Extracellular Heme Uptake and the Challenge of Bacterial Cell Membranes.

Iron is essential for the survival of most bacteria but presents a significant challenge given its limited bioavailability. Furthermore, the toxicity of iron combined with the need to maintain physiological iron levels within a narrow concentration range requires sophisticated systems to sense, regulate, and transport iron. Most bacteria have evolved mechanisms to chelate and transport ferric iron (Fe3+) via siderophore receptor systems, and pathogenic bacteria have further lowered this barrier by employing mechanisms to utilize the host's hemoproteins. Once internalized, heme is cleaved by both oxidative and nonoxidative mechanisms to release iron. Heme, itself a lipophilic and toxic molecule, presents a significant challenge for transport into the cell. As such, pathogenic bacteria have evolved sophisticated cell surface signaling and transport systems to obtain heme from the host. In this review, we summarize the structure and function of the heme-sensing and transport systems of pathogenic bacteria and the potential of these systems as antimicrobial targets.

Lutetium texaphyrin: A photocatalyst that triggers pyroptosis via biomolecular photoredox catalysis.

Photon-controlled pyroptosis activation (PhotoPyro) is a promising technique for cancer immunotherapy due to its noninvasive nature, precise control, and ease of operation. Here, we report that biomolecular photoredox catalysis in cells might be an important mechanism underlying PhotoPyro. Our findings reveal that the photocatalyst lutetium texaphyrin (MLu) facilitates rapid and direct photoredox oxidation of nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate, and various amino acids, thereby triggering pyroptosis through the caspase 3/GSDME pathway. This mechanism is distinct from the well-established role of MLu as a photodynamic therapy sensitizer in cells. Two analogs of MLu, bearing different coordinated central metal cations, were also explored as controls. The first control, gadolinium texaphyrin (MGd), is a weak photocatalyst but generates reactive oxygen species (ROS) efficiently. The second control, manganese texaphyrin (MMn), is ineffective as both a photocatalyst and a ROS generator. Neither MGd nor MMn was found to trigger pyroptosis under the conditions where MLu was active. Even in the presence of a ROS scavenger, treating MDA-MB-231 cells with MLu at concentrations as low as 50 nM still allows for pyroptosis photo-activation. The present findings highlight how biomolecular photoredox catalysis could contribute to pyroptosis activation by mechanisms largely independent of ROS.

Structural Dynamics of the Methyl-Coenzyme M Reductase Active Site Are Influenced by Coenzyme F430 Modifications.

Methyl-coenzyme M reductase (MCR) is a central player in methane biogeochemistry, governing methanogenesis and the anaerobic oxidation of methane (AOM) in methanogens and anaerobic methanotrophs (ANME), respectively. The prosthetic group of MCR is coenzyme F430, a nickel-containing tetrahydrocorphin. Several modified versions of F430 have been discovered, including the 172-methylthio-F430 (mtF430) used by ANME-1 MCR. Here, we employ molecular dynamics (MD) simulations to investigate the active site dynamics of MCR from Methanosarcina acetivorans and ANME-1 when bound to the canonical F430 compared to 172-thioether coenzyme F430 variants and substrates (methyl-coenzyme M and coenzyme B) for methane formation. Our simulations highlight the importance of the Gln to Val substitution in accommodating the 172 methylthio modification in ANME-1 MCR. Modifications at the 172 position disrupt the canonical substrate positioning in M. acetivorans MCR. However, in some replicates, active site reorganization to maintain substrate positioning suggests that the modified F430 variants could be accommodated in a methanogenic MCR. We additionally report the first quantitative estimate of MCR intrinsic electric fields that are pivotal in driving methane formation. Our results suggest that the electric field aligned along the CH3-S-CoM thioether bond facilitates homolytic bond cleavage, coinciding with the proposed catalytic mechanism. Structural perturbations, however, weaken and misalign these electric fields, emphasizing the importance of the active site structure in maintaining their integrity. In conclusion, our results deepen the understanding of MCR active site dynamics, the enzyme's organizational role in intrinsic electric fields for catalysis, and the interplay between active site structure and electrostatics.

