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International Journal of Molecular... May 2020Heme and Fe-S clusters regulate a plethora of essential biological processes ranging from cellular respiration and cell metabolism to the maintenance of genome... (Review)
Review
Heme and Fe-S clusters regulate a plethora of essential biological processes ranging from cellular respiration and cell metabolism to the maintenance of genome integrity. Mutations in genes involved in heme metabolism and Fe-S cluster biogenesis cause different forms of ataxia, like posterior column ataxia and retinitis pigmentosa (PCARP), Friedreich's ataxia (FRDA) and X-linked sideroblastic anemia with ataxia (XLSA/A). Despite great efforts in the elucidation of the molecular pathogenesis of these disorders several important questions still remain to be addressed. Starting with an overview of the biology of heme metabolism and Fe-S cluster biogenesis, the review discusses recent progress in the understanding of the molecular pathogenesis of PCARP, FRDA and XLSA/A, and highlights future line of research in the field. A better comprehension of the mechanisms leading to the degeneration of neural circuity responsible for balance and coordinated movement will be crucial for the therapeutic management of these patients.
Topics: Anemia, Sideroblastic; Animals; Ataxia; Friedreich Ataxia; Genetic Diseases, X-Linked; Heme; Humans; Iron-Sulfur Proteins; Retinitis Pigmentosa; Spinocerebellar Ataxias
PubMed: 32466579
DOI: 10.3390/ijms21113760 -
Frontiers in Pharmacology Dec 2013The traditional role of iron chelation therapy has been to reduce body iron burden via chelation of excess metal from organs and fluids and its excretion via... (Review)
Review
The traditional role of iron chelation therapy has been to reduce body iron burden via chelation of excess metal from organs and fluids and its excretion via biliary-fecal and/or urinary routes. In their present use for hemosiderosis, chelation regimens might not be suitable for treating disorders of iron maldistribution, as those are characterized by toxic islands of siderosis appearing in a background of normal or subnormal iron levels (e.g., sideroblastic anemias, neuro- and cardio-siderosis in Friedreich ataxia- and neurosiderosis in Parkinson's disease). We aimed at clearing local siderosis from aberrant labile metal that promotes oxidative damage, without interfering with essential local functions or with hematological iron-associated properties. For this purpose we introduced a conservative mode of iron chelation of dual activity, one based on scavenging labile metal but also redeploying it to cell acceptors or to physiological transferrin. The "scavenging and redeployment" mode of action was designed both for correcting aberrant iron distribution and also for minimizing/preventing systemic loss of chelated metal. We first examine cell models that recapitulate iron maldistribution and associated dysfunctions identified with Friedreich ataxia and Parkinson's disease and use them to explore the ability of the double-acting agent deferiprone, an orally active chelator, to mediate iron scavenging and redeployment and thereby causing functional improvement. We subsequently evaluate the concept in translational models of disease and finally assess its therapeutic potential in prospective double-blind pilot clinical trials. We claim that any chelator applied to diseases of regional siderosis, cardiac, neuronal or endocrine ought to preserve both systemic and regional iron levels. The proposed deferiprone-based therapy has provided a paradigm for treating regional types of siderosis without affecting hematological parameters and systemic functions.
PubMed: 24427136
DOI: 10.3389/fphar.2013.00167 -
BioMed Research International 2015Heme is a prosthetic group comprising ferrous iron (Fe(2+)) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport... (Review)
Review
Heme is a prosthetic group comprising ferrous iron (Fe(2+)) and protoporphyrin IX and is an essential cofactor in various biological processes such as oxygen transport (hemoglobin) and storage (myoglobin) and electron transfer (respiratory cytochromes) in addition to its role as a structural component of hemoproteins. Heme biosynthesis is induced during erythroid differentiation and is coordinated with the expression of genes involved in globin formation and iron acquisition/transport. However, erythroid and nonerythroid cells exhibit distinct differences in the heme biosynthetic pathway regulation. Defects of heme biosynthesis in developing erythroblasts can have profound medical implications, as represented by sideroblastic anemia. This review will focus on the biology of heme in mammalian erythroid cells, including the heme biosynthetic pathway as well as the regulatory role of heme and human disorders that arise from defective heme synthesis.
Topics: Anemia, Sideroblastic; Animals; Erythroid Cells; Heme; Humans; Mice; Porphyria, Erythropoietic
PubMed: 26557657
DOI: 10.1155/2015/278536 -
British Medical Journal Dec 1961
Topics: Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Genetic Diseases, X-Linked; Pyridoxine; Vitamin B 6; beta-Thalassemia
PubMed: 13905463
DOI: 10.1136/bmj.2.5269.1756 -
Canadian Family Physician Medecin de... Dec 1976Hypochromic anemia is the commonest type of anemia encountered in family practice. Although iron deficiency is by far the most common cause, it cannot be readily...
