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1.
Peroxidase Activity of Human Hemoproteins: Keeping the Fire under Control.
Vlasova, II
Molecules (Basel, Switzerland). 2018;(10)
Abstract
The heme in the active center of peroxidases reacts with hydrogen peroxide to form highly reactive intermediates, which then oxidize simple substances called peroxidase substrates. Human peroxidases can be divided into two groups: (1) True peroxidases are enzymes whose main function is to generate free radicals in the peroxidase cycle and (pseudo)hypohalous acids in the halogenation cycle. The major true peroxidases are myeloperoxidase, eosinophil peroxidase and lactoperoxidase. (2) Pseudo-peroxidases perform various important functions in the body, but under the influence of external conditions they can display peroxidase-like activity. As oxidative intermediates, these peroxidases produce not only active heme compounds, but also protein-based tyrosyl radicals. Hemoglobin, myoglobin, cytochrome c/cardiolipin complexes and cytoglobin are considered as pseudo-peroxidases. Рeroxidases play an important role in innate immunity and in a number of physiologically important processes like apoptosis and cell signaling. Unfavorable excessive peroxidase activity is implicated in oxidative damage of cells and tissues, thereby initiating the variety of human diseases. Hence, regulation of peroxidase activity is of considerable importance. Since peroxidases differ in structure, properties and location, the mechanisms controlling peroxidase activity and the biological effects of peroxidase products are specific for each hemoprotein. This review summarizes the knowledge about the properties, activities, regulations and biological effects of true and pseudo-peroxidases in order to better understand the mechanisms underlying beneficial and adverse effects of this class of enzymes.
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2.
Porphyrias and photosensitivity: pathophysiology for the clinician.
Kakoullis, L, Louppides, S, Papachristodoulou, E, Panos, G
Postgraduate medicine. 2018;(8):673-686
Abstract
Porphyrias are disorders caused by defects in the biosynthetic pathway of heme. Their manifestations can be divided into three distinct syndromes, each attributable to the accumulation of three distinct classes of molecules. The acute neurovisceral syndrome is caused by the accumulation of the neurotoxic porphyrin precursors, delta aminolevulinic acid, and porphobilinogen; the syndrome of immediate painful photosensitivity is caused by the lipid-soluble protoporphyrin IX and, the syndrome of delayed blistering photosensitivity, caused by the water-soluble porphyrins, uroporphyrin, and coproporphyrin. Porphyrias can manifest with one, or with a combination, of these syndromes, depending on whether one or more types of molecules are being accumulated. Iron plays a significant role in some of these conditions, as evidenced by improvements in both clinical manifestations and laboratory parameters, following iron depletion in porphyria cutanea tarda, or iron administration in some cases of X-linked erythropoietic protoporphyria. While the pathophysiology of a specific type of porphyrias, the protoporphyrias, appears to favor the administration of zinc, results so far have been conflicting, necessitating further studies in order to assess its potential benefit. The pathways involved in each disease, as well as insights into their pathobiological processes are presented, with an emphasis on the development of photosensitivity reactions.
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3.
Design of a heme-binding peptide motif adopting a β-hairpin conformation.
Nagarajan, D, Sukumaran, S, Deka, G, Krishnamurthy, K, Atreya, HS, Chandra, N
The Journal of biological chemistry. 2018;(24):9412-9422
Abstract
Heme-binding proteins constitute a large family of catalytic and transport proteins. Their widespread presence as globins and as essential oxygen and electron transporters, along with their diverse enzymatic functions, have made them targets for protein design. Most previously reported designs involved the use of α-helical scaffolds, and natural peptides also exhibit a strong preference for these scaffolds. However, the reason for this preference is not well-understood, in part because alternative protein designs, such as those with β-sheets or hairpins, are challenging to perform. Here, we report the computational design and experimental validation of a water-soluble heme-binding peptide, Pincer-1, composed of predominantly β-scaffold secondary structures. Such heme-binding proteins are rarely observed in nature, and by designing such a scaffold, we simultaneously increase the known fold space of heme-binding proteins and expand the limits of computational design methods. For a β-scaffold, two tryptophan zipper β-hairpins sandwiching a heme molecule were linked through an N-terminal cysteine disulfide bond. β-Hairpin orientations and residue selection were performed computationally. Heme binding was confirmed through absorbance experiments and surface plasmon resonance experiments (KD = 730 ± 160 nm). CD and NMR experiments validated the β-hairpin topology of the designed peptide. Our results indicate that a helical scaffold is not essential for heme binding and reveal the first designed water-soluble, heme-binding β-hairpin peptide. This peptide could help expand the search for and design space to cytoplasmic heme-binding proteins.
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4.
Red Meat Consumption (Heme Iron Intake) and Risk for Diabetes and Comorbidities?
