Iron Metabolism in the Disorders of Heme Biosynthesis

Abstract

Given its remarkable property to easily switch between different oxidative states, iron is essential in countless cellular functions which involve redox reactions. At the same time, uncontrolled interactions between iron and its surrounding milieu may be damaging to cells and tissues. Heme—the iron-chelated form of protoporphyrin IX—is a macrocyclic tetrapyrrole and a coordination complex for diatomic gases, accurately engineered by evolution to exploit the catalytic, oxygen-binding, and oxidoreductive properties of iron while minimizing its damaging effects on tissues. The majority of the body production of heme is ultimately incorporated into hemoglobin within mature erythrocytes; thus, regulation of heme biosynthesis by iron is central in erythropoiesis. Additionally, heme is a cofactor in several metabolic pathways, which can be modulated by iron-dependent signals as well. Impairment in some steps of the pathway of heme biosynthesis is the main pathogenetic mechanism of two groups of diseases collectively known as porphyrias and congenital sideroblastic anemias. In porphyrias, according to the specific enzyme involved, heme precursors accumulate up to the enzyme stop in disease-specific patterns and organs. Therefore, different porphyrias manifest themselves under strikingly different clinical pictures. In congenital sideroblastic anemias, instead, an altered utilization of mitochondrial iron by erythroid precursors leads to mitochondrial iron overload and an accumulation of ring sideroblasts in the bone marrow. In line with the complexity of the processes involved, the role of iron in these conditions is then multifarious. This review aims to summarise the most important lines of evidence concerning the interplay between iron and heme metabolism, as well as the clinical and experimental aspects of the role of iron in inherited conditions of altered heme biosynthesis.

Proteomic Analysis of Ferrochelatase Interactome in Erythroid and Non-Erythroid Cells

“…HSPA9, along with ABCB7 and GLRX5, play crucial roles in the metabolism of the iron-sulfur cluster [ 52 , 53 , 54 ], a cofactor of human FECH [ 55 ]. The function of these proteins in the interactome and the connection to human diseases, including sideroblastic anemia [ 56 , 57 ], are areas for further studies.…”

Iron Load Toxicity in Medicine: From Molecular and Cellular Aspects to Clinical Implications

“…In addition to the different rate of RBC transfusions between the various hematologic and other categories of iron-loaded patients, there are also many patient categories needing transfusions because of different causes of anemia, such as sideroblastic anemia, where iron is deposited in the mitochondria of sideroblasts [ 44 , 45 , 46 ]. In all RBC, transfusional iron-loaded categories and non-transfusional iron-loaded categories such as idiopathic hemochromatosis patients where venesection is contraindicated, iron chelation therapy needs to be introduced in order to reduce or eliminate the iron toxicity ( Table 1 ) [ 34 , 47 , 48 ].…”

Accumulation of Toxic Elements Disrupts Metabolic Processes in the Human: Review

“…Protoporphyrin ferrochelatase is an enzyme that encodes the ferrochelatase gene in the human body [65]. Protoporphyrin ferrochelatase activates the enzyme ferrochelatase by converting protoporphyrin 9 to heme B, where a chelation reaction occurs with iron (II) ions [65,66]. Protoporphyrin and ferrous form a complex called heme.…”