STRUCTURAL FEATURES AND BIOCHEMICAL-PROPERTIES OF TNF-ALPHA CONVERTING-ENZYME (TACE)

Tumor necrosis factor-alpha is a potent cytokine, secreted primarily b y activated monocytes and macrophages, that possesses a broad range of immunomodulating properties. Involvement of this cytokine has been va lidated in disease states such as arthritis and Crohn's disease and im plicated in diverse neuroimmunological pathologies such as multiple sc lerosis, Alzheimers and stroke. TNF-alpha is initially synthesized as a 26 kDa precursor molecule that is subsequently processed to the matu re form by cleavage of the Ala(76)-Val(77) bond. The 17 kDa carboxy-te rminal protein is then secreted to function in a paracrine manner. The enzyme that processes precursor TNF-alpha has previously been identif ied as a microsomal metalloprotease called TNF-alpha converting enzyme (TACE). We have now purified and partially cloned the enzyme. TACE re presents a novel target for therapeutic intervention in a variety of i nflammatory and neuroimmunological diseases.