The heme oxygenase-1 metalloporphyrin inhibitor stannsoporfin enhances the bactericidal activity of a novel regimen for multidrug-resistant tuberculosis in a murine model.

Multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) poses significant challenges to global tuberculosis (TB) control efforts. Host-directed therapies (HDTs) offer a novel approach to TB treatment by enhancing immune-mediated clearance of Mtb. Prior preclinical studies found that the inhibition of heme oxygenase-1 (HO-1), an enzyme involved in heme metabolism, with tin-protoporphyrin IX (SnPP) significantly reduced mouse lung bacillary burden when co-administered with the first-line antitubercular regimen. Here, we evaluated the adjunctive HDT activity of a novel HO-1 inhibitor, stannsoporfin (SnMP), in combination with a novel MDR-TB regimen comprising a next-generation diarylquinoline, TBAJ-876 (S), pretomanid (Pa), and a new oxazolidinone, TBI-223 (O) (collectively, SPaO), in Mtb-infected BALB/c mice. After 4 weeks of treatment, SPaO + SnMP 5mg/kg reduced mean lung bacillary burden by an additional 0.69 log10 (P = 0.01) relative to SPaO alone. As early as 2 weeks post-treatment initiation, SnMP adjunctive therapy differentially altered the expression of pro-inflammatory cytokine genes and CD38, a marker of M1 macrophages. Next, we evaluated the sterilizing potential of SnMP adjunctive therapy in a mouse model of microbiological relapse. After 6 weeks of treatment, SPaO + SnMP 10mg/kg reduced lung bacterial burdens to 0.71 ± 0.23 log10 colony-forming units (CFUs), a 0.78 log-fold greater decrease in lung CFU compared to SpaO alone (P = 0.005). However, adjunctive SnMP did not reduce microbiological relapse rates after 5 or 6 weeks of treatment. SnMP was well tolerated and did not significantly alter gross or histological lung pathology. SnMP is a promising HDT candidate requiring further study in combination with regimens for drug-resistant TB.

Novel Catalytic Antioxidant Formulation Decreases Oxidative Stress, Neuroinflammation and Cognitive Dysfunction in a Model of Nerve Agent Intoxication.

Reactive oxygen species have an emerging role in the pathologic consequences of status epilepticus. We have previously demonstrated the efficacy of a water-for-injection formulation of the meso-porphyrin catalytic antioxidant, manganese (III) meso-tetrakis (N-N-diethylimidazole) porphyrin (AEOL10150) against oxidative stress, neuroinflammation, and neuronal death initiated by kainic acid, pilocarpine, diisopropylflurophosphate (DFP), and soman. This previous dose and dosing strategy of AEOL10150 required smaller multiple daily injections, precluding our ability to test its efficacy against delayed consequences of nerve agent exposure such as neurodegeneration and cognitive dysfunction. Therefore, we developed formulations of AEOL10150 designed to deliver a larger dose once daily with improved brain pharmacodynamics. We examined four new formulations of AEOL10150 that resulted in 8 times higher subcutaneous dose with lower acute toxicity, slower absorption, longer half-life, and higher maximal plasma concentrations compared with our previous strategy. AEOL10150 brain levels exhibited improved pharmacodynamics over 24 hours with all four formulations. We tested a subcutaneous dose of 40 mg/kg AEOL10150 in two formulations (2% carboxymethyl cellulose and 4% polyethylene glycol-4000) in the DFP rat model, and both formulations exhibited significant protection against DFP-induced oxidative stress. Additionally, and in one formulation (4% polyethylene glycol-4000), AEOL10150 significantly protected against DFP-induced neuronal death, microglial activation, delayed memory impairment, and mortality. These results suggest that reformulation of AEOL10150 can attenuate acute and delayed outcomes of organophosphate neurotoxicity. SIGNIFICANCE STATEMENT: Reformulation of manganese (III) meso-tetrakis (N-N-diethylimidazole) porphyrin allowed higher tolerated doses of the compound with improved pharmacodynamics. Specifically, one new formulation allowed fewer daily doses and improvement in acute and delayed outcomes of organophosphate toxicity.

