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1.
Heme metabolism as a therapeutic target against protozoan parasites.
Lechuga, GC, Pereira, MCS, Bourguignon, SC
Journal of drug targeting. 2019;(7):767-779
Abstract
Neglected tropical diseases caused by protozoan parasites affect the life of millions of people worldwide, causing mortality, morbidity and high economic and social burden. The search for new drug targets and therapeutic strategies to fight these pathogens are necessary, since many current drugs have limited effects, cause severe side effects and their use has resulted in pathogen resistance. Heme (iron protoporphyrin IX) is a ubiquitous molecule important in many biological processes, including the homeostasis, growth and development of human pathogens such as trypanosomatids (Trypanosoma cruzi, Trypanosoma brucei and Leishmania spp.) and Plasmodium spp. In this review, several chemotherapy approaches and strategies are discussed that target heme transport, catabolism, crystallization and hemeproteins.
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2.
Heme Uptake and Utilization by Gram-Negative Bacterial Pathogens.
Richard, KL, Kelley, BR, Johnson, JG
Frontiers in cellular and infection microbiology. 2019;:81
Abstract
Iron is a transition metal utilized by nearly all forms of life for essential cellular processes, such as DNA synthesis and cellular respiration. During infection by bacterial pathogens, the host utilizes various strategies to sequester iron in a process termed, nutritional immunity. To circumvent these defenses, Gram-negative pathogens have evolved numerous mechanisms to obtain iron from heme. In this review we outline the systems that exist in several Gram-negative pathogens that are associated with heme transport and utilization, beginning with hemolysis and concluding with heme degradation. In addition, Gram-negative pathogens must also closely regulate the intracellular concentrations of iron and heme, since high levels of iron can lead to the generation of toxic reactive oxygen species. As such, we also provide several examples of regulatory pathways that control heme utilization, showing that co-regulation with other cellular processes is complex and often not completely understood.
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3.
5-Aminolevulinate synthase catalysis: The catcher in heme biosynthesis.
Stojanovski, BM, Hunter, GA, Na, I, Uversky, VN, Jiang, RHY, Ferreira, GC
Molecular genetics and metabolism. 2019;(3):178-189
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Abstract
5-Aminolevulinate (ALA) synthase (ALAS), a homodimeric pyridoxal-5'-phosphate (PLP)-dependent enzyme, catalyzes the first step of heme biosynthesis in metazoa, fungi and α-proteobacteria. In this review, we focus on the advances made in unraveling the mechanism of the ALAS-catalyzed reaction during the past decade. The interplay between the PLP cofactor and the protein moiety determines and modulates the multi-intermediate reaction cycle of ALAS, which involves the decarboxylative condensation of two substrates, glycine and succinyl-CoA. Substrate binding and catalysis are rapid, and product (ALA) release dominates the overall ALAS kinetic mechanism. Interconversion between a catalytically incompetent, open conformation and a catalytically competent, closed conformation is linked to ALAS catalysis. Reversion to the open conformation, coincident with ALA dissociation, defines the slowest step of the reaction cycle. These findings were further substantiated by introducing seven mutations in the16-amino acid loop that gates the active site, yielding an ALAS variant with a greatly increased rate of catalytic turnover and heightened specificity constants for both substrates. Recently, molecular dynamics (MD) simulation analysis of various dimeric ALAS forms revealed that the seven active site loop mutations caused the proteins to adopt different conformations. In particular, the emergence of a β-strand in the mutated loop, which interacted with two preexisting β-strands to form an anti-parallel three-stranded β-sheet, conferred the murine heptavariant with a more stable open conformation and prompted faster product release than wild-type mALAS2. Moreover, the dynamics of the mALAS2 active site loop anti-correlated with that of the 35 amino acid C-terminal sequence. This led us to propose that this C-terminal extension, which is absent in prokaryotic ALASs, finely tunes mammalian ALAS activity. Based on the above results, we extend our previous proposal to include that discovery of a ligand inducing the mammalian C-terminal extension to fold offers a good prospect for the development of a new drug for X-linked protoporphyria and/or other porphyrias associated with enhanced ALAS activity and/or porphyrin accumulation.
