Mammalian iron-dependent enzymes

Mammalian iron-dependent enzymes represent a broad and diverse class of proteins that utilize iron as a critical cofactor for catalytic activity, including both heme-containing enzymes (like Cytochrome P450s) and non-heme iron enzymes (such as JmjC-domain histone demethylases and TET DNA hydroxylases). In cancer cells, these enzymes are often upregulated to support rapid proliferation, metabolic reprogramming, and epigenetic plasticity; for instance, ribonucleotide reductase (RNR) is essential for DNA synthesis, while iron-dependent demethylases regulate oncogenic gene expression programs. Because cancer cells frequently exhibit an increased 'iron addiction' to maintain the activity of these enzymes, they are therapeutic targets for iron chelators and small-molecule inhibitors. However, because this term describes a functional group of hundreds of distinct enzymes rather than a single molecular entity, it is considered a broad category rather than a specific drug target. Targeting this group requires balancing the high iron demand of malignant cells against the essential physiological roles of iron in normal cellular respiration and oxygen transport.

Other names

Iron-dependent oxygenasesNon-heme iron enzymesHeme-containing enzymesIron-sulfur cluster proteins

Iron-dependent enzymes are typically targeted through iron chelation, which deprives the enzymes of their essential metal cofactor, or through competitive inhibition at the active site where iron coordinates with substrates (e.g., alpha-ketoglutarate analogs).