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Nonhematological Manifestations of Iron Deficiency
Published in Bo Lönnerdal, Iron Metabolism in Infants, 2020
In summary, the attribution of specific physical findings to tissue heme protein deficiency at this moment is largely speculative. However, it is likely that iron deficiency interferes with the overall oxidative metabolism in man.69,70 Although our understanding of the consequences of tissue iron deficiency is undoubtedly fragmentary at this time, the studies discussed above provide ample reason for concern and a convincing rationale for programs to ensure adequate iron nutrition in the growing child.
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
The pathway of heme formation has been demonstrated a long time ago.414,510,511 All nitrogen atoms and eight carbon atoms of the heme molecule are derived from glycine, the remaining carbon atoms derive from succinate via the Krebs’ cycle. In the first step, glycine and succinate are combined, and two of the resulting δ-aminolevulinic acid molecules are condensed to give monopyrrole porphobilinogen. The next step is an enzymatic polymerization of four porphobilinogen units leading to the formation of uroporphyrinogen. Subsequently, decarboxylation yields coproporphyrinogen; a side chain modification transforms this compound to protoporphyrinogen IX and finally, the incorporation of ferrous ion gives rise to heme and the addition of a globin leads to hemoglobin459 (Figure 8). The heme molecule is the prostetic group of a variety of hemoproteins such as hemoglobin, myoglobin, cytochromes, catalase, peroxidase, and others.
Conversion of Natural Products from Renewable Resources in Pharmaceuticals by Cytochromes P450
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Giovanna Di Nardo, Gianfranco Gilardi
The active site of cytochromes P450 is characterized by a heme prosthetic group. The catalytic cycle has been widely characterized thanks to the information from spectroscopic different techniques, including x-ray crystallography (Schlichting et al., 2000; Krest et al., 2013; Yosca et al., 2017). The cycle starts with heme in the resting state and it is shown in Fig. 17.2. In the resting state, the heme iron is hexa-coordinated by the four nitrogen atoms of the porphyrin ring, the thiol group of a conserved cysteine residue in the proximal axial position and a water molecule in the distal axial position. The heme iron is positioned almost in the plane of the porphyrin ring. In this state, the ferric iron Fe3+ is in the low-spin configuration (S = 1/2) and its five outer electrons are in the higher energy 3d orbitals with two couples of electrons paired and one unpaired electron.
Molecular effects of ozone on amino acids and proteins, especially human hemoglobin and albumin, and the need to personalize ozone concentration in major ozone autohemotherapy
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Fouad Mehraban, Arefeh Seyedarabi
Hb is a tetrameric macromolecule consisting of two alpha subunits (7-helices) and two beta subunits (8-helices) that are structurally similar and have approximately the same molecular weight (141 to 146 amino acids). Each subunit contains a heme attachment pocket (prosthetic group) made of E and F helices (containing hydrophobic amino acids) located close to the surface of the Hb molecule. The heme inside this envelope has an iron atom in the center with four connections coordinated by the nitrogen atoms of the porphyrin ring. The iron atom is covalently attached to the proximal histidine (His F8) of Hb, and this structure allows the covalent attachment of oxygen and other gases to the iron in the heme of Hb. Distal histidine (His E7) also stabilizes bound oxygen by hydrogen bonding interaction. The prosthetic groups are active centers for the binding and transport of oxygen [80,81].
The structure of CLEC-2: mechanisms of dimerization and higher-order clustering
Published in Platelets, 2021
Eleyna M Martin, Malou Zuidscherwoude, Luis a Morán, Ying Di, Angel García, Steve P Watson
Bourne et al [5]. recently identified hemin as an endogenous ligand for CLEC-2. Hemin, the oxidized form of heme, is a protoporphyrin IX containing an Fe3+ ion with an associated chloride ligand, structure displayed in Figure 5. Hemin is found in the bloodstream during hemolytic conditions during which prothrombotic and proinflammatory responses are induced. The work of Bourne et al [5]. demonstrated that hemin is able to activate human and mouse platelets through direct binding to CLEC-2. They revealed that hemin at low micromolar concentrations induced rapid aggregation of human platelets in association with phosphorylation of Syk and PLCγ2, and that aggregation was blocked by inhibitors of Syk, SFKs and Btk consistent with an ITAM receptor-based pathway. SPR was used to confirm direct binding to CLEC-2 and determine the affinity of hemin to dimeric Fc-fusion human and mouse CLEC-2 to be in the order of 200 nM. Platelet aggregation induced by hemin was not blocked by anti-human CLEC-2 monoclonal antibody AYP1 suggesting that hemin binds to a site distinct from rhodocytin and podoplanin, which compete with AYP1 for CLEC-2 binding (discussed further below)[17].
Impact of bacterial infections on erythropoiesis
Published in Expert Review of Anti-infective Therapy, 2021
Lara Valente de Souza, Alexander Hoffmann, Günter Weiss
Iron is an essential trace element for almost every organism. Reversible shifting of electrons between its ferrous (Fe2+) and ferric (Fe3+) forms is crucial for various enzymatic processes. Heme is a protein with a central iron ion that can bind oxygen. It exists mainly in hemoglobin in the erythroid lineage, and in myoglobin, playing an essential role in transporting and reversible binding of oxygen [1,2]. As iron is important for cell reproduction as well as for various enzymatic functions, a reduced availability of this metal leads to impaired metabolic activity, reduced mitochondrial functionality and respiration and a diminished cellular proliferation [3–5]. In contrast, iron overload can catalyze toxic hydroxyl radical formation thereby resulting in cellular dysfunction, metabolic alterations and tissue damage over time [1,6].