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Nature Chemical Biology Jul 2021
Topics: Heme; Iron
PubMed: 34103722
DOI: 10.1038/s41589-021-00821-7 -
Biophysical Journal Mar 2020
Topics: Heme; Hemoglobins; Humans; RNA, Viral; Virus Assembly
PubMed: 32070479
DOI: 10.1016/j.bpj.2019.12.041 -
Critical Reviews in Biochemistry and... Feb 2022Heme is an essential biomolecule and cofactor involved in a myriad of biological processes. In this review, we focus on how heme binding to heme regulatory motifs... (Review)
Review
Heme is an essential biomolecule and cofactor involved in a myriad of biological processes. In this review, we focus on how heme binding to heme regulatory motifs (HRMs), catalytic sites, and gas signaling molecules as well as how changes in the heme redox state regulate protein structure, function, and degradation. We also relate these heme-dependent changes to the affected metabolic processes. We center our discussion on two HRM-containing proteins: human heme oxygenase-2, a protein that binds and degrades heme (releasing Fe and CO) in its catalytic core and binds Fe-heme at HRMs located within an unstructured region of the enzyme, and the transcriptional regulator Rev-erbβ, a protein that binds Fe-heme at an HRM and is involved in CO sensing. We will discuss these and other proteins as they relate to cellular heme composition, homeostasis, and trafficking. In addition, we will discuss the HRM-containing family of proteins and how the stability and activity of these proteins are regulated in a dependent manner through the HRMs. Then, after reviewing CO-mediated protein regulation of heme proteins, we turn our attention to the involvement of heme, HRMs, and CO in circadian rhythms. In sum, we stress the importance of understanding the various roles of heme and the distribution of the different heme pools as they relate to the heme redox state, CO, and heme binding affinities.
Topics: Heme; Humans; Oxidation-Reduction; Protein Binding; Receptors, Cytoplasmic and Nuclear; Repressor Proteins
PubMed: 34517731
DOI: 10.1080/10409238.2021.1961674 -
Langmuir : the ACS Journal of Surfaces... Jun 2022As the oxidative stress is related to human aging and many diseases, a diversity of antioxidant biomimetic enzymes to eliminate reactive oxygen species in vivo and...
As the oxidative stress is related to human aging and many diseases, a diversity of antioxidant biomimetic enzymes to eliminate reactive oxygen species in vivo and maintain the redox balance has attracted intensive attention. Of particular interest are superoxide dismutase (SOD)-mimicking artificial enzymes that bear inherent characteristics of natural counterparts but overcome their deficiencies in thermal and acidic stability. Inspired by the metallized active center of natural SODs, here, we engineered different groups of metalloporphyrins and found that Sn-metallized porphyrins can act as novel SOD mimics, in which Sn-metallized meso-tetra(4-carboxyphenyl) porphine (Sn-TCPP) can more effectively catalyze the disproportionation of superoxide radical anions (•O) into hydrogen peroxide and oxygen. Especially, Sn-TCPP-based metal-organic frame nanozyme (Sn-PCN222) displays an unusually high catalytic activity that remarkably exceeds those of commonly used counterparts. Such unprecedented catalytic behaviors are proposed to depend on the Sn(IV)/Sn(II) transition at the center of Sn-TCPP. In addition, the metal-organic framework (MOF) nanozymes also display higher thermal and acidic stability than natural SODs. Interestingly, we find that Sn-complexed methylated tetra-(4-aminophenyl) porphyrin shows an aggregation-induced SOD activity in an acidic environment, whereas conventional SOD mimics do not function well in this case. Given these unique features, our reported Sn-porphyrin-based nanozymes would be potent alternatives for natural SODs to be widely used in clinical treatments of oxidative stress-related diseases.
Topics: Humans; Metalloporphyrins; Oxidation-Reduction; Oxygen; Porphyrins; Superoxide Dismutase; Tin
PubMed: 35638128
DOI: 10.1021/acs.langmuir.2c00778 -
Cell Communication and Signaling : CCS Jan 2024Red blood cells (RBCs) transfusion is related to perioperative neurocognitive disorders. The toxic effect of free heme has been identified in many pathologies. However,...
BACKGROUND
Red blood cells (RBCs) transfusion is related to perioperative neurocognitive disorders. The toxic effect of free heme has been identified in many pathologies. However, the underlying mechanisms of RBCs transfusion or free heme in cognitive impairment have not been clearly explored. Therefore, this research was conducted to determine the mechanism of free heme-induced neuroinflammation and cognitive impairment.
