Heme as key regulator of major mammalian cellular functions: molecular, cellular, and pharmacological aspects

Heme (iron protoporphyrin IX) exists as prosthetic group in several hemoproteins, which include respiration cytochromes, gas sensors, P450 enzymes (CYPs), catalases, peroxidases, nitric oxide synthases (NOS), guanyl cyclases, and even transcriptional factors. Hemin (the oxidized form of iron protoporphyrin IX) on the other hand is an essential regulator of gene expression and growth promoter of hematopoietic progenitor cells. This review is focused on the major developments occurred in this field of heme biosynthesis and catabolism and their implications in our understanding the pathogenesis of heme-related disorders like anemias, acute porphyrias, hematological malignancies (leukemias), and other disorders. Heme is transported into hematopoietic cells and enters the nucleus where it activates gene expression by removing transcriptional potential repressors, like Bach1, from enhancer DNA sequences. Evidence also exists to indicate that heme acts like a signaling ligand in cell respiration and metabolism, stress response adaptive processes, and even transcription of several genes. Impaired heme biosynthesis or heme deficiency lead to hematological disorders, tissue degeneration, and aging, while heme prevents cell damage via activation of heme oxygenase-1 (HO-1) gene. Therefore, heme, besides being a key regulator of mammalian functions, can be also a useful therapeutic agent alone or in combination with other drugs in several heme-related disorders.