ni as a physiological metal substrate, but also Co as a nonphysiological substrate with higher activity than for Ni. The Ni/Co-chelatase function found in CfbA is also observed in SirB, a descendant, monomeric-type class II chelatase. This is despite the distinct active site structure of CfbA and SirB; specifically, CfbA shows a unique four His residue arrangement, unlike other monomeric class II chelatases such as SirB. Herein, we studied the Ni-chelatase activity of SirB variants R134H, L200H, and R134H/L200H, the latter of which mimics the His alignment of CfbA. Our results showed that the SirB R134H variant exhibited the highest Ni-chelatase activity among the SirB enzymes, which in turn suggests that the position of His134 could be more important for the Ni-chelatase activity than that of His200. The SirB R134H/L200H variant showed lower activity than R134H, despite the four His residues found in SirB R134H/L200H. CD spectroscopy showed secondary structure denaturation and a slight difficulty in Ni-binding of SirB R134H/L200H, which may be related to its lower activity. Finally, a docking simulation suggested that the His134 of the SirB R134H variant could function as a base catalyst for the Ni-chelatase reaction in a class II chelatase architecture.
PubMed: 38923868
DOI: 10.1002/2211-5463.13849 -
Pharmacology Research & Perspectives Aug 2024Drug repurposing has gained significant interest in recent years due to the high costs associated with de novo drug development; however, comprehensive pharmacological... (Review)
Review
Drug repurposing has gained significant interest in recent years due to the high costs associated with de novo drug development; however, comprehensive pharmacological information is needed for the translation of pre-existing drugs across clinical applications. In the present study, we explore the current pharmacological understanding of the orphan drug, hemin, and identify remaining knowledge gaps with regard to hemin repurposing for the treatment of cardiovascular disease. Originally approved by the United States Food and Drug Administration in 1983 for the treatment of porphyria, hemin has attracted significant interest for therapeutic repurposing across a variety of pathophysiological conditions. Yet, the clinical translation of hemin remains limited to porphyria. Understanding hemin's pharmacological profile in health and disease strengthens our ability to treat patients effectively, identify therapeutic opportunities or limitations, and predict and prevent adverse side effects. However, requirements for the pre-clinical and clinical characterization of biologics approved under the U.S. FDA's Orphan Drug Act in 1983 (such as hemin) differed significantly from current standards, presenting fundamental gaps in our collective understanding of hemin pharmacology as well as knowledge barriers to clinical translation for future applications. Using information extracted from the primary and regulatory literature (including documents submitted to Health Canada in support of hemin's approval for the Canadian market in 2018), we present a comprehensive case study of current knowledge related to hemin's biopharmaceutical properties, pre-clinical/clinical pharmacokinetics, pharmacodynamics, dosing, and safety, focusing specifically on the drug's effects on heme regulation and in the context of acute myocardial infarction.
Topics: Drug Repositioning; Humans; Hemin; Cardiovascular Diseases; United States; United States Food and Drug Administration; Animals; Orphan Drug Production; Drug Approval
PubMed: 38923404
DOI: 10.1002/prp2.1225 -
Angewandte Chemie (International Ed. in... Jun 2024Electrocatalytic nitrite reduction (eNO2RR) is a promising alternative route to produce ammonia (NH3). Until now, several molecular catalysts have shown capability to...
Electrocatalytic nitrite reduction (eNO2RR) is a promising alternative route to produce ammonia (NH3). Until now, several molecular catalysts have shown capability to homogeneously reduce nitrite to NH3, while taking advantage of added secondary-sphere functionalities to direct catalytic performance. Yet, realizing such control over heterogeneous electrocatalytic surfaces remains a challenge. Herein, we demonstrate that heterogenization of a Fe-porphyrin molecular catalyst within a 2D Metal-Organic Framework (MOF), allows efficient eNO2RR to NH3. On top of that, installation of pendant proton relaying moieties proximal to the catalytic site, resulted in significant improvement in catalytic activity and selectivity. Notably, systematic manipulation of NH3 faradaic efficiency (up to 90%) and partial current (5-fold increase) was achieved by varying the proton relay-to-catalyst molar ratio. Electrochemical and spectroscopic analysis show that the proton relays simultaneously aid in generating and stabilizing of reactive Fe-bound NO intermediate. Thus, this concept offers new molecular tools to tune heterogeneous electrocatalytic systems.
PubMed: 38923372
DOI: 10.1002/anie.202407667 -
Angewandte Chemie (International Ed. in... Jun 2024Due to the challenge of cleaving O-O bonds at single Co sites, mononuclear Co complexes typically show poor selectivity for the four-electron (4e-) oxygen reduction...
