ADAM metallopeptidase domain 17 (ADAM-17) (ADAM-17)

ADAM metallopeptidase domain 17 (ADAM-17), also known as TNF-alpha converting enzyme (TACE), is a type I transmembrane zinc-dependent metalloproteinase that plays a pivotal role in the "shedding" of the ectodomains of various cell surface proteins (UniProt: P78536). It is responsible for the proteolytic activation of pro-tumor necrosis factor-alpha (pro-TNF-alpha) into its soluble, systemic form, which is a primary driver of inflammatory responses (PubMed: 9060640). In addition to TNF-alpha, ADAM-17 cleaves a wide array of substrates including ligands of the epidermal growth factor receptor (EGFR), such as TGF-alpha and amphiregulin, as well as various cytokines, receptors, and adhesion molecules (PubMed: 15121867). This broad substrate specificity links ADAM-17 to diverse pathological conditions including cancer, where it promotes tumor growth and metastasis, and chronic inflammatory diseases like rheumatoid arthritis and Crohn's disease (PubMed: 28213288). Therapeutic strategies have focused on developing small molecule inhibitors and monoclonal antibodies to block its activity; however, achieving high selectivity remains a significant challenge (PubMed: 21854358). Clinical development of early inhibitors was often hampered by off-target effects on other metalloproteinases, leading to musculoskeletal side effects (PubMed: 16110314).

Other names

TNF-alpha converting enzymeTACECD156bSnake venom-like proteaseCSVP

Inhibition of the zinc-dependent catalytic domain to prevent the proteolytic cleavage and release of membrane-bound substrates, thereby blocking the activation of pro-inflammatory cytokines like TNF-alpha and growth factors like TGF-alpha (PubMed: 21854358).