Fig. 4

The signaling and structural functions of heme in human cells. Human cells can synthesize heme de novo in mitochondria (the first and rate-limiting enzyme is ALAS, 5-aminolevulinate synthase) or import heme via heme transporters, such as HRG1 and HCP1. Inside cells, heme serves as a prosthetic group in numerous enzymes and proteins that transport, store, or use oxygen, such as mitochondrial cytochromes and cytochrome P450. Additionally, heme directly regulates the activity of diverse cellular signaling and regulatory molecules, such as Bach1, Rev-ERBα, and Rev-ERBβ (transcriptional regulators), as well as DGCR8 (an essential miRNA processing factor) in the nucleus. Heme also regulates HRI (the heme-regulated inhibitor kinase controlling protein synthesis) and the Ras-ERK signaling pathway in the cytoplasm. Furthermore, heme regulates the activity of the NMDA receptor, the SloBK potassium channel, and the ENaCs sodium channel on the cell membrane