Bioproduction of porphyrins, phycobilins, and their proteins using microbial cell factories: engineering, metabolic regulations, challenges, and perspectives.

Porphyrins, phycobilins, and their proteins have abundant π-electrons and strongly absorb visible light, some of which bind a metal ion in the center. Because of the structural and optical properties, they not only play critical roles as an essential component in natural systems but also have attracted much attention as a high value specialty chemical in various fields, including renewable energy, cosmetics, medicines, and foods. However, their commercial application seems to be still limited because the market price of porphyrins and phycobilins is generally expensive to apply them easily. Furthermore, their petroleum-based chemical synthesis is energy-intensive and emits a pollutant. Recently, to replace petroleum-based production, many studies on the bioproduction of metalloporphyrins, including Zn-porphyrin, Co-porphyrin, and heme, porphyrin derivatives including chlorophyll, biliverdin, and phycobilins, and their proteins including hemoproteins, phycobiliproteins, and phytochromes from renewable carbon sources using microbial cell factories have been reported. This review outlines recent advances in the bioproduction of porphyrins, phycobilins, and their proteins using microbial cell factories developed by various microbial biotechnology techniques, provides well-organized information on metabolic regulations of the porphyrin metabolism, and then critically discusses challenges and future perspectives. Through these, it is expected to be able to achieve possible solutions and insights and to develop an outstanding platform to be applied to the industry in future research.

Amphiphilic Block Copolymers Containing Benzenesulfonyl Azide Groups as Visible Light-Responsive Drug Carriers for Image-Guided Delivery.

Nanoparticles (NPs) containing light-responsive polymers and imaging agents show great promise for controlled drug delivery. However, most light-responsive NPs rely on short-wavelength excitation, resulting in poor tissue penetration and potential cytotoxicity. Moreover, excessively sensitive NPs may prematurely release drugs during storage and circulation, diminishing their efficacy and causing off-target toxicity. Herein, we report visible-light-responsive NPs composed of an amphiphilic block copolymer containing responsive 4-acrylamide benzenesulfonyl azide (ABSA) and hydrophilic N,N'-dimethylacrylamide (DMA) units. The polymer pDMA-ABSA was loaded with the chemotherapy drug dasatinib and zinc tetraphenylporphyrin (ZnTPP). ZnTPP acted as an imaging reagent and a photosensitizer to reduce ABSA upon visible light irradiation, converting hydrophobic units to hydrophilic units and disrupting NPs to trigger drug release. These NPs enabled real-time fluorescence imaging in cells and exhibited synergistic chemophotodynamic therapy against multiple cancer cell lines. Our light-responsive NP platform holds great promise for controlled drug delivery and cancer theranostics, circumventing the limitations of traditional photosensitive nanosystems.

Metal Complexes of Porphyrinoids Containing Nonpyrrolic Heterocycles.

The replacement of one or more pyrrolic building block(s) of a porphyrin by a nonpyrrolic heterocycle leads to the formation of so-called pyrrole-modified porphyrins (PMPs), porphyrinoids of broad structural variability. The wide range of coordination environments (type, number, charge, and architecture of the donor atoms) that the pyrrole-modified frameworks provide to the central metal ions, the frequent presence of donor atoms at their periphery, and their often observed nonplanarity or conformational flexibility distinguish the complexes of the PMPs clearly from those of the traditional square-planar, dianionic, N4-coordinating (hydro)porphyrins. Their different coordination properties suggest their utilization in areas beyond which regular metalloporphyrins are suitable. Following a general introduction to the synthetic methodologies available to generate pyrrole-modified porphyrins, their general structure, history, coordination chemistry, and optical properties, this Review highlights the chemical, electronic (optical), and structural differences of specific classes of metalloporphyrinoids containing nonpyrrolic heterocycles. The focus is on macrocycles with similar "tetrapyrrolic" architectures as porphyrins, thusly excluding the majority of expanded porphyrins. We highlight the relevance and application of these metal complexes in biological and technical fields as chemosensors, catalysts, photochemotherapeutics, or imaging agents. This Review provides an introduction to the field of metallo-PMPs as well as a comprehensive snapshot of the current state of the art of their synthesis, structures, and properties. It also aims to provide encouragement for the further study of these intriguing and structurally versatile metalloporphyrinoids.