Hypochromic anemia is the commonest type of anemia encountered in family practice. Although iron deficiency is by far the most common cause, it cannot be readily distinguished from hypochromic anemia due to other causes (thalassemia, secondary anemia and sideroblastic anemia) without knowing the state of the tissue iron stores. Treatment with iron should not be commenced until this is known. To establish the reason for the hypochromic state, the following tests are suggested: serum ferritin, bone marrow assessment of iron stores, plus serum iron and iron binding capacity.
PubMed: 20469272
DOI: No ID Found -
Trends in Genetics : TIG Aug 2008Iron-sulfur (Fe-S) clusters are essential for numerous biological processes, including mitochondrial respiratory chain activity and various other enzymatic and... (Review)
Review
Iron-sulfur (Fe-S) clusters are essential for numerous biological processes, including mitochondrial respiratory chain activity and various other enzymatic and regulatory functions. Human Fe-S cluster assembly proteins are frequently encoded by single genes, and inherited defects in some of these genes cause disease. Recently, the spectrum of diseases attributable to abnormal Fe-S cluster biogenesis has extended beyond Friedreich ataxia to include a sideroblastic anemia with deficiency of glutaredoxin 5 and a myopathy associated with a deficiency of a Fe-S cluster assembly scaffold protein, ISCU. Mutations within other mammalian Fe-S cluster assembly genes could be causative for human diseases that manifest distinctive combinations of tissue-specific impairments. Thus, defects in the iron-sulfur cluster biogenesis pathway could underlie many human diseases.
Topics: ATP-Binding Cassette Transporters; Anemia, Sideroblastic; Friedreich Ataxia; Glutaredoxins; Humans; Iron-Binding Proteins; Iron-Sulfur Proteins; Models, Biological; Muscular Diseases; Mutation; Frataxin
PubMed: 18606475
DOI: 10.1016/j.tig.2008.05.008 -
Cellular and Molecular Biology... Feb 20095-Aminolevulinate synthase is a homodimeric pyridoxal 5'-phosphate-dependent enzyme that catalyzes the first step of the heme biosynthetic pathway in animals, fungi, and... (Review)
Review
5-Aminolevulinate synthase is a homodimeric pyridoxal 5'-phosphate-dependent enzyme that catalyzes the first step of the heme biosynthetic pathway in animals, fungi, and the alpha-subclass of the photosynthetic purple bacteria. The reaction cycle involves condensation of glycine with succinyl-coenzyme A to yield 5-aminolevulinate, carbon dioxide, and CoA. Mutations in the human erythroid-specific aminolevulinate synthase gene are associated with the erythropoietic disorder X-linked sideroblastic anemia. Recent kinetic and crystallographic data have facilitated an unprecedented understanding of how this important enzyme produces 5-aminolevulinate, and suggest possible directions for future research that may lead to treatments not only for X-linked sideroblastic anemia, but also other diseases.
Topics: 5-Aminolevulinate Synthetase; Aminolevulinic Acid; Anemia, Sideroblastic; Heme; Humans; Kinetics; Models, Molecular; Mutation; Structure-Activity Relationship
PubMed: 19268008
DOI: No ID Found -
The Journal of Biological Chemistry Mar 2022Heme is a critical biomolecule that is synthesized in vivo by several organisms such as plants, animals, and bacteria. Reflecting the importance of this molecule,... (Review)
Review
Heme is a critical biomolecule that is synthesized in vivo by several organisms such as plants, animals, and bacteria. Reflecting the importance of this molecule, defects in heme biosynthesis underlie several blood disorders in humans. Aminolevulinic acid synthase (ALAS) initiates heme biosynthesis in α-proteobacteria and nonplant eukaryotes. Debilitating and painful diseases such as X-linked sideroblastic anemia and X-linked protoporphyria can result from one of more than 91 genetic mutations in the human erythroid-specific enzyme ALAS2. This review will focus on recent structure-based insights into human ALAS2 function in health and how it dysfunctions in disease. We will also discuss how certain genetic mutations potentially result in disease-causing structural perturbations. Furthermore, we use thermodynamic and structural information to hypothesize how the mutations affect the human ALAS2 structure and categorize some of the unique human ALAS2 mutations that do not respond to typical treatments, that have paradoxical in vitro activity, or that are highly intolerable to changes. Finally, we will examine where future structure-based insights into the family of ALA synthases are needed to develop additional enzyme therapeutics.
