Update on heme biosynthesis, tissue-specific regulation, heme transport, relation to iron metabolism and cellular energy.

Heme is a primordial macrocycle upon which most aerobic life on Earth depends. It is essential to the survival and health of nearly all cells, functioning as a prosthetic group for oxygen-carrying proteins and enzymes involved in oxidation/reduction and electron transport reactions. Heme is essential for the function of numerous hemoproteins and has numerous other roles in the biochemistry of life.

Quantitative analysis of heme and hemoglobin for the detection of intravascular hemolysis.

Background: Intravascular hemolysis is associated with massive release of hemoglobin and consequently labile heme into the blood, resulting in prothrombotic and proinflammatory events in patients. Though heme is well-known to participate in these adverse effects, it is not monitored. Instead, haptoglobin and hemoglobin serve as clinical biomarkers.

Melatonin alleviated cadmium accumulation and toxicity by modulating phytohormonal balance and antioxidant metabolism in rice.

Cadmium (Cd) contamination is an eminent dilemma that jeopardizes global food safety and security, especially through its phytotoxicity in rice; one of the most edible crops. Melatonin (MET) has emerged as a protective phytohormone in stress conditions, but the defensive role and underlying mechanisms of MET against Cd toxicity in rice still remain unclear. To fulfill this knowledge gap, the present study is to uncover the key mechanisms for MET-mediated Cd-stress tolerance in rice.

Notes from the Underground: Heme Homeostasis in .

Heme is an iron-containing tetrapyrrole that plays a critical role in various biological processes, including oxygen transport, electron transport, signal transduction, and catalysis. However, free heme is hydrophobic and potentially toxic to cells. Organisms have evolved specific pathways to safely transport this essential but toxic macrocycle within and between cells.

Synthesis, characterization, and applications of iron oxide nanoparticles.

Objective: The green synthesis method for nanoparticles is getting more attention globally, due to its lesser cost, non-hazardous, and eco-friendly nature. The novelty of the present work is to investigate the anti-bacterial and degradation activity of the green synthesized Iron Oxide NPs.

Methods: In this study, the Iron Oxide NPs were synthesized through a green synthesis route from leaves of Ficus Palmata.

HRG-9 homologues regulate haem trafficking from haem-enriched compartments.

Haem is an iron-containing tetrapyrrole that is critical for a variety of cellular and physiological processes. Haem binding proteins are present in almost all cellular compartments, but the molecular mechanisms that regulate the transport and use of haem within the cell remain poorly understood. Here we show that haem-responsive gene 9 (HRG-9) (also known as transport and Golgi organization 2 (TANGO2)) is an evolutionarily conserved haem chaperone with a crucial role in trafficking haem out of haem storage or synthesis sites in eukaryotic cells.

Molecular Mechanisms of Iron and Heme Metabolism.

An abundant metal in the human body, iron is essential for key biological pathways including oxygen transport, DNA metabolism, and mitochondrial function. Most iron is bound to heme but it can also be incorporated into iron-sulfur clusters or bind directly to proteins. Iron's capacity to cycle between Fe and Fe contributes to its biological utility but also renders it toxic in excess.

MRP5 and MRP9 play a concerted role in male reproduction and mitochondrial function.

Multidrug Resistance Proteins (MRPs) are transporters that play critical roles in cancer even though the physiological substrates of these enigmatic transporters are poorly elucidated. In , MRP5/ABCC5 is an essential heme exporter because mutants are unviable due to their inability to export heme from the intestine to extraintestinal tissues. Heme supplementation restores viability of these mutants but fails to restore male reproductive deficits.

Heme oxygenase-2 (HO-2) binds and buffers labile ferric heme in human embryonic kidney cells.