4-Carboxyphenyl as efficient donor group in nano Zn-Porphyrin for dye sensitized solar cells.

Dye-sensitized solar cells, represent the alternate technology in solar research due to their cost effective, easy fabrication processes, higher efficiencies, and design flexibility. In this research, dual donor group modified zinc porphyrin dyes, have been synthesized for DSSCs. The complexes of zinc porphyrin functioned as acceptor or attaching groups within each mesophenyl ring and carboxylic acid. These complexes exhibited diverse alkyl substituents and sizable electron-donating substituents, contributing to their varied chemical structures and potential applications. The dual Donor-π bridge -Acceptor group sensitizers, Zn[5,15-diphenylcarbazole-10,20-(4-carboxyphenyl) Porphyrin] (KSR-1) and Zn [5,15-thiadiazole-10,20-(4-carboxyphenyl) Porphyrin] (KSR-2) have been synthesized and adopted for DSSCs implementation. The molar absorption coefficients (ε) of KSR-2 and KSR-1 Soret bands were 0.56 x 105 mol/L/cm and 0.47 x 105 mol/L/cm, respectively. The Q bands of the KSR-1 and KSR-2 dyes were 1.10 x 105 mol/L/cm and 1.0 x 105 mol/L/cm, respectively and the molar absorption coefficient of the KSR-1 dye was greater when compared to the KSR-2 dye. The molar absorption coefficient of 0.71 x 105 mol/L/cm was visible in the KSR -1 Q-band. DFT calculations and the electrochemical characteristics of the KSR-1 and KSR-2 dyes have been studied and discussed. The exploration involved in investigating the photophysical properties and photovoltaic performance which were affected by varying the length and number of the donor entities. The wall-plug efficiency of the KSR-1 based solar panel was Voc = 0.68 V, Jsc = 8.94 mA/m2, FF = 56 and Efficiency (µ) = 3.44%. The wall-plug efficiency of the KSR-2 based solar panel was Voc = 0.63 V, Jsc = 5.42 mA/m2, FF = 53 and Efficiency (µ) = 1.83%.

Distinct concentration-dependent oxidative stress profiles by cadmium in a rat kidney proximal tubule cell line.

Levels and chemical species of reactive oxygen/nitrogen species (ROS/RNS) determine oxidative eustress and distress. Abundance of uptake pathways and high oxygen consumption for ATP-dependent transport makes the renal proximal tubule particularly susceptible to cadmium (Cd2+)-induced oxidative stress by targeting ROS/RNS generation or antioxidant defence mechanisms, such as superoxide dismutase (SOD) or H2O2-metabolizing catalase (CAT). Though ROS/RNS are well-evidenced, the role of distinct ROS profiles in Cd2+ concentration-dependent toxicity is not clear. In renal cells, Cd2+ (10-50 µM) oxidized dihydrorhodamine 123, reaching a maximum at 2-3 h. Increases (up to fourfold) in lipid peroxidation by TBARS assay and H2O2 by Amplex Red were evident within 30 min. ROS and loss in cell viability by MTT assay with 50 µM Cd2+ could not be fully reversed by SOD mimetics Tempol and MnTBAP nor by SOD1 overexpression, whereas CAT expression and α-tocopherol were effective. SOD and CAT activities were attenuated below controls only with >6 h 50 µM Cd2+, yet augmented by up to 1.5- and 1.2-fold, respectively, by 10 µM Cd2+. Moreover, 10 µM, but not 25-50 µM Cd2+, caused 1.7-fold increase in superoxide anion (O2•-), detected by dihydroethidium, paralled by loss in cell viability, that was abolished by Tempol, MnTBAP, α-tocopherol and SOD1 or CAT overexpression. H2O2-generating NADPH oxidase 4 (NOX4) was attenuated by ~50% with 10 µM Cd2+ at 3 h compared to upregulation by 50 µM Cd2+ (~1.4-fold, 30 min), which was sustained for 24 h. In summary, O2•- predominates with low-moderate Cd2+, driving an adaptive response, whereas oxidative stress by elevated H2O2 at high Cd2+ triggers cell death signaling pathways.Highlights Different levels of reactive oxygen species are generated, depending on cadmium concentration. Superoxide anion predominates and H2O2 is suppressed with low cadmium representing oxidative eustress. High cadmium fosters H2O2 by inhibiting catalase and increasing NOX4 leading to oxidative distress. Superoxide dismutase mimetics and overexpression were less effective with high versus low cadmium. Oxidative stress profile could dictate downstream signalling pathways.

