Zinc-dependent metalloenzymes and zinc-finger transcription factors

Zinc-dependent metalloenzymes and zinc-finger transcription factors represent two vast and distinct classes of proteins that utilize zinc ions for structural stability or catalytic activity. Metalloenzymes, such as matrix metalloproteinases (MMPs), carbonic anhydrases, and angiotensin-converting enzyme (ACE), use the zinc ion as a Lewis acid to facilitate chemical reactions essential for metabolism, tissue remodeling, and blood pressure regulation [1]. Zinc-finger transcription factors, characterized by coordinated zinc ions that stabilize DNA-binding domains, are critical regulators of gene expression across diverse biological processes including cell growth and differentiation [2]. These proteins are significant therapeutic targets; for instance, ACE inhibitors are standard treatments for hypertension, while histone deacetylase (HDAC) inhibitors are utilized in oncology [3]. However, the ubiquity of zinc-binding motifs in the human proteome—estimated to be present in approximately 10 percent of all proteins—presents a major challenge for drug discovery [4]. Achieving high selectivity for a specific zinc-containing protein without affecting others is difficult, often leading to off-target toxicities and therapeutic challenges [5]. (Citations: [1] McCall et al., 2000, J. Nutr.; [2] Klug, 2010, Annu. Rev. Biochem.; [3] Ho, 2004, J. Nutr. Biochem.; [4] Maret, 2013, Encyclopedia of Metalloproteins; [5] Jacobsen et al., 2007, Chem. Commun.)

Other names

Zinc-binding proteinsZinc metalloproteinsZn-dependent enzymesZinc-finger proteinsMetalloenzymes

Drugs targeting these proteins typically act by chelating the active-site zinc ion to inhibit enzymatic activity or by competing with natural ligands to modulate DNA binding and transcriptional regulation.