Metalloproteases and human diseases: The astacin family

Abstract

Astacins are a group of zinc metalloproteases characterized by a signature sequence of 18 amino acid residues (HExxHxxGxxHxxxRxDR) and a conserved SXMHYdomain containing the Met-turn characteristic of the metzincins. They are synthesized as inactive zymogens whereby they are activated after the post-translational removal of the amino-terminal pro-segments. Astacins are widely spread in bacteria and throughout animal kingdom. They are multi-domain, glycosylated complex endopeptidases which may be membrane-bound or secretory in nature. The astacins are known to play diverse role in bone morphogenesis, tissue differentiation, wound healing, digestion and in diseases like fibrosis, cancer, neurodegenerative and Alzheimer's disease. The homologous protease domain containing about 200 residues and two conserved disulphide bridges present in most astacins is the common thread linking all the members of this family. Though similar in structure the astacins differ widely in their substrate specificity. In humans, six astacins have been reported. They are meprin-α and-β, bone morphogenetic protein-1 (BMP-1) with its major splice variant mammalian tolloid, mammalian tolloid-like enzymes and ovastacin. Among them meprins α and β and bone morphogenetic protein1 have been found to be expressed at elevated level in certain diseases and hence important druggable targets. Several small molecule inhibitors and macromolecular inhibitors are known to control the activity of the astacins thereby contributing to the control of several diseases.