1. Departments of ^*, Molecular Biochemistry, ^**, Diversity Sciences, ^, Molecular Sciences, ^§, Analytical Chemistry, ^£Structural Chemistry
2. ^¶Molecular Pharmacology, Glaxo Wellcome Research and Development Inc., 5 Moore Drive Research Triangle Park, North Carolina 27709, USA
3. Present addresses: ^††, Dow Corning Corporation, Midland, Michigan 48686-0994; ^, RPR, 600 Arcola Road, Collegeville, Pennsylvania 19426; ^†Stanford University School of Medicine, Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford, California 94305, USA.

Abstract

Tumour-necrosis factor- (TNF-) is a cytokine that contributes to a variety of inflammatory disease states¹. The protein exists as a membrane-bound precursor^2,3 of relative molecular mass 26K which can be processed by a TNF--converting enzyme (TACE), to generate secreted 17K mature TNF-. We have purified TACE and cloned its complementary DNA. TACE is a membrane-bound disintegrin metalloproteinase. Structural comparisons with other disintegrin-containing enzymes indicate that TACE is unique, with noteable sequence identity to MADM⁴, an enzyme implicated in myelin degradation, and to KUZ⁵, a Drosophila homologue of MADM important for neuronal development. The expression of recombinant TACE (rTACE) results in the production of functional enzyme that correctly processes precursor TNF- to the mature form. The rTACE provides a readily available source of enzyme to help in the search for new anti-inflammatory agents that target the final processing stage of TNF- production.