De novo biosynthesis of a nonnatural cobalt porphyrin cofactor in E. coli and incorporation into hemoproteins.

Enzymes that bear a nonnative or artificially introduced metal center can engender novel reactivity and enable new spectroscopic and structural studies. In the case of metal-organic cofactors, such as metalloporphyrins, no general methods exist to build and incorporate new-to-nature cofactor analogs in vivo. We report here that a common laboratory strain, Escherichia coli BL21(DE3), biosynthesizes cobalt protoporphyrin IX (CoPPIX) under iron-limited, cobalt-rich growth conditions. In supplemented minimal media containing CoCl2, the metabolically produced CoPPIX is directly incorporated into multiple hemoproteins in place of native heme b (FePPIX). Five cobalt-substituted proteins were successfully expressed with this new-to-nature cobalt porphyrin cofactor: myoglobin H64V V68A, dye decolorizing peroxidase, aldoxime dehydratase, cytochrome P450 119, and catalase. We show conclusively that these proteins incorporate CoPPIX, with the CoPPIX making up at least 95% of the total porphyrin content. In cases in which the native metal ligand is a sulfur or nitrogen, spectroscopic parameters are consistent with retention of native metal ligands. This method is an improvement on previous approaches with respect to both yield and ease-of-implementation. Significantly, this method overcomes a long-standing challenge to incorporate nonnatural cofactors through de novo biosynthesis. By utilizing a ubiquitous laboratory strain, this process will facilitate spectroscopic studies and the development of enzymes for CoPPIX-mediated biocatalysis.

Photoelectrochemical immunoassay of cardiac troponin I based on ZnTCPP/CdIn2S4 type-II heterojunction and co-catalyzed precipitation biolabeling.

CdIn2S4 and zinc tetrakis(4-carboxyphenyl)porphyrin (ZnTCPP) were synthesized by hydrothermal method, and an organic dye-sensitized inorganic semiconductor ZnTCPP/CdIn2S4 type II heterojunction was constructed on a fluorine-doped tin oxide (FTO) substrate electrode. A sandwich immunostructure for signal-attenuation photoelectrochemical (PEC) detection of cardiac troponin I (cTnI) was constructed using the ZnTCPP/CdIn2S4/FTO photoanode and a horseradish peroxidase (HRP)-ZnFe2O4-Ab2-bovine serum albumin (BSA) immunolabeling complex. The bioenzyme HRP and the HRP-like nanozyme ZnFe2O4 can co-catalyze the oxidation of 4-chloro-1-naphthol (4-CN) by H2O2 to produce an insoluble precipitate on the photoanode, thus notably reducing the anodic photocurrent for quantitative determination of cTnI. Under the optimal conditions, the photocurrent at 0 V vs. SCE in 0.1 M phosphate buffer solution (pH 7.40) containing 0.1 M ascorbic acid was linear with the logarithm of cTnI concentration from 500 fg mL-1 to 50.0 ng mL-1, and the limit of detection (LOD, S/N = 3) is 0.15 pg mL-1. Spiked recoveries were 95.1% ~ 104% for assay of cTnI in human serum samples.

Reactivity Factors in Catalytic Methanogenesis and Their Tuning upon Coenzyme F430 Biosynthesis.