METHODS
Rats were received intraperitoneal injection of hemin alone or combined with intracerebroventricular injection of Hemopexin (HPX), and MWM test was conducted to measure cognitive function. The amount of heme-HPX complexes was evaluated by flow cytometry for CD91 + cells. The microglial inflammatory response in rat brain was observed by immunofluorescence staining of Iba-1, and the inflammatory factors of TNF-α, IL-1β and IL-6 in rat brain and BV2 cells were detected by ELISA analysis. Furthermore, neuronal apoptosis in HT22 cells alone and in HT22 + BV2 coculture system was detected by flow cytometry and immunofluorescence staining. Finally, western blot was conducted to detect TLR4/MyD88/NF-κB proteins in rat brain and BV2 cells treated with hemin or combined with pathway inhibitors. Additionally, the M1 surface marker CD86 was observed in BV2 cells to further confirm neuroinflammation.
RESULTS
Intraperitoneal injection of hemin induced cognitive impairment, increase of CD91 + cells, up-regulation of TNF-α and IL-1β, down-regulation of IL-6, activation of microglia, and activation of the TLR4/MyD88/NF-κB signaling pathway in rat brain. Significantly, intracerebroventricular injection of HPX reduced the above effects. Hemin induced boost of TNF-α, IL-1β and IL-6 in BV2 cells, as well as apoptosis in HT22 cells. Notably, when HT22 cells were cocultured with BV2 cells, apoptosis was significantly increased. Hemin also induced activation of the TLR4/MyD88/NF-κB signaling pathway and increased the M1 surface marker CD86 in BV2 cells, and inhibiting this pathway reduced the inflammatory responses.
CONCLUSIONS
Free heme induces cognitive impairment, and the underlying mechanism may involve neuronal apoptosis and microglial inflammation via the TLR4/MyD88/NF-κB signaling pathway. HPX may have potential therapeutic effects. Video Abstract.
Topics: Animals; Rats; NF-kappa B; Heme; Microglia; Myeloid Differentiation Factor 88; Hemin; Neuroinflammatory Diseases; Interleukin-6; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Adaptor Proteins, Signal Transducing; Cognitive Dysfunction; Signal Transduction
PubMed: 38183122
DOI: 10.1186/s12964-023-01387-8 -
Chemical Reviews Jul 2022Metalloenzymes catalyze a variety of reactions using a limited number of natural amino acids and metallocofactors. Therefore, the environment beyond the primary... (Review)
Review
Metalloenzymes catalyze a variety of reactions using a limited number of natural amino acids and metallocofactors. Therefore, the environment beyond the primary coordination sphere must play an important role in both conferring and tuning their phenomenal catalytic properties, enabling active sites with otherwise similar primary coordination environments to perform a diverse array of biological functions. However, since the interactions beyond the primary coordination sphere are numerous and weak, it has been difficult to pinpoint structural features responsible for the tuning of activities of native enzymes. Designing artificial metalloenzymes (ArMs) offers an excellent basis to elucidate the roles of these interactions and to further develop practical biological catalysts. In this review, we highlight how the secondary coordination spheres of ArMs influence metal binding and catalysis, with particular focus on the use of native protein scaffolds as templates for the design of ArMs by either rational design aided by computational modeling, directed evolution, or a combination of both approaches. In describing successes in designing heme, nonheme Fe, and Cu metalloenzymes, heteronuclear metalloenzymes containing heme, and those ArMs containing other metal centers (including those with non-native metal ions and metallocofactors), we have summarized insights gained on how careful controls of the interactions in the secondary coordination sphere, including hydrophobic and hydrogen bonding interactions, allow the generation and tuning of these respective systems to approach, rival, and, in a few cases, exceed those of native enzymes. We have also provided an outlook on the remaining challenges in the field and future directions that will allow for a deeper understanding of the secondary coordination sphere a deeper understanding of the secondary coordintion sphere to be gained, and in turn to guide the design of a broader and more efficient variety of ArMs.
Topics: Catalysis; Catalytic Domain; Heme; Metalloproteins; Metals
PubMed: 35816578
DOI: 10.1021/acs.chemrev.2c00106 -
ACS Sensors Nov 2021Early and effective malaria diagnosis is vital to control the disease spread and to prevent the emergence of severe cases and death. Currently, malaria diagnosis relies... (Review)
Review
Early and effective malaria diagnosis is vital to control the disease spread and to prevent the emergence of severe cases and death. Currently, malaria diagnosis relies on optical microscopy and immuno-rapid tests; however, these require a drop of blood, are time-consuming, or are not specific and sensitive enough for reliable detection of low-level parasitaemia. Thus, there is an urge for simpler, prompt, and accurate alternative diagnostic methods. Particularly, hemozoin has been increasingly recognized as an attractive biomarker for malaria detection. As the disease proliferates, parasites digest host hemoglobin, in the process releasing toxic haem that is detoxified into an insoluble crystal, the hemozoin, which accumulates along with infection progression. Given its magnetic, optical, and acoustic unique features, hemozoin has been explored for new label-free diagnostic methods. Thereby, herein, we review the hemozoin-based malaria detection methods and critically discuss their challenges and potential for the development of an ideal diagnostic device.
