Manganese-porphyrin and -salen redox therapeutics catalyze redox reactions involving O
˙
, H
O
, and other reactive oxygen species, thereby modulating cellular redox states. Many of these complexes ...perform catalase reactions
high-valent Mn-oxo or -hydroxo intermediates that oxidize H
O
to O
, but these intermediates can also oxidize other molecules (
, thiols), which is peroxidase reactivity. Whether catalase or peroxidase reactivity predominates depends on the metal-ligand set and the local environment, complicating predictions of what therapeutic effects (
, promoting
suppressing apoptosis) a complex might produce in a given disease. We recently reported an organoruthenium complex (Ru1) that catalyzes ABTS˙
reduction to ABTS
with H
O
as the terminal reductant. Given that H
O
is thermodynamically a stronger oxidant than ABTS˙
, we reasoned that the intermediate that reduced ABTS˙
would also be able to reduce H
O
to H
O. Herein we demonstrate Ru1-catalyzed H
O
disproportionation into O
and H
O, exhibiting an 8,580-fold faster catalase TOF
peroxidase TOF, which is 89.2-fold greater than the highest value reported for a Mn-porphyin or -salen complex. Furthermore, Ru1 was 120-fold more stable to H
O
than the best MnSOD mimic (TON = 4000
33.4) Mechanistic studies provide evidence that the mechanism for Ru1-catalyzed H
O
disproportionation is conserved with the mechanism for ABTS˙
reduction. Therapeutic effects of redox catalysts can be predicted with greater accuracy for catalysts that exhibit exclusively catalase activity, thereby facilitating the development of future redox therapeutic strategies for diseases.
This review is centered on the antioxidant enzyme catalase and will present different aspects of this particular protein. Among them: historical discovery, biological functions, types of catalases ...and recent data with regard to molecular mechanisms regulating its expression. The main goal is to understand the biological consequences of chronic exposure of cells to hydrogen peroxide leading to cellular adaptation. Such issues are of the utmost importance with potential therapeutic extrapolation for various pathologies. Catalase is a key enzyme in the metabolism of H
and reactive nitrogen species, and its expression and localization is markedly altered in tumors. The molecular mechanisms regulating the expression of catalase, the oldest known and first discovered antioxidant enzyme, are not completely elucidated. As cancer cells are characterized by an increased production of reactive oxygen species (ROS) and a rather altered expression of antioxidant enzymes, these characteristics represent an advantage in terms of cell proliferation. Meanwhile, they render cancer cells particularly sensitive to an oxidant insult. In this context, targeting the redox status of cancer cells by modulating catalase expression is emerging as a novel approach to potentiate chemotherapy.
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► We model the catalase reaction by ab initio QM/MM metadynamics. ► Reduction of Compound I can follow two distinct pathways. ► The reaction proceeds by two one-electron transfers. ► ...Electron transfer to Compound I facilitates protonation of the oxoferryl group.
Catalases are ubiquitous enzymes that prevent cell oxidative damage by degrading hydrogen peroxide to water and oxygen (2H2O2 → 2H2O+O2) with high efficiency. The enzyme is first oxidized to a high-valent iron intermediate, known as Compound I (Cpd I, Por+–FeIV=O) which, at difference from other hydroperoxidases, is reduced back to the resting state by further reacting with H2O2. The normal catalase activity is reduced if Cpd I is consumed in a competing side reaction, forming a species named Cpd I∗. In recent years, Density Functional Theory (DFT) methods have unraveled the electronic configuration of these high-valent iron species, helping to assign the intermediates trapped in the crystal structures of oxidized catalases. It has been demonstrated that the a priori assumption that the H+/H− type of mechanism for Cpd I reduction leads to the generation of singlet oxygen is not justified. Moreover, it has been shown by ab initio metadynamics simulations that two pathways are operative for Cpd I reduction: a His-mediated mechanism (described as H·/H++e−) in which the distal His acts as an acid–base catalyst and a direct mechanism (described as H·/H·) in which the distal His does not play a direct role. Independently of the mechanism, the reaction proceeds by two one-electron transfers rather than one two-electron transfer, as previously assumed. Electron transfer to Cpd I, regardless of whether the electron is exogenous or endogenous, facilitates protonation of the oxoferryl group, to the point that formation of Cpd I∗ may be controlled by the easiness of protonation of reduced Cpd I.
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► Detailed molecular evolution of metalloenzymes that catalyse the dismutation of hydrogen peroxide. ► Three protein families of differing structure, catalytic mechanism, distribution ...and evolutionary age. ► Catalatic enzymes in pathogenic organisms are promising targets for drug design. ► Occurrence of biotechnological interesting representatives in extremophiles.
