A half century ago, Max Perutz and John Kendrew determined the crystal structure of two heme-containing proteins: hemoglobin and myoglobin, respectively. 1, 2 These landmark discoveries created the foundation for a detailed biochemical understanding of how protein structure influences and affects its ability to bind and carry oxygen. Perutz and Kendrew were awarded the Nobel Prize in 1962. Since then, scores of hemoprotein structures have been solved, although the mechanisms and molecules responsible for assembling heme into hemoglobin (Hb) and other hemoproteins remain unknown. 3

Heme is the prosthetic group of proteins that perform diverse functions such as oxygen transport (globins), xenobiotic detoxification (cytochrome P450s), oxidative metabolism (cytochrome c oxidase), gas sensing (soluble guanylate cyclases), input/regulation of the circadian clock (nuclear hormone receptor, Rev-erb R, mPER2), microRNA processing (DGCR8),