A Review of the ADAMTS Family, Pharmaceutical Targets of the Future

Abstract

The disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of metalloproteases consists of 19 members. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their altered regulation has been implicated in diseases such as cancer, arthritis and atherosclerosis. Unlike other metalloproteinases, ADAMTS members demonstrate a narrow substrate specificity due to the various exosites located in the C-terminal regions of the enzymes, which influence protein recognition and matrix localization. The tight substrate specificity exhibited by ADAMTS enzymes makes them potentially safe pharmaceutical targets, as selective inhibitors designed for each member will result in the inhibition or cleavage of only a limited number of proteins. With the recent elucidation of crystal structures for ADAMTS-1, -4 and -5, the design of potent and selective small molecule inhibitors is underway and will lead to drug candidates for evaluation in clinical trials in the next 5-10 years.

Self-cleavage of Human CLCA1 Protein by a Novel Internal Metalloprotease Domain Controls Calcium-activated Chloride Channel Activation

“…Cys-rich domains are found in a number of ADAM and ADAMTS family members; they control substrate selectivity and access to the catalytic site (26). MMP (39) and ADAM family (26,31) proteases play key roles as modulators of inflammation and innate immunity through activation or inactivation of cytokines, chemokines, or other proteins. The major substrate of the CLCA metalloprotease domains appears to be the CLCA protein itself, but given the central involvement of CLCAs in chronic inflammatory airway diseases, additional CLCA protease substrates should also be considered.…”

“…For example, MMPs and ADAM family proteases both contain an N-terminal prodomain, consisting of about 80 amino acids at the N terminus of the protein, that blocks access to the protease active site. This domain must be proteolytically removed for substrate access (27,31). Structure predictions of the CLCA-N domain metalloprotease region indicate that the characteristic catalytic fold would begin around residue 45, which would leave a short stretch of ϳ20 amino acids that may act as a prodomain.…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…ADAMTS (a disintegrin and metalloprotease with thrombospondin motif) are a group of proteins closely related to ADAMs (see for a review Apte et al, 2009;Jones and Riley, 2005;Porter et al, 2005;Salter et al, 2010;Shiomi et al, 2010;Tortorella et al, 2009;Wagstaff et al, 2011).…”

ADAMTSL3 as a candidate gene for schizophrenia: Gene sequencing and ultra-high density association analysis by imputation

“…ADAMTS family members demonstrate a narrow substrate specificity, making them potentially safe pharmaceutical targets (Tortorella et al, 2009). This could open a new paradigm for schizophrenia therapy and address some of the considerable unmet medical need for schizophrenia therapeutics with a more limited side-effect profile.…”