For efficient removal of intra- and/or extracellular hydrogen peroxide by dismutation to harmless dioxygen and water (2H2O2→O2+2H2O), nature designed three metalloenzyme families that differ in oligomeric organization, monomer architecture as well as active site geometry and catalytic residues. Here we report on the updated reconstruction of the molecular phylogeny of these three gene families. Ubiquitous typical (monofunctional) heme catalases are found in all domains of life showing a high structural conservation. Their evolution was directed from large subunit towards small subunit proteins and further to fused proteins where the catalase fold was retained but lost its original functionality. Bifunctional catalase–peroxidases were at the origin of one of the two main heme peroxidase superfamilies (i.e. peroxidase–catalase superfamily) and constitute a protein family predominantly present among eubacteria and archaea, but two evolutionary branches are also found in the eukaryotic world. Non-heme manganese catalases are arelatively small protein family with very old roots only present among bacteria and archaea. Phylogenetic analyses of the three protein families reveal features typical (i) for the evolution of whole genomes as well as (ii) for specific evolutionary events including horizontal gene transfer, paralog formation and gene fusion. As catalases have reached a striking diversity among prokaryotic and eukaryotic pathogens, understanding their phylogenetic and molecular relationship and function will contribute to drug design for prevention of diseases of humans, animals and plants.
Photodynamic therapy (PDT) typically involves oxygen (O2) consumption and therefore suffers from greatly limited anticancer therapeutic efficacy in tumor hypoxia. Here, it is reported for the first ...time that amine‐terminated, PAMAM dendrimer‐encapsulated gold nanoclusters (AuNCs‐NH2) can produce O2 for PDT via their intrinsic catalase‐like activity. The AuNCs‐NH2 not only show optimum H2O2 consumption via the catalase‐like activity over the physiological pH range (i.e., pH 4.8–7.4), but also extend such activity to acidic conditions. The possible mechanism is deduced from that the enriched tertiary amines of dendrimers are easily protonated in acidic solutions to facilitate the preadsorption of OH on the metal surface, thereby favorably triggering the catalase‐like reaction. By taking advantage of the exciting feature on AuNCs‐NH2, the possibility to supply O2 via the catalase‐like activity of AuNCs‐NH2 for PDT against hypoxia of cancer cells was further studied. This proof‐of‐concept study provides a simple way to combine current O2‐dependent cancer therapy of PDT to overcome cancer cell hypoxia, thus achieving more effective anticancer treatments.
PAMAM dendrimer‐encapsulated gold nanoclusters (AuNCs‐NH2) exhibit their catalase‐like activity over a pH range relevant to biological microenvironments (i.e., pH 4.8–7.4), such that AuNCs‐NH2 can catalyze physiological hydrogen peroxide (H2O2) to produce O2 that self‐supplies for photodynamic therapy against hypoxic cancer cells.
Exosomes are naturally occurring nanosized vesicles that have attracted considerable attention as drug delivery vehicles in the past few years. Exosomes are comprised of natural lipid bilayers with ...the abundance of adhesive proteins that readily interact with cellular membranes. We posit that exosomes secreted by monocytes and macrophages can provide an unprecedented opportunity to avoid entrapment in mononuclear phagocytes (as a part of the host immune system), and at the same time enhance delivery of incorporated drugs to target cells ultimately increasing drug therapeutic efficacy. In light of this, we developed a new exosomal-based delivery system for a potent antioxidant, catalase, to treat Parkinson's disease (PD). Catalase was loaded into exosomes ex vivo using different methods: the incubation at room temperature, permeabilization with saponin, freeze–thaw cycles, sonication, or extrusion. The size of the obtained catalase-loaded exosomes (exoCAT) was in the range of 100–200nm. A reformation of exosomes upon sonication and extrusion, or permeabilization with saponin resulted in high loading efficiency, sustained release, and catalase preservation against proteases degradation. Exosomes were readily taken up by neuronal cells in vitro. A considerable amount of exosomes was detected in PD mouse brain following intranasal administration. ExoCAT provided significant neuroprotective effects in in vitro and in vivo models of PD. Overall, exosome-based catalase formulations have a potential to be a versatile strategy to treat inflammatory and neurodegenerative disorders.
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Metal-organic frameworks (MOFs) have recently garnered consideration as an attractive solid substrate because the highly tunable MOF framework can not only serve as an inert host but also enhance the ...selectivity, stability, and/or activity of the enzymes. Herein, we demonstrate the advantages of using a mechanochemical strategy to encapsulate enzymes into robust MOFs. A range of enzymes, namely β-glucosidase, invertase, β-galactosidase, and catalase, are encapsulated in ZIF-8, UiO-66-NH
, or Zn-MOF-74 via a ball milling process. The solid-state mechanochemical strategy is rapid and minimizes the use of organic solvents and strong acids during synthesis, allowing the encapsulation of enzymes into three prototypical robust MOFs while maintaining enzymatic biological activity. The activity of encapsulated enzyme is demonstrated and shows increased resistance to proteases, even under acidic conditions. This work represents a step toward the creation of a suite of biomolecule-in-MOF composites for application in a variety of industrial processes.