Due to the challenge of cleaving O-O bonds at single Co sites, mononuclear Co complexes typically show poor selectivity for the four-electron (4e-) oxygen reduction reaction (ORR). Herein, we report on selective 4e- ORR catalyzed by a Co porphyrin with a hanged ZnII ion. Inspired by Cu/Zn-superoxide dismutase, we designed and synthesized 1-CoZn with a hanging ZnII at the second sphere of a Co porphyrin. Complex 1-CoZn is much more effective than its Zn-lacking analogues to catalyze the 4e- ORR in neutral aqueous solutions, giving an electron number of 3.91 per O2 reduction. With spectroscopic studies, the hanging ZnII was demonstrated to be able to facilitate the electron transfer from CoII to O2, through an electronic "pull effect", to give CoIII-superoxo. Theoretical studies further suggested that this "pull effect" plays crucial roles in assisting O-O bond cleavage. This work is significant to present a new strategy of hanging a ZnII to improve O2 activation and O-O bond cleavage.
PubMed: 38923266
DOI: 10.1002/anie.202409793 -
Biosensors May 2024Biosensors function as sophisticated devices, converting biochemical reactions into electrical signals. Contemporary emphasis on developing biosensor devices with... (Review)
Review
Biosensors function as sophisticated devices, converting biochemical reactions into electrical signals. Contemporary emphasis on developing biosensor devices with refined sensitivity and selectivity is critical due to their extensive functional capabilities. However, a significant challenge lies in the binding affinity of biosensors to biomolecules, requiring adept conversion and amplification of interactions into various signal modalities like electrical, optical, gravimetric, and electrochemical outputs. Overcoming challenges associated with sensitivity, detection limits, response time, reproducibility, and stability is essential for efficient biosensor creation. The central aspect of the fabrication of any biosensor is focused towards forming an effective interface between the analyte electrode which significantly influences the overall biosensor quality. Polymers and macromolecular systems are favored for their distinct properties and versatile applications. Enhancing the properties and conductivity of these systems can be achieved through incorporating nanoparticles or carbonaceous moieties. Hybrid composite materials, possessing a unique combination of attributes like advanced sensitivity, selectivity, thermal stability, mechanical flexibility, biocompatibility, and tunable electrical properties, emerge as promising candidates for biosensor applications. In addition, this approach enhances the electrochemical response, signal amplification, and stability of fabricated biosensors, contributing to their effectiveness. This review predominantly explores recent advancements in utilizing macrocyclic and macromolecular conjugated systems, such as phthalocyanines, porphyrins, polymers, etc. and their hybrids, with a specific focus on signal amplification in biosensors. It comprehensively covers synthetic strategies, properties, working mechanisms, and the potential of these systems for detecting biomolecules like glucose, hydrogen peroxide, uric acid, ascorbic acid, dopamine, cholesterol, amino acids, and cancer cells. Furthermore, this review delves into the progress made, elucidating the mechanisms responsible for signal amplification. The Conclusion addresses the challenges and future directions of macromolecule-based hybrids in biosensor applications, providing a concise overview of this evolving field. The narrative emphasizes the importance of biosensor technology advancement, illustrating the role of smart design and material enhancement in improving performance across various domains.
Topics: Biosensing Techniques; Nanoparticles; Polymers; Humans; Electrochemical Techniques
PubMed: 38920581
DOI: 10.3390/bios14060277 -
Journal of Hazardous Materials Jun 2024Covalent organic frameworks (COFs) are a type of novel organic catalysts which show great potential in the treatment of environmental contaminations. Herein, we...
Covalent organic frameworks (COFs) are a type of novel organic catalysts which show great potential in the treatment of environmental contaminations. Herein, we synthesized three isoreticular halogen-functionalized (F, Cl and Br) porphyrin COFs for visible-light (420 nm ≤ λ ≤ 780 nm) photocatalytic reduction of Cr(VI) to Cr(III). Halogen substituents with tunable electronegativity can regulate the band structure and modulate the charge carrier kinetics of COFs. In the absence of any sacrificial reagent, the isoreticular COFs exhibited good photocatalytic reduction activity of Cr(VI). Particularly, the TAPP-2F showed nearly 100 % conversion efficiency and the highest reaction rate constants (k) on account of the strong electronegativity of F substituent. Experimental results and theoretical calculations showed that the conduction band (CB) potentials of COFs became more negative and charge carrier separation increased with the enhancement of electronegativity (Br < Cl < F), which could provide sufficient driving force for the photoreduction of Cr(VI) to Cr(III). The halogen substituents strategy for regulating the electronic structure of COFs can provide opportunities for designing efficient photocatalysts for environmental remediation. Meanwhile, the mechanistic insights reported in this study help to understand the photocatalytic degradation pathways of heavy metals.
PubMed: 38917630
DOI: 10.1016/j.jhazmat.2024.134956 -
ACS Applied Materials & Interfaces Jun 2024Covalent organic frameworks (COFs) are ideal platforms to spatially control the integration of multiple molecular motifs throughout a single nanoporous framework....
