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Dual role of heme iron in cancer; promotor of carcinogenesis and an inducer of tumour suppression.
Gamage, SMK, Lee, KTW, Dissabandara, DLO, Lam, AK, Gopalan, V
Experimental and molecular pathology. 2021;:104642
Abstract
PURPOSE Heme is a crucial compound for cell survival but is also equipped with the potential to be toxic and carcinogenic to cells. However, with the recent advancement of knowledge regarding ferroptosis, the iron mediated cell death, heme can be postulated to induce tumour suppression through ferroptosis. This review summarizes the literature on the carcinogenic and anticarcinogenic properties of heme with specific emphasis on the alterations observed on heme synthesis, metabolism and transport in tumour cells. METHODS Literature search was performed in PubMed data base using the MeSH terms 'heme iron or heme', 'cancer or carcinogenesis' and 'tumour suppression' or 'anticarcinogenic properties. Out of 189 results, 166 were relevant to the current review. RESULTS Heme supports carcinogenesis via modulation of immune cell function, promoting inflammation and gut dysbiosis, impeding tumour suppressive potential of P53 gene, promoting cellular cytotoxicity and reactive oxygen species generation and modulating Nfr2 /HO-1 axis. The carcinogenic and anticarcinogenic properties of heme are both dose and oxygen concentration dependant. At low doses, heme is harmless and even helpful in maintaining the much-needed redox balance within the cell. However, when heme exceeds physiological concentrations, it could initiate and propagate carcinogenesis, due to its ability to produce reactive oxygen species (ROS). The same phenomenon of heme mediated ROS generation could be manipulated to initiate tumour suppression via ferroptosis, but the therapeutic doses are yet to be determined. CONCLUSION Heme iron possesses powerful carcinogenic and anticarcinogenic properties which are dosage and oxygen availability dependant.
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Activation of O2 and NO in heme-copper oxidases - mechanistic insights from computational modelling.
Blomberg, MRA
Chemical Society reviews. 2020;(20):7301-7330
Abstract
Heme-copper oxidases are transmembrane enzymes involved in aerobic and anaerobic respiration. The largest subgroup contains the cytochrome c oxidases (CcO), which reduce molecular oxygen to water. A significant part of the free energy released in this exergonic process is conserved as an electrochemical gradient across the membrane, via two processes, electrogenic chemistry and proton pumping. A deviant subgroup is the cytochrome c dependent NO reductases (cNOR), which reduce nitric oxide to nitrous oxide and water. This is also an exergonic reaction, but in this case none of the released free energy is conserved. Computational studies applying hybrid density functional theory to cluster models of the bimetallic active sites in the heme-copper oxidases are reviewed. To obtain a reliable description of the reaction mechanisms, energy profiles of the entire catalytic cycles, including the reduction steps have to be constructed. This requires a careful combination of computational results with certain experimental data. Computational studies have elucidated mechanistic details of the chemical parts of the reactions, involving cleavage and formation of covalent bonds, which have not been obtainable from pure experimental investigations. Important insights regarding the mechanisms of energy conservation have also been gained. The computational studies show that the reduction potentials of the active site cofactors in the CcOs are large enough to afford electrogenic chemistry and proton pumping, i.e. efficient energy conservation. These results solve a conflict between different types of experimental data. A mechanism for the proton pumping, involving a specific and crucial role for the active site tyrosine, conserved in all CcOs, is suggested. For the cNORs, the calculations show that the low reduction potentials of the active site cofactors are optimized for fast elimination of the toxic NO molecules. At the same time, the low reduction potentials lead to endergonic reduction steps with high barriers. To prevent even higher barriers, which would lead to a too slow reaction, when the electrochemical gradient across the membrane is present, the chemistry must occur in a non-electrogenic manner. This explains why there is no energy conservation in cNOR.
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Mechanism of colorectal carcinogenesis triggered by heme iron from red meat.
Seiwert, N, Heylmann, D, Hasselwander, S, Fahrer, J
Biochimica et biophysica acta. Reviews on cancer. 2020;(1):188334
Abstract
Colorectal cancer (CRC) is one of the major tumor entities worldwide, with an increasing incidence in younger people. CRC formation is causally linked to various genetic, life-style and dietary risk factors. Among the ladder, the consumption of red meat has emerged as important risk factor contributing to CRC. A large body of evidence shows that heme iron is the critical component of red meat, which promotes colorectal carcinogenesis. In this review, we describe the uptake and cellular fate of both heme and inorganic iron in intestinal epithelial cells. Next, an overview on the DNA damaging properties of heme iron is provided, highlighting the DNA adducts relevant for CRC etiology. Moreover, heme triggered mechanisms leading to colonic hyperproliferation are presented, which are intimately linked to changes in the intestinal microbiota induced by heme. A special focus was set on the impact of heme iron on innate and adaptive immune cells, which could be relevant in the context of CRC. Finally, we recapitulate in vivo studies providing evidence for the tumor-promoting potential of dietary heme iron. Altogether, heme iron affects numerous key pathways involved in the pathogenesis of CRC.
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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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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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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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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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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.