Catalase is an important antioxidant enzyme that dismutates hydrogen peroxide into water and molecular oxygen. The catalase gene has all the characteristics of a housekeeping gene (no TATA box, no ...initiator element sequence, high GC content in promoter) and a core promoter that is highly conserved among species. We demonstrate in this review that within this core promoter, the presence of DNA binding sites for transcription factors, such as NF-Y and Sp1, plays an essential role in the positive regulation of catalase expression. Additional transcription factors, such as FoxO3a, are also involved in this regulatory process. There is strong evidence that the protein Akt/PKB in the PI3K signaling pathway plays a major role in the expression of catalase by modulating the activity of FoxO3a. Over the past decade, other transcription factors (PPARγ, Oct-1, etc.), as well as genetic, epigenetic, and posttranscriptional processes, have emerged as crucial contributors to the regulation of catalase expression. Altered expression levels of catalase have been reported in cancer tissues compared to their normal counterparts. Deciphering the molecular mechanisms that regulate catalase expression could, therefore, be of crucial importance for the future development of pro-oxidant cancer chemotherapy.
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•Multiple transcription factors control the expression of catalase.•Multiple mechanisms of regulation are involved in catalase expression.•Catalase expression is markedly altered and variable in tumors
Catalases play a key role in the defense against oxidative stress in bacteria by catalyzing the decomposition of H
O
. In addition, catalases are also involved in multiple cellular processes, such as ...cell development and differentiation, as well as metabolite production. However, little is known about the abundance, diversity, and distribution of catalases in bacteria. In this study, we systematically surveyed and classified the homologs of three catalase families from 2,634 bacterial genomes. It was found that both of the typical catalase and Mn-catalase families could be divided into distinct groups, while the catalase-peroxidase homologs formed a tight family. The typical catalases are rich in all the analyzed bacterial phyla except Chlorobi, in which the catalase-peroxidases are dominant. Catalase-peroxidases are rich in many phyla, but lacking in Deinococcus-Thermus, Spirochetes, and Firmicutes. Mn-catalases are found mainly in Firmicutes and Deinococcus-Thermus, but are rare in many other phyla. Given the fact that catalases were reported to be involved in secondary metabolite biosynthesis in several
strains, the distribution of catalases in the genus
was given more attention herein. On average, there are 2.99 typical catalases and 0.99 catalase-peroxidases in each
genome, while no Mn-catalases were identified. To understand detailed properties of catalases in
, we characterized all the five typical catalases from
ATCC 10970, the oxytetracycline-producing strain. The five catalases showed typical catalase activity, but possessed different catalytic properties. Our findings contribute to the more detailed classification of catalases and facilitate further studies about their physiological roles in secondary metabolite biosynthesis and other cellular processes, which might facilitate the yield improvement of valuable secondary metabolites in engineered bacteria.
Nanozyme‐based tumor catalytic therapy has attracted widespread attention in recent years. However, its therapeutic outcomes are diminished by many factors in the tumor microenvironment (TME), such ...as insufficient endogenous hydrogen peroxide (H2O2) concentration, hypoxia, and immunosuppressive microenvironment. Herein, an immunomodulation‐enhanced nanozyme‐based tumor catalytic therapy strategy is first proposed to achieve the synergism between nanozymes and TME regulation. TGF‐β inhibitor (TI)‐loaded PEGylated iron manganese silicate nanoparticles (IMSN) (named as IMSN‐PEG‐TI) are constructed to trigger the therapeutic modality. The results show that IMSN nanozyme exhibits both intrinsic peroxidase‐like and catalase‐like activities under acidic TME, which can decompose H2O2 into hydroxyl radicals (•OH) and oxygen (O2), respectively. Besides, it is demonstrated that both IMSN and TI can regulate the tumor immune microenvironment, resulting in macrophage polarization from M2 to M1, and thus inducing the regeneration of H2O2, which can promote catalytic activities of IMSN nanozyme. The potent antitumor effect of IMSN‐PEG‐TI is proved by in vitro multicellular tumor spheroids (MCTS) and in vivo CT26‐tumor‐bearing mice models. It is believed that the immunomodulation‐enhanced nanozyme‐based tumor treatment strategy is a promising tool to kill cancer cells.
An immunomodulation‐enhanced nanozyme‐based tumor catalytic treatment strategy is developed to fight against cancer. By regulating the tumor immune microenvironment, an increased generation level of hydrogen peroxide is demonstrated, thus effectively improving the catalytic activities of iron manganese silicate nanoparticle nanozymes. As a result, a high tumor therapeutic effect with a tumor inhibition rate of 87.5% is achieved.
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