Topics: 5-Aminolevulinate Synthetase; Aminolevulinic Acid; Anemia, Sideroblastic; Animals; Genetic Diseases, X-Linked; Heme; Humans; Structure-Activity Relationship
PubMed: 35093382
DOI: 10.1016/j.jbc.2022.101643 -
Journal of Family Medicine and Primary... Jul 2019Tuberculosis is an infectious disease caused by mycobacterium tuberculosis. It is one of the deadliest disease and a major burden on the healthcare system in India....
UNLABELLED
Tuberculosis is an infectious disease caused by mycobacterium tuberculosis. It is one of the deadliest disease and a major burden on the healthcare system in India. India, a second most populous country in the world, has a very high global annual incidence of tuberculosis. Multiple hematological changes have been reported in patients with tuberculosis such as iron deficiency anemia, folate deficiency, and sideroblastic anemia.
AIMS AND OBJECTIVES
The present study was planned to find the prevalence and characteristics of anemia in the new cases of pulmonary tuberculosis. The secondary objective was to assess the predictors of anemia in new cases of pulmonary tuberculosis.
METHODS
The retrospective study was carried out at a tertiary care hospital of Uttarakhand and included all the new cases of tuberculosis aged more than 18 years attending medicine outpatient and inpatient departments over a period of 1 year. Detailed demographic, clinical, and biochemical data were obtained from the hospital record section and tabulated.
RESULTS
Most patients with tuberculosis and anemia were more than 50 years of age. Clearly, males outnumbered females. Approximately, 80% patients were illiterates. A majority (71, 39.2%) of the patients had BMI within the range of 18.5 to 24.9 kg/m. The most common symptoms of tubercular patients with and without anemia were cough, fever, breathlessness, and hemoptysis. However, pallor was the most common sign. Clearly, hematological indices were lower in patients with anemia. In total, 112 (60%) patients had mild anemia and 103 (56.9%) patients had normocytic normochromic anemia. Significant association was found between Body Mass Index (BMI) and anemia in patients with pulmonary tuberculosis. Similarly, severity of anemia co-related significantly with BMI of patients with pulmonary tuberculosis. BMI showed a significant correlation with hemoglobin, packed cell volume, mean corpuscular cell volume, and red cell distribution width (RDW). In addition, age showed a significant correlation with hemoglobin and RDW.
CONCLUSION
Normocytic normochromic anemia is a common hematological abnormality in patients with pulmonary tuberculosis. Thus, it warrants frequent screening for anemia in all the cases of pulmonary tuberculosis to improve morbidity and mortality in these patients.
PubMed: 31463274
DOI: 10.4103/jfmpc.jfmpc_311_19 -
Molecular basis of inherited microcytic anemia due to defects in iron acquisition or heme synthesis.Haematologica Mar 2009Microcytic anemia is the most commonly encountered anemia in general medical practice. Nutritional iron deficiency and beta thalassemia trait are the primary causes in... (Review)
Review
Microcytic anemia is the most commonly encountered anemia in general medical practice. Nutritional iron deficiency and beta thalassemia trait are the primary causes in pediatrics, whereas bleeding disorders and anemia of chronic disease are common in adulthood. Microcytic hypochromic anemia can result from a defect in globin genes, in heme synthesis, in iron availability or in iron acquisition by the erythroid precursors. These microcytic anemia can be sideroblastic or not, a trait which reflects the implications of different gene abnormalities. Iron is a trace element that may act as a redox component and therefore is integral to vital biological processes that require the transfer of electrons as in oxygen transport, oxidative phosphorylation, DNA biosynthesis and xenobiotic metabolism. However, it can also be pro-oxidant and to avoid its toxicity, iron metabolism is strictly controlled and failure of these control systems could induce iron overload or iron deficient anemia. During the past few years, several new discoveries mostly arising from human patients or mouse models have highlighted the implication of iron metabolism components in hereditary microcytic anemia, from intestinal absorption to its final inclusion into heme. In this paper we will review the new information available on the iron acquisition pathway by developing erythrocytes and its regulation, and we will consider only inherited microcytosis due to heme synthesis or to iron metabolism defects. This information could be useful in the diagnosis and classification of these microcytic anemias.
Topics: 5-Aminolevulinate Synthetase; Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Heme; Humans; Iron; Models, Biological; Mutation
PubMed: 19181781
DOI: 10.3324/haematol.13619