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4.
In order for the light to shine so brightly, the darkness must be present-why do cancers fluoresce with 5-aminolaevulinic acid?
McNicholas, K, MacGregor, MN, Gleadle, JM
British journal of cancer. 2019;(8):631-639
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Abstract
Photodynamic diagnosis and therapy have emerged as a promising tool in oncology. Using the visible fluorescence from photosensitisers excited by light, clinicians can both identify and treat tumour cells in situ. Protoporphyrin IX, produced in the penultimate step of the haem synthesis pathway, is a naturally occurring photosensitiser that visibly fluoresces when exposed to light. This fluorescence is enhanced considerably by the exogenous administration of the substrate 5-aminolaevulinic acid (5-ALA). Significantly, 5-ALA-induced protoporphyrin IX accumulates preferentially in cancer cells, and this enhanced fluorescence has been harnessed for the detection and photodynamic treatment of brain, skin and bladder tumours. However, surprisingly little is known about the mechanistic basis for this phenomenon. This review focuses on alterations in the haem pathway in cancer and considers the unique features of the cancer environment, such as altered glucose metabolism, oncogenic mutations and hypoxia, and their potential effects on the protoporphyrin IX phenomenon. A better understanding of why cancer cells fluoresce with 5-ALA would improve its use in cancer diagnostics and therapies.
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Features of Organization and Mechanism of Catalysis of Two Families of Terminal Oxidases: Heme-Copper and bd-Type.
Borisov, VB, Siletsky, SA
Biochemistry. Biokhimiia. 2019;(11):1390-1402
Abstract
Terminal oxidases of aerobic respiratory chains catalyze the transfer of electrons from the respiratory substrate, cytochrome c or quinol, to O2 with the formation of two H2O molecules. There are two known families of these membrane oxidoreductases: heme-copper oxidase superfamily and bd-type oxidase family (cytochromes bd) found in prokaryotes only. The redox reaction catalyzed by these enzymes is coupled to the generation of proton motive force used by the cell to synthesize ATP and to perform other useful work. Due to the presence of the proton pump, heme-copper oxidases create the membrane potential with a greater energy efficiency than cytochromes bd. The latter, however, play an important physiological role that enables bacteria, including pathogenic ones, to survive and reproduce under adverse environmental conditions. This review discusses the features of organization and molecular mechanisms of functioning of terminal oxidases from these two families in the light of recent experimental data.
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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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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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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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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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10.
What Can Be Learned from Nuclear Resonance Vibrational Spectroscopy: Vibrational Dynamics and Hemes.
Scheidt, WR, Li, J, Sage, JT
Chemical reviews. 2017;(19):12532-12563
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Abstract
Nuclear resonance vibrational spectroscopy (NRVS; also known as nuclear inelastic scattering, NIS) is a synchrotron-based method that reveals the full spectrum of vibrational dynamics for Mössbauer nuclei. Another major advantage, in addition to its completeness (no arbitrary optical selection rules), is the unique selectivity of NRVS. The basics of this recently developed technique are first introduced with descriptions of the experimental requirements and data analysis including the details of mode assignments. We discuss the use of NRVS to probe 57Fe at the center of heme and heme protein derivatives yielding the vibrational density of states for the iron. The application to derivatives with diatomic ligands (O2, NO, CO, CN-) shows the strong capabilities of identifying mode character. The availability of the complete vibrational spectrum of iron allows the identification of modes not available by other techniques. This permits the correlation of frequency with other physical properties. A significant example is the correlation we find between the Fe-Im stretch in six-coordinate Fe(XO) hemes and the trans Fe-N(Im) bond distance, not possible previously. NRVS also provides uniquely quantitative insight into the dynamics of the iron. For example, it provides a model-independent means of characterizing the strength of iron coordination. Prediction of the temperature-dependent mean-squared displacement from NRVS measurements yields a vibrational "baseline" for Fe dynamics that can be compared with results from techniques that probe longer time scales to yield quantitative insights into additional dynamical processes.