Covalent organic frameworks (COFs) are ideal platforms to spatially control the integration of multiple molecular motifs throughout a single nanoporous framework. Despite this design flexibility, COFs are typically synthesized using only two monomers. One bears the functional motif for the envisioned application, while the other is used as an inert connecting building block. Integrating more than one functional motif extends the functionality of COFs immensely, which is particularly useful for multistep reactions such as electrochemical reduction of CO. In this systematic study, we synthesized five Ni(II)- and Zn(II)-porphyrin-based COFs, including two pure component COFs (Ni and Zn) and three mixed Ni/Zn-COFs (Ni/Zn, Ni/Zn, and Ni/Zn). Among these, the Ni/Zn-COF exhibited the highest catalytic performance for the electroreduction of CO to CO and formate at -0.6 V vs RHE, as was observed in an H-cell. The catalytic performance of the COF catalysts was further extended to a zero-gap membrane electrode assembly (MEA) operation where, utilizing Ni/Zn, CH was detected along with CO and formate at a high current density of 150 mA cm. In contrast, under these conditions predominantly H and CO were detected at Ni and Zn respectively, indicating a clear synergistic effect between the Ni- and Zn-porphyrin units.
PubMed: 38914515
DOI: 10.1021/acsami.4c02511 -
Inorganic Chemistry Jun 2024Two new vanadyl complexes of N-confused porphyrins (NCPs), [VONCTPP] () and [VONCP(OMe)] (), have been synthesized for the first time and investigated as a catalyst for...
Two new vanadyl complexes of N-confused porphyrins (NCPs), [VONCTPP] () and [VONCP(OMe)] (), have been synthesized for the first time and investigated as a catalyst for the oxidative bromination reaction of phenol and its derivatives. This article further delineates crystal structures, photophysical, and redox properties of both the vanadyl complexes. Complexes and exhibited a significant red shift in their absorption spectra compared with their respective free bases. The single-crystal structure of revealed that the complex is in the 2H tautomeric form, while EPR studies revealed the +4 oxidation state of vanadium metal having an axial compression with d configuration. Catalytic potential for -like activity has been explored for both complexes and for the first time in NCP chemistry with excellent TOF values (4.7-6.3 s for and 7.3-8.7 s for ) using KBr as a source of bromine and HO as a green oxidant in aqueous acidic medium at 298 K. Notably, both catalysts show excellent recyclability over five cycles. The vanadyl-metalated NCPs exhibit excellent stability in the air.
PubMed: 38912934
DOI: 10.1021/acs.inorgchem.4c01222 -
Nano Letters Jun 2024Wound infections, especially those caused by pathogenic bacteria, present a considerable public health concern due to associated complications and poor therapeutic...
Wound infections, especially those caused by pathogenic bacteria, present a considerable public health concern due to associated complications and poor therapeutic outcomes. Herein, we developed antibacterial nanoparticles, namely, PGTP, by coordinating guanidine derivatives with a porphyrin-based sonosensitizer. The synthesized PGTP nanoparticles, characterized by their strong positive charge, effectively disrupted the bacterial biosynthesis process through charge interference, demonstrating efficacy against both Gram-negative and Gram-positive bacteria. Additionally, PGTP nanoparticles generated reactive oxygen species under ultrasound stimulation, resulting in the disruption of biofilm integrity and efficient elimination of pathogens. RNA-seq analysis unveiled the detailed mechanism of wound healing, revealing that PGTP nanoparticles, when coupled with ultrasound, impair bacterial metabolism by interfering with the synthesis and transcription of amino acids. This study presents a novel approach to combatting wound infections through ultrasound-driven charge-interfering therapy, facilitated by advanced antibacterial nanomaterials.
PubMed: 38912706
DOI: 10.1021/acs.nanolett.4c00930 -
ACS Omega Jun 2024Water electrolysis for clean hydrogen production requires high-activity, high-stability, and low-cost catalysts for its particularly sluggish half-reaction, the oxygen...
Water electrolysis for clean hydrogen production requires high-activity, high-stability, and low-cost catalysts for its particularly sluggish half-reaction, the oxygen evolution reaction (OER). Currently, the most promising of such catalysts working in alkaline conditions is a core-shell nanostructure, NiFe@NC, whose Fe-doped Ni (NiFe) nanoparticles are encapsulated and interconnected by N-doped graphitic carbon (NC) layers, but the exact OER mechanism of these catalysts is still unclear, and even the location of the OER active site, either on the core side or on the shell side, is still debated. Therefore, we herein derive a plausible active-site model for each side based on various experimental evidence and density functional theory calculations and then build OER free-energy diagrams on both sides to determine the active-site location. The core-side model is an FeO-type (rather than NiO-type) active site where an Fe atom sits on Ni oxide layers grown on top of the core surface during catalyst activation, whose facile dissolution provides an explanation for the activity loss of such catalysts directly exposed to the electrolyte. The shell-side model is a NiN-type (rather than FeN-type) active site where a Ni atom is intercalated into the porphyrin-like NC site of the NC shell during catalyst synthesis. Their OER free-energy diagrams indicate that both sites require similar amounts of overpotentials, despite a complete shift in their potential-determining steps, i.e., the final O evolution from the oxophilic Fe on the core and the initial OH adsorption to the hydrophobic shell. We conclude that the major active sites are located on the core, but the NC shell not only protects the vulnerable FeO active sites on the core from the electrolyte but also provides independent active sites, owing to the N doping.
PubMed: 38911812
DOI: 10.1021/acsomega.3c09920