Topics: Heme; Hemeproteins; Humans; Malaria; Microscopy
PubMed: 34735120
DOI: 10.1021/acssensors.1c01750 -
Redox Biology Nov 2023We recently reported a previously unknown salutary role for xanthine oxidoreductase (XOR) in intravascular heme overload whereby hepatocellular export of XOR to the...
We recently reported a previously unknown salutary role for xanthine oxidoreductase (XOR) in intravascular heme overload whereby hepatocellular export of XOR to the circulation was identified as a seminal step in affording protection. However, the cellular signaling and export mechanisms underpinning this process were not identified. Here, we present novel data showing hepatocytes upregulate XOR expression/protein abundance and actively release it to the extracellular compartment following exposure to hemopexin-bound hemin, hemin or free iron. For example, murine (AML-12 cells) hepatocytes treated with hemin (10 μM) exported XOR to the medium in the absence of cell death or loss of membrane integrity (2.0 ± 1.0 vs 16 ± 9 μU/mL p < 0.0001). The path of exocytosis was found to be noncanonical as pretreatment of the hepatocytes with Vaculin-1, a lysosomal trafficking inhibitor, and not Brefeldin A inhibited XOR release and promoted intracellular XOR accumulation (84 ± 17 vs 24 ± 8 hemin vs 5 ± 3 control μU/mg). Interestingly, free iron (Fe and Fe) induced similar upregulation and release of XOR compared to hemin. Conversely, concomitant treatment with hemin and the classic transition metal chelator DTPA (20 μM) or uric acid completely blocked XOR release (p < 0.01). Our previously published time course showed XOR release from hepatocytes likely required transcriptional upregulation. As such, we determined that both Sp1 and NF-kB were acutely activated by hemin treatment (∼2-fold > controls for both, p < 0.05) and that silencing either or TLR4 with siRNA prevented hemin-induced XOR upregulation (p < 0.01). Finally, to confirm direct action of these transcription factors on the Xdh gene, chromatin immunoprecipitation was performed indicating that hemin significantly enriched (∼5-fold) both Sp1 and NF-kB near the transcription start site. In summary, our study identified a previously unknown pathway by which XOR is upregulated via SP1/NF-kB and subsequently exported to the extracellular environment. This is, to our knowledge, the very first study to demonstrate mechanistically that XOR can be specifically targeted for export as the seminal step in a compensatory response to heme/Fe overload.
Topics: Animals; Mice; Xanthine Dehydrogenase; Hemin; Iron; NF-kappa B; Heme; Hepatocytes
PubMed: 37703667
DOI: 10.1016/j.redox.2023.102866 -
The FEBS Journal Jun 2021Heme is an iron-containing complex involved in fundamental cellular functions including oxygen transport. Free heme accumulation in blood, during intravascular hemolysis...
Heme is an iron-containing complex involved in fundamental cellular functions including oxygen transport. Free heme accumulation in blood, during intravascular hemolysis and other pathological conditions, triggers vascular dysfunction, pro-inflammatory, and prothrombotic cascade. Studies by May et al present a novel finding that heme is a ligand for RAGE and that heme binds to the V domain of RAGE and induces RAGE oligomerization. Furthermore, they show that the in vivo consequences of heme-RAGE interaction lead to a pro-inflammatory and procoagulant phenotype in the lungs. This discovery of heme as a ligand for RAGE sets the stage for probing the role of RAGE in heme homeostasis and the pathogenic role of heme-RAGE interaction in hemolytic diseases.
Topics: Heme; Ligands; Receptor for Advanced Glycation End Products
PubMed: 33565264
DOI: 10.1111/febs.15723 -
Faraday Discussions May 2021We discuss our recently reported femtosecond (fs) X-ray emission spectroscopy results on the ligand dissociation and recombination in nitrosylmyoglobin (MbNO) in the...
We discuss our recently reported femtosecond (fs) X-ray emission spectroscopy results on the ligand dissociation and recombination in nitrosylmyoglobin (MbNO) in the context of previous studies on ferrous haem proteins. We also present a preliminary account of femtosecond X-ray absorption studies on MbNO, pointing to the presence of more than one species formed upon photolysis.
Topics: Heme; Ligands; Photolysis; Spectrum Analysis; X-Rays
PubMed: 33565544
DOI: 10.1039/d0fd00131g