Misra, R, Balagopal, P, Raj, S, Patel, TG
Current diabetes reports. 2018;(11):100
Abstract
PURPOSE OF REVIEW To examine the role of red meat consumption, especially heme iron intake, and risk for diabetes and its comorbidities. RECENT FINDINGS Studies consistently show that consumption of red meat has been contributory to a multitude of chronic conditions such as diabetes, CVD, and malignancies. There are various emerging reasons that strengthen this link-from the basic constituents of red meat like the heme iron component, the metabolic reactions that take place after consumption, and finally to the methods used to cook it. The causative links show that even occasional use raises the risk of T2DM. Prior studies show how nitrites and nitrates in red meat can lead to increased insulin resistance, dysregulated blood glucose levels, and elevated oxidative stress all leading to chronic diseases. With the rise in these preventable chronic diseases, we examine how disease-causing links can be eliminated with appropriate lifestyle choices.
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5.
Lysine as a heme iron ligand: A property common to three truncated hemoglobins from Chlamydomonas reinhardtii.
Johnson, EA, Russo, MM, Nye, DB, Schlessman, JL, Lecomte, JTJ
Biochimica et biophysica acta. General subjects. 2018;(12):2660-2673
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Abstract
BACKGROUND The nuclear genome of Chlamydomonas reinhardtii encodes a dozen hemoglobins of the truncated lineage. Four of these, named THB1-4, contain a single ~130-residue globin unit. THB1, which is cytoplasmic and capable of nitric oxide dioxygenation activity, uses a histidine and a lysine as axial ligands to the heme iron. In the present report, we compared THB2, THB3, and THB4 to THB1 to gain structural and functional insights into algal globins. METHODS We inspected properties of the globin domains prepared by recombinant means through site-directed mutagenesis, electronic absorption, CD, and NMR spectroscopies, and X-ray crystallography. RESULTS Recombinant THB3, which lacks the proximal histidine but has a distal histidine, binds heme weakly. NMR data demonstrate that the recombinant domains of THB2 and THB4 coordinate the ferrous heme iron with the proximal histidine and a lysine from the distal helix. An X-ray structure of ferric THB4 confirms lysine coordination. THB1, THB2, and THB4 have reduction potentials between -65 and -100 mV, are capable of nitric oxide dioxygenation, are reduced at different rates by the diaphorase domain of C. reinhardtii nitrate reductase, and show different response to peroxide treatment. CONCLUSIONS Three single-domain C. reinhardtii hemoglobins use lysine as a distal heme ligand in both Fe(III) and Fe(II) oxidation states. This common feature is likely related to enzymatic activity in the management of reactive oxygen species. GENERAL SIGNIFICANCE Primary structure analysis of hemoglobins has limited power in the prediction of heme ligation. Experimental determination reveals variations in this essential property across the superfamily.
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6.
Alternative pathway linked by hydrogen bonds connects heme-Fe of cytochrome c with subunit II-CuA of cytochrome a.
Ramasarma, T, Vaigundan, D
Biochemical and biophysical research communications. 2018;(2):445-447
Abstract
The bridging element for electron transfer in proteins is the hydrogen bond according to the new experimental perspective in preference to carbon-carbon σ-bond presently used. The purpose of this study is to identify an alternative pathway linked by hydrogen bonds suitable for electron transfer from heme-Fe of cytochrome c to subunit II-CuA of cytochrome a. A pathway consisting of 15 delocalized electron systems including peptide bonds, 5 polar groups of side chains of amino acid residues and 8 water molecules, linked by 27 hydrogen bonds, exists between the two metal electron centers of heme-Fe of cytochrome c, cytochrome c and of subunit II-CuA of cytochrome a. Pathways built of delocalized π-electron systems, polar groups and water molecules linked by hydrogen bonds may be considered for intramolecular and intermolecular electron transfer in proteins.
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7.
Increased total iron and zinc intake and lower heme iron intake reduce the risk of esophageal cancer: A dose-response meta-analysis.
Ma, J, Li, Q, Fang, X, Chen, L, Qiang, Y, Wang, J, Wang, Q, Min, J, Zhang, S, Wang, F
Nutrition research (New York, N.Y.). 2018;:16-28
Abstract
Several epidemiological studies investigated the relationship between dietary intake of essential trace elements and the risk of esophageal cancer (EC), yielding inconsistent results. We therefore conducted a systematic meta-analysis to investigate and quantify the putative association between the intake of various essential trace elements and the risk of EC. We searched Embase, PubMed, and Web of Science for eligible articles published through April 2018 reporting the odds ratio (OR) with 95% confidence interval (95% CI). Pooled results were then calculated using fixed and random effect models. A total of 20 articles containing 4855 cases from 1 387 482 participants were included in our analysis. We found a significant inverse correlation between total iron intake and the risk of EC (OR = 0.81, 95% CI: 0.70-0.94), particularly in Asian populations. A dose-response analysis revealed that each 5 mg/day increase in total iron intake was associated with a 15% reduction in EC risk (OR = 0.85, 95% CI: 0.79-0.92). In contrast, each 1 mg/day increase in heme iron intake was associated with a 21% increase in EC risk (OR = 1.21, 95% CI: 1.02-1.45). Lastly, a pooled risk estimate revealed that each 5 mg/day increase in zinc intake was associated with a 15% reduction in EC risk (OR = 0.85, 95% CI: 0.77-0.93). Taken together, our analysis indicates that increased dietary intake of total iron and zinc, as well as decreased heme iron intake, may be associated with a lower risk of developing esophageal cancer. These findings have important public health implications with respect to preventing this relatively common form of cancer.
