Synthesis, delivery and regulation of eukaryotic heme and Fe–S cluster cofactors

• Iron's remarkable chemical reactivity makes it essential to sustain life.
• The role of Fe in Eukaryotes is discussed in detail in this review.
• Heme and Fe–S cluster biosynthesis pathways are outlined in detail.
• Pathways for production regulation are dissected in several organisms.
• Molecular details of disease states related to cofactor biosynthesis are identified.
• New interactions of chemists, cell biologists needed for new details of Fe biology.

In humans, the bulk of iron in the body (over 75%) is directed towards heme- or Fe–S cluster cofactor synthesis, and the complex, highly regulated pathways in place to accomplish biosynthesis have evolved to safely assemble and load these cofactors into apoprotein partners. In eukaryotes, heme biosynthesis is both initiated and finalized within the mitochondria, while cellular Fe–S cluster assembly is controlled by correlated pathways both within the mitochondria and within the cytosol. Iron plays a vital role in a wide array of metabolic processes and defects in iron cofactor assembly leads to human diseases. This review describes progress towards our molecular-level understanding of cellular heme and Fe–S cluster biosynthesis, focusing on the regulation and mechanistic details that are essential for understanding human disorders related to the breakdown in these essential pathways.