Heme oxygenases (HOs) detoxify heme by oxidatively degrading it into carbon monoxide, iron, and biliverdin, which is reduced to bilirubin and excreted. Humans express two isoforms of HO: the inducible HO-1, which is upregulated in response to excess heme and other stressors, and the constitutive HO-2. Much is known about the regulation and physiological function of HO-1, whereas comparatively little is known about the role of HO-2 in regulating heme homeostasis.

One ring to bring them all and in the darkness bind them: The trafficking of heme without deliverers.

Heme, as a hydrophobic iron-containing organic ring, is lipid soluble and can interact with biological membranes. The very same properties of heme that nature exploits to support life also renders heme potentially cytotoxic. In order to utilize heme, while also mitigating its toxicity, cells are challenged to tightly control the concentration and bioavailability of heme.

Toxoplasma gondii requires its plant-like heme biosynthesis pathway for infection.

Heme, an iron-containing organic ring, is essential for virtually all living organisms by serving as a prosthetic group in proteins that function in diverse cellular activities ranging from diatomic gas transport and sensing, to mitochondrial respiration, to detoxification. Cellular heme levels in microbial pathogens can be a composite of endogenous de novo synthesis or exogenous uptake of heme or heme synthesis intermediates. Intracellular pathogenic microbes switch routes for heme supply when heme availability fluctuates in their replicative environment throughout infection.

Iron and Heme Metabolism at the Leishmania-Host Interface.

Species of the protozoan Leishmania are causative agents of human leishmaniasis, a disease that results in significant death, disability, and disfigurement around the world. The parasite is transmitted to a mammalian host by a sand fly vector where it develops as an intracellular parasite within macrophages. This process requires the acquisition of nutritional iron and heme from the host as Leishmania lacks the capacity for de novo heme synthesis and does not contain cytosolic iron-storage proteins.

Hemozoin produced by mammals confers heme tolerance.

Free heme is cytotoxic as exemplified by hemolytic diseases and genetic deficiencies in heme recycling and detoxifying pathways. Thus, intracellular accumulation of heme has not been observed in mammalian cells to date. Here we show that mice deficient for the heme transporter SLC48A1 (also known as HRG1) accumulate over ten-fold excess heme in reticuloendothelial macrophage lysosomes that are 10 to 100 times larger than normal.

Zebrafish as a model system to delineate the role of heme and iron metabolism during erythropoiesis.

Coordination of iron acquisition and heme synthesis is required for effective erythropoiesis. The small teleost zebrafish (Danio rerio) is an ideal vertebrate animal model to replicate various aspects of human physiology and provides an efficient and cost-effective way to model human pathophysiology. Importantly, zebrafish erythropoiesis largely resembles mammalian erythropoiesis.

Structural basis for promotion of duodenal iron absorption by enteric ferric reductase with ascorbate.

Dietary iron absorption is regulated by duodenal cytochrome (Dcytb), an integral membrane protein that catalyzes reduction of nonheme Fe by electron transfer from ascorbate across the membrane. This step is essential to enable iron uptake by the divalent metal transporter. Here we report the crystallographic structures of human Dcytb and its complex with ascorbate and Zn.

Hrg1 promotes heme-iron recycling during hemolysis in the zebrafish kidney.

Heme-iron recycling from senescent red blood cells (erythrophagocytosis) accounts for the majority of total body iron in humans. Studies in cultured cells have ascribed a role for HRG1/SLC48A1 in heme-iron transport but the in vivo function of this heme transporter is unclear. Here we present genetic evidence in a zebrafish model that Hrg1 is essential for macrophage-mediated heme-iron recycling during erythrophagocytosis in the kidney.

A MFS-like plasma membrane transporter required for Leishmania virulence protects the parasites from iron toxicity.

Iron is essential for many cellular processes, but can generate highly toxic hydroxyl radicals in the presence of oxygen. Therefore, intracellular iron accumulation must be tightly regulated, by balancing uptake with storage or export. Iron uptake in Leishmania is mediated by the coordinated action of two plasma membrane proteins, the ferric iron reductase LFR1 and the ferrous iron transporter LIT1.