Liver Diseases
George Feuer, Felix A. de la Iglesia in Molecular Biochemistry of Human Disease, 2020
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.
Heme Oxygenase-1 in Kidney Health and Disease
Shamim I. Ahmad in Handbook of Mitochondrial Dysfunction, 2019
Heme is an iron-containing porphyrin complex and constitutes the prosthetic group of several hemoproteins with important biological functions. Heme is synthesized in the mitochondria with protoporphyrins supplied from its precursor succinyl-CoA from mitochondria TCA (Kreb) cycle, which then subsequently exported out via the mitochondrial transporter ATP-binding cassette (ABC) B10 after biosynthesis (7). Hemes are most commonly recognized as components of hemoglobin from red blood cells (erythrocytes). Some other examples of hemoproteins include myoglobin (enriched in muscle), catalases, heme peroxidase, cytochromes, and endothelial nitric oxide synthase (eNOS) (8). The redox-active nature of iron makes heme critically involved in modulation of oxidating-reducing activities of hemoproteins which engaged in oxygen transport (hemoglobin) and storage (myoglobin), mitochondrial electron transfer and energy transformation (cytochromes), hydrogen peroxide activation (heme peroxidase) or inactivation (catalases) and nitro oxide synthesis (eNOS) (9). In physiology, significant level of heme could arise from the destruction of aged red blood cells. Because heme also catalyzes the formation of toxic reactive oxygen species (ROS) and free hydroxyl radicals to induce pro-oxidant and cytotoxic effects, level of “free-heme” must be tightly regulated. Disturbed heme metabolism causes mitochondrial decay, oxidative stress, and iron accumulation has been linked to age-related diseases (10).
Cutaneous Porphyrias
Henry W. Lim, Herbert Hönigsmann, John L. M. Hawk in Photodermatology, 2007
The porphyrias are uncommon disorders due to deficiencies of enzymes in the metabolic pathway for synthesizing heme (Fig. 1). These enzyme deficiencies can lead to accumulation of pathway intermediates and either skin photosensitivity (caused by porphyrins in the cutaneous porphyrias) or neurological attacks (associated with increases in porphyrin precursors in the acute porphyrias). Intermediates accumulate first in either the bone marrow, where erythrocyte precursors actively synthesize heme for hemoglobin, or in liver, which produces large amounts of cytochrome P450 enzymes. On this basis, porphyrias are classified as either erythropoietic or hepatic (Table 1). Heme is also produced in other tissues for a variety of essential hemoproteins such as respiratory cytochromes, catalase and myoglobin.
Stabilization of Nrf2 leading to HO-1 activation protects against zinc oxide nanoparticles-induced endothelial cell death
Published in Nanotoxicology, 2021
Longbin Zhang, Liyong Zou, Xuejun Jiang, Shuqun Cheng, Jun Zhang, Xia Qin, Zhexue Qin, Chengzhi Chen, Zhen Zou
HO-1 has received considerable attention as a master protective sentinel, that plays a prominent role in different organs and tissues, as well as different pathological scenarios (Otterbein, Foresti, and Motterlini 2016; Satta et al. 2017). As the rate-limiting step in the catabolism of heme into bioactive signaling molecules, the main function of HO-1 is to degrade heme to generate carbon monoxide (CO) and biliverdin and with the simultaneous releasing of iron. These products induce signaling and cytoprotective activities that mitigate apoptosis and inflammation, regulate vasomotor tone, and exhibit antioxidant and immunomodulatory functions. In addition to generation of HO-1-derived products, the role of this enzyme is to counteract oxidative tissue injury triggered by free heme. Large amounts of heme can be released from specific hemoproteins upon oxidative stress, contributing to the amplification of cell and tissue injury (Gozzelino, Jeney, and Soares 2010). Although HO-1 is a crucial arbiter of oxidative stress and inflammatory responses, the precise mechanism of HO-1 in endothelial cell death induced by ZnONPs needs further investigation. Another interesting role of HO-1 may be related to the release of free iron ions upon its profound upregulation, which might trigger nonapoptotic, iron-dependent cell death, called ferroptosis (Dixon et al. 2012; Yang et al. 2014). Our group recently reported that ZnONPs could induce ferroptosis in endothelial cell death (Qin et al. 2021), however whether HO-1 is involved in this process needs further investigation.
A novel treatment strategy to prevent Parkinson’s disease: focus on iron regulatory protein 1 (IRP1)
Published in International Journal of Neuroscience, 2023
Thomas M. Berry, Ahmed A. Moustafa
Rotenone inhibits complex I of the electron transport chain by dysregulating iron-sulfur clusters of complex I [84]. Rotenone increases IRP1 and decreases activity of ACO1 [85]. Silencing of IRP1 protects cells from death induced by complex I inhibition [78]. Upon gaining an iron-sulfur cluster due to increases in iron IRP1 becomes aconitase 1 [86]. The goal of supplemental iron would be constant absorption of iron, constant systematic levels of iron and tight iron utilization. Hemoglobin levels could be misleading as to the status of iron-sulfur proteins. Heme is not an iron-sulfur protein. Heme proteins could be normal is PD while iron-sulfur proteins could be dysregulated. In Friedreich’s ataxia iron-sulfur cluster formation is dysregulated, however, hemoglobin levels are normal [87].
The brain heme oxygenase/biliverdin reductase system as a target in drug research and development
Published in Expert Opinion on Therapeutic Targets, 2022
Heme oxygenase is a microsomal enzyme which catalyzes the oxidative cleavage of the α-meso-carbon bridge of hemoprotein heme moieties in a 4-step, energy-dependent manner. From a chemical point of view, HO itself is not a hemoprotein, but it attains this characteristic after binding to heme-Fe2+ [13]. The activation of the heme catabolic pathway requires not only HO, but also oxygen and NADPH-cytochrome-P-450 reductase. The latter provide the necessary electrons to catalyze the transformation of the cyclic tetrapyrrole heme into equimolar amounts of Fe2+, CO, and BV (Figure 1) [14]. Heme oxygenase exists in two main isoforms, HO-1 and HO-2. They are the products of two different genes, and their homology is limited (43%), but the active core of both enzymes is a preserved 24-amino-acid segment, forming the hydrophobic heme-binding pocket in the folded protein [5]. This pocket also binds metalloporphyrins, including cobalt-protoporphyrin- IX (Co-PP-IX), zinc-protoporphyrin-IX (Zn-PP-IX), tin-protoporphyrin-IX (Sn-PP-IX) and tin-mesoporphyrin-IX (Sn-MP-IX). The interaction of Zn-PP-IX, Sn-PP-IX and Sn-MP-IX does not catalyze hydrolysis (or at least not to the extent as heme binding), therefore these agents inhibit in vitro and in vivo HO activity [15]. However, since metalloporphyrins are also able to induce HO-1 both at the gene and protein levels, their final effect (inhibition versus activation) depends on the net result [16,17]. With regard to selectivity, the inhibitory potency of each metalloporphyrin is nearly identical for both HO isoforms, with Zn-PP-IX having the greatest inhibitory effect on HO-1 and Sn-PP-IX on HO-2 [18].
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