Methyl-coenzyme M reductase, responsible for the biological production of methane by catalyzing the reaction between coenzymes B (CoBS-H) and M (H3C-SCoM), hosts in its core an F430 cofactor with the low-valent NiI ion. The critical methanogenic step involves F430-assisted reductive cleavage of the H3C-S bond in coenzyme M, yielding the transient CH3 radical capable of hydrogen atom abstraction from the S-H bond in coenzyme B. Here, we computationally explored whether and why F430 is unique for methanogenesis in comparison to four identified precursors formed consecutively during its biosynthesis. Indeed, all precursors are less proficient than the native F430, and catalytic competence improves at each biosynthetic step toward F430. Against the expectation that F430 is tuned to be the strongest possible reductant to expedite the rate-determining reductive cleavage of H3C-S by NiI, we discovered the opposite. The unfavorable increase in reduction potential along the F430 biosynthetic pathway is outweighed by strengthening of the Ni-S bond formed upon reductive cleavage of the H3C-S bond. We found that F430 is the weakest electron donor, compared to its precursors, giving rise to the most covalent Ni-S bond, which stabilizes the transition state and hence reduces the rate-determining barrier. In addition, the transition state displays high pro-reactive motion of the transient CH3 fragment toward the H-S bond, superior to its biosynthetic ancestors and likely preventing the formation of a deleterious radical intermediate. Thus, we show a plausible view of how the evolutionary driving force shaped the biocatalytic proficiency of F430 toward CH4 formation.

SERS Tracking Oxidative Stress on a Metalloporphyrin Framework by Vitamin C.

Accurate control of charge transfer is crucial to investigate the catalytic reaction mechanism of the biological oxidation process that biomedicine participates in. Herein, we have established an assembly model of metalloporphyrin framework (MPF) nanosheets as the active centers of biological enzymes. The introduction of Vitamin C (VC) into the MPF system can precisely modulate its content of charges. The surface-enhanced Raman scattering activity and peroxidase-like catalytic performance are enhanced simultaneously for the first time by manipulating the optimal molar ratio of an MPF to VC and the reaction sequence with target model molecules. We have confirmed that the formation of the intermediate of Fe(2+)-OOH species is specifically enhanced after VC modulation, which indicates that VC can regulate the oxidative stress of the active center of biological enzymes. This discovery not only accurately resolves the mechanism of VC-selective anticancer therapy but also has important significance for the precise treatment of VC synergistic targeting medicines.

Metalloporphyrins as Catalytic Models for Studying Hydrogen and Oxygen Evolution and Oxygen Reduction Reactions.

The hydrogen evolution reaction (HER), oxygen evolution reaction (OER), and oxygen reduction reaction (ORR) are involved in biological and artificial energy conversions. H-H and O-O bond formation/cleavage are essential steps in these reactions. In nature, intermediates involved in the H-H and O-O bond formation/cleavage are highly reactive and short-lived, making their identification and investigation difficult. In artificial catalysis, the realization of these reactions at considerable rates and close to their thermodynamic reaction equilibria remains a challenge. Therefore, the elucidation of the reaction mechanisms and structure-function relationships is of fundamental significance to understand these reactions and to develop catalysts.This Account describes our recent investigations on catalytic HER, OER, and ORR with metalloporphyrins and derivatives. Metalloporphyrins are used in nature for light harvesting, energy conversion, electron transfer, O2 activation, and peroxide degradation. Synthetic metal porphyrin complexes are shown to be active for these reactions. We focused on exploring metalloporphyrins to study reaction mechanisms and structure-function relationships because they have stable and tunable structures and characteristic spectroscopic properties.For HER, we identified three H-H bond formation mechanisms and established the correlation between these processes and metal hydride electronic structures. Importantly, we provided direct experimental evidence for the bimetallic homolytic H-H bond formation mechanism by using sterically bulky porphyrins. Homolytic HER has been long proposed but rarely verified because the coupling of active hydride intermediates occurs spontaneously and quickly, making their detection challenging. By blocking the bimolecular mechanism through steric effects, we stabilized and characterized the NiIII-H intermediate and verified homolytic HER by comparing the reaction behaviors of Ni porphyrins with and without steric effects. We therefore provided an unprecedented example to control homolytic versus heterolytic HER mechanisms through tuning steric effects of molecular catalysts.For the OER, the water nucleophilic attack (WNA) on high-valent terminal Mn-oxo has been proposed for the O-O bond formation in natural and artificial water oxidation. By using Mn tris(pentafluorophenyl)corrole, we identified MnV(O) and MnIV-peroxo intermediates in chemical and electrochemical OER and provided direct experimental evidence for the Mn-based WNA mechanism. Moreover, we demonstrated several catalyst design strategies to enhance the WNA rate, including the pioneering use of protective axial ligands. By studying Cu porphyrins, we proposed a bimolecular coupling mechanism between two metal-hydroxide radicals to form O-O bonds. Note that late-transition metals do not likely form terminal metal-oxo/oxyl.For the ORR, we presented several strategies to improve activity and selectivity, including providing rapid electron transfer, using electron-donating axial ligands, introducing hydrogen-bonding interactions, constructing dinuclear cooperation, and employing porphyrin-support domino catalysis. Importantly, we used Co porphyrin atropisomers to realize both two-electron and four-electron ORR, representing an unparalleled example to control ORR selectivity by tuning only steric effects without modifying molecular and/or electronic structures.Lastly, we developed several strategies to graft metalloporphyrins on various electrode materials through different covalent bonds. The molecular-engineered materials exhibit boosted electrocatalytic performance, highlighting promising applications of molecular electrocatalysis. Taken together, this Account demonstrates the benefits of exploring metalloporphyrins for the HER, OER, and ORR. The knowledge learned herein is valuable for the development of porphyrin-based catalysts and also other molecular and material catalysts for small molecule activation reactions.