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8.
Association between pre-pregnancy consumption of meat, iron intake, and the risk of gestational diabetes: the SUN project.
Marí-Sanchis, A, Díaz-Jurado, G, Basterra-Gortari, FJ, de la Fuente-Arrillaga, C, Martínez-González, MA, Bes-Rastrollo, M
European journal of nutrition. 2018;(3):939-949
Abstract
PURPOSE We assessed the association of total meat, processed, and unprocessed red meat and iron intake with the risk of developing gestational diabetes mellitus (GDM) in pregnant women. METHODS We conducted a prospective study among 3298 disease-free Spanish women participants of the SUN cohort who reported at least one pregnancy between December 1999 and March 2012. Meat consumption and iron intake were assessed at baseline through a validated, 136-item semi-quantitative, food frequency questionnaire. We categorized total, red, and processed meat consumption and iron intake into quartiles. Logistic regression models were used to adjust for potential confounders. RESULTS We identified 172 incident cases of GDM. In the fully adjusted analysis, total meat consumption was significantly associated with a higher risk of GDM [OR = 1.67 (95% CI 1.06-2.63, p-trend 0.010)] for the highest versus the lowest quartile of consumption. The observed associations were particularly strong for red meat consumption [OR = 2.37 (95% CI 1.49-3.78, p-trend < 0.001)] and processed meat consumption [OR = 2.01 (95% CI 1.26-3.21, p-trend 0.003)]. Heme iron intake was also directly associated with GDM [OR = 2.21 (95% CI 1.37-3.58, p-trend 0.003)], although the association was attenuated and lost its statistical significance when we adjusted for red meat consumption [OR = 1.57 (95% CI 0.91-2.70, p-trend 0.213)]. No association was observed for non-heme and total iron intake, including supplements. CONCLUSIONS Our overall findings suggest that higher pre-pregnancy consumption of total meat, especially red and processed meat, and heme iron intake, are significantly associated with an increased GDM risk in a Mediterranean cohort of university graduates.
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9.
Heme-mediated cell activation: the inflammatory puzzle of sickle cell anemia.
Guarda, CCD, Santiago, RP, Fiuza, LM, Aleluia, MM, Ferreira, JRD, Figueiredo, CVB, Yahouedehou, SCMA, Oliveira, RM, Lyra, IM, Gonçalves, MS
Expert review of hematology. 2017;(6):533-541
Abstract
Hemolysis triggers the onset of several clinical manifestations of sickle cell anemia (SCA). During hemolysis, heme, which is derived from hemoglobin (Hb), accumulates due to the inability of detoxification systems to scavenge sufficiently. Heme exerts multiple harmful effects, including leukocyte activation and migration, enhanced adhesion molecule expression by endothelial cells and the production of pro-oxidant molecules. Area covered: In this review, we describe the effects of heme on leukocytes and endothelial cells, as well as the features of vascular endothelial cells related to vaso-occlusion in SCA. Expert commentary: Free Hb, heme and iron, potent cytotoxic intravascular molecules released during hemolysis, can exacerbate, modulate and maintain the inflammatory response, a main feature of SCA. Endothelial cells in the vascular environment, as well as leukocytes, can become activated via the molecular signaling effects of heme. Due to the hemolytic nature of SCA, hemolysis represents an interesting therapeutic target for heme-scavenging purposes.
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Prebiotics increase heme iron bioavailability and do not affect non-heme iron bioavailability in humans.
Weinborn, V, Valenzuela, C, Olivares, M, Arredondo, M, Weill, R, Pizarro, F
Food & function. 2017;(5):1994-1999
Abstract
The aim of this study was to establish the effect of a prebiotic mix on heme and non-heme iron (Fe) bioavailability in humans. To this purpose, twenty-four healthy women were randomized into one of two study groups. One group ate one yogurt per day for 12 days with a prebiotic mix (prebiotic group) and the other group received the same yogurt but without the prebiotic mix (control group). Before and after the intake period, the subjects participated in Fe absorption studies. These studies used 55Fe and 59Fe radioactive isotopes as markers of heme Fe and non-heme Fe, respectively, and Fe absorption was measured by the incorporation of radioactive Fe into erythrocytes. The results showed that there were no significant differences in heme and non-heme Fe bioavailability in the control group. Heme Fe bioavailability of the prebiotic group increased significantly by 56% post-prebiotic intake. There were no significant differences in non-heme Fe bioavailability in this group. We concluded that daily consumption of a prebiotic mix increases heme Fe bioavailability and does not affect non-heme iron bioavailability.