Biology of Heme in Mammalian Erythroid Cells and Related Disorders

Abstract

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.

Figure 1

Heme biosynthetic pathway in erythroid cells. Schematic representation of the heme biosynthetic pathway in erythroid cells. Heme synthesis begins with the condensation of glycine and succinyl-CoA to form ALA. Next, ALA is transported outside of the mitochondria and catalyzed to form coproporphyrinogen III. CPOX converts coproporphyrinogen III to protoporphyrinogen IX, which is subsequently oxidized into protoporphyrin IX by PPOX. Finally, ferrous iron is incorporated into protoporphyrinogen IX to form heme in a reaction catalyzed by FECH. FECH is localized in the inner mitochondrial membrane and associates with MFRN1 and ABCB10. SLC25A38 and ABCB10 have been proposed as mitochondrial ALA exporters located on the inner mitochondrial membrane. ABCB6 and TMEM14C have been proposed as putative coproporphyrinogen III and protoporphyrinogen IX importers, respectively. FLVCR1b is a mitochondrial heme exporter. Tf-bound Fe³⁺ is bound to TfR, released into endosome, and reduced to Fe²⁺ by STEAP3. Subsequently, Fe²⁺ exits the endosome via DMT1 and enters the mitochondria via MFRN1. ALAS2: erythroid-specific δ-aminolevulinate synthase, ALA: δ-aminolevulinic acid, PBGS: porphobilinogen synthase, HMBS: hydroxymethylbilane synthase, UROS: uroporphyrinogen synthase, UROD: uroporphyrinogen decarboxylase, CPOX: coproporphyrinogen oxidase, PPOX: protoporphyrinogen IX oxidase, FECH: ferrochelatase, MFRN1: mitoferrin 1, Vit. B6: vitamin B6, SLC25A38: solute carrier family 25 member 38, ABCB10: ATP-binding cassette subfamily B member 10, TMEM14C: transmembrane protein 14C, FLVCR1b: feline leukemia virus subgroup C receptor, Tf: transferrin, TfR: transferrin receptor, STEAP3: six-transmembrane epithelial antigen of prostate 3, and DMT1: divalent metal transporter 1. Adapted and modified from [–14].