Editorial [Hot Topic: ADAMs: Targets for Drug Discovery (Executive Editor: Marcia L. Moss)]

From cancer to obesity to bacterial infections, dysregulation of metalloproteinases, can be a causative factor in disease states. A subclass of metalloproteinases, the metzincins, defines a super family that is involved in a number of pathophysiological conditions. Each member contains a HEXGHXXGXXHD region that coordinates the active site zinc atom and is critical for catalysis. In addition, they also have a structural motif downstream from the coordination site, beginning with a methionine residue that is known as the met turn. Early on, much promise was given to the metzincin family members, the matrixins. The matrixins are a family composed of matrix metalloproteinases (MMPs) that are important for extracellular matrix turnover, and are also capable of driving progression of diseases such as cancer and arthritis. At approximately the same time as MMPs were falling out of favor due to unwanted side effects associated with their inhibition, a new family was added to the metzincins metalloproteinases; the adamalysins. The first in the adamalysin family, ADAM1, was discovered by Carl Blobel in Judith White's laboratory at the University of Virginia. ADAM1, also named Fertilin, was found to be important for sperm/egg fusion. Since then a total of 25 ADAMs have been uncovered by cloning and/or sequencing of the human genome. ADAM family members now make up the majority of pharmaceutical targets currently undergoing preclinical and clinical evaluation. The ADAM family was expanded in 1997 to include the ADAMTS proteins, which are ADAMs with thrombospondin motifs. Kuno et al. reported the gene sequence encoding a proteinase that was upregulated in tumors, which was named ADAMTS-1. Shortly after this discovery, when pharmaceutical companies were actively searching for the enzyme(s) responsible for promoting osteoarthritis by the degradation of aggrecan, ADMP-1 and ADMP-2 were found by a group led by Elizabeth Arner while at Dupont Merck, and these were subsequently renamed ADAMTS-4 and 5. There are currently 19 ADAMTS family members.