Dynamic Metalloporphyrin-Based [2]Rotaxane Molecular Shuttles Stimulated by Neutral Lewis Base and Anion Coordination.

A series of dynamic metalloporphyrin [2]rotaxane molecular shuttles comprising of bis-functionalised Zn(II) porphyrin axle and pyridyl functionalised macrocycle components are prepared in high yield via active metal template synthetic methodology. Extensive variable temperature 1 H NMR and quantitative UV-Vis spectroscopic titration studies demonstrate dynamic macrocycle translocation is governed by an inter-component co-ordination interaction between the macrocycle pyridyl and axle Zn(II) metalloporphyrin, which serves to bias a 'resting state' co-conformation. The dynamic shuttling behaviour of the interlocked structures is dramatically inhibited by the addition of a neutral Lewis base such as pyridine, but can also be tuned via post-synthetic rotaxane demetallation of the porphyrin axle core to give free-base, or upon subsequent metallation, Ni(II) [2]rotaxane analogues. Importantly, the Lewis acidic Zn(II) porphyrin axle component is also capable of coordinating anions which induces mechanical bond shuttling behaviour resulting in a novel optical sensing response.

Metal Modulation: An Effortless Tactic for Refining Photoredox Catalysis in Living Cells.

The remarkable impact of photoredox catalytic chemistries has sparked a wave of innovation, opening doors to novel biotechnologies in the realm of catalytic antitumor therapy. Yet, the quest for novel photoredox catalysts (PCs) suitable for living systems, or the enhancement of catalytic efficacy in existing biocompatible PC systems, persists as a formidable challenge. Within this context, we introduce a readily applicable metal modulation strategy that significantly augments photoredox catalysis within living cells, exemplified by a set of metalloporphyrin complexes termed M-TCPPs (M = Zn, Mn, Ni, Co, Cu). Among these complexes, Zn-TCPP emerges as an exceptional catalyst, displaying remarkable photocatalytic activity in the oxidation of nicotinamide adenine dinucleotide (NADH), nicotinamide adenine dinucleotide phosphate (NADPH), and specific amino acids. Notably, comprehensive investigations reveal that Zn-TCPP's superior catalytic prowess primarily arises from the establishment of an efficient oxidative cycle for PC, in contrast to previously reported PCs engaged in reductive cycles. Moreover, theoretical calculations illuminate that amplified intersystem crossing rates and geometry alterations in Zn-TCPP contribute to its heightened photocatalytic performance. In vitro studies demonstrated that Zn-TCPP exhibits therapeutic potential and is found to be effective for photocatalytic antitumor therapy in both glioblastoma G98T cells and 3D multicellular spheroids. This study underscores the transformative role of "metal modulation" in advancing high-performance PCs for catalytic antitumor therapy, marking a significant stride toward the realization of this innovative therapeutic approach.

