Iron-dependent and zinc-dependent enzymes and proteins

Iron-dependent and zinc-dependent enzymes and proteins constitute a massive superfamily of metalloproteins that require specific metal ions as cofactors for catalytic activity, structural stability, or regulatory functions [Maret, 2013, Molecular Medicine]. Iron-dependent proteins, including heme-containing proteins like hemoglobin and non-heme proteins like prolyl hydroxylases, are essential for oxygen transport, DNA synthesis, and cellular respiration [Muckenthaler et al., 2017, Cell]. Zinc-dependent proteins represent approximately 10% of the human proteome and include critical enzymes such as carbonic anhydrases, matrix metalloproteinases (MMPs), and histone deacetylases (HDACs), as well as thousands of zinc-finger transcription factors [Andreini et al., 2006, Journal of Proteome Research]. These proteins are central to various pathologies, including cancer, where MMPs and HDACs are often overexpressed, and cardiovascular diseases, where angiotensin-converting enzyme (ACE) plays a key role in blood pressure regulation [West and Johnstone, 2014, Journal of Clinical Investigation]. Therapeutic strategies targeting this group often involve small molecules that coordinate with the metal ion in the active site to inhibit enzymatic function, such as ACE inhibitors or HDAC inhibitors [Patel et al., 2017, StatPearls]. However, achieving high selectivity remains a primary challenge for drug development due to the structural conservation of metal-binding motifs across different protein families, which can lead to significant off-target toxicity [Kaur et al., 2023, Pharmaceuticals].

Other names

MetalloproteinsMetalloenzymesIron-binding proteinsZinc-binding proteinsMetal-dependent enzymes

Drugs targeting these proteins typically act via chelation of the metal cofactor, competitive inhibition at the metal-binding active site, or by mimicking the natural substrate to block enzymatic activity [Patel et al., 2017, StatPearls].