Elucidation of the biosynthesis of the methane catalyst coenzyme F430.

Methane biogenesis in methanogens is mediated by methyl-coenzyme M reductase, an enzyme that is also responsible for the utilization of methane through anaerobic methane oxidation. The enzyme uses an ancillary factor called coenzyme F430, a nickel-containing modified tetrapyrrole that promotes catalysis through a methyl radical/Ni(ii)-thiolate intermediate. However, it is unclear how coenzyme F430 is synthesized from the common primogenitor uroporphyrinogen iii, incorporating 11 steric centres into the macrocycle, although the pathway must involve chelation, amidation, macrocyclic ring reduction, lactamization and carbocyclic ring formation. Here we identify the proteins that catalyse the biosynthesis of coenzyme F430 from sirohydrochlorin, termed CfbA-CfbE, and demonstrate their activity. The research completes our understanding of how the repertoire of tetrapyrrole-based pigments are constructed, permitting the development of recombinant systems to use these metalloprosthetic groups more widely.

Oxidation Products from the Neolignan Licarin A by Biomimetic Reactions and Assessment of in vivo Acute Toxicity.

Licarin A, a dihydrobenzofuranic neolignan presents in several medicinal plants and seeds of nutmeg, exhibits strong activity against protozoans responsible for Chagas disease and leishmaniasis. From biomimetic reactions by metalloporphyrin and Jacobsen catalysts, seven products were determined: four isomeric products yielded by epoxidation from licarin A, besides a new product yielded by a vicinal diol, a benzylic aldehyde, and an unsaturated aldehyde in the structure of the licarin A. The incubation with rat and human liver microsomes partially reproduced the biomimetic reactions by the production of the same epoxidized product of m/z 343 [M + H]+. In vivo acute toxicity assays of licarin A suggested liver toxicity based on biomarker enzymatic changes. However, microscopic analysis of tissues sections did not show any tissue damage as indicative of toxicity after 14 days of exposure. New metabolic pathways of the licarin A were identified after in vitro biomimetic oxidation reaction and in vitro metabolism by rat or human liver microsomes.

Oxaliplatin Pt(IV) prodrugs conjugated to gadolinium-texaphyrin as potential antitumor agents.

Described here is the development of gadolinium(III) texaphyrin-platinum(IV) conjugates capable of overcoming platinum resistance by 1) localizing to solid tumors, 2) promoting enhanced cancer cell uptake, and 3) reactivating p53 in platinum-resistant models. Side by side comparative studies of these Pt(IV) conjugates to clinically approved platinum(II) agents and previously reported platinum(II)-texaphyrin conjugates demonstrate that the present Pt(IV) conjugates are more stable against hydrolysis and nucleophilic attack. Moreover, they display high potent antiproliferative activity in vitro against human and mouse cell cancer lines. Relative to the current platinum clinical standard of care (SOC), a lead Gd(III) texaphyrin-Pt(IV) prodrug conjugate emerging from this development effort was found to be more efficacious in subcutaneous (s.c.) mouse models involving both cell-derived xenografts and platinum-resistant patient-derived xenografts. Comparative pathology studies in mice treated with equimolar doses of the lead Gd texaphyrin-Pt(IV) conjugate or the US Food and Drug Administration (FDA)-approved agent oxaliplatin revealed that the conjugate was better tolerated. Specifically, the lead could be dosed at more than three times (i.e., 70 mg/kg per dose) the tolerable dose of oxaliplatin (i.e., 4 to 6 mg/kg per dose depending on the animal model) with little to no observable adverse effects. A combination of tumor localization, redox cycling, and reversible protein binding is invoked to explain the relatively increased tolerability and enhanced anticancer activity seen in vivo. On the basis of the present studies, we conclude that metallotexaphyrin-Pt conjugates may have substantial clinical potential as antitumor agents.