Metalloproteases and Proteolytic Processing

Proteolytic enzymes constitute around 2% of the human genome and are involved in all stages of cell and organism development from fertilization through to cell death. In the human genome the major classes of peptidases are represented by cysteine-, serine- and metalloenzymes, which possess a wide spectrum of substrate specificity and physiological functions. The identification of many novel peptidases from genome sequencing programmes has suggested potential new therapeutic targets. In addition, several well characterised peptidases were recently shown to possess new and unexpected biological roles in neuroinflammation, cancer and angiogenesis, cardiovascular diseases and neurodegeneration. This chapter will briefly characterize the main classes of metallopeptidases and their roles in health and disease. Particular attention will be paid to the angiotensin-converting enzyme (ACE), neprilysin (NEP) and adamalysin (ADAM) families of proteases and their pathophysiological roles with a particular emphasis on cancer and neurodegeneration. The roles and mechanisms of protein shedding which primarily involve the ADAMs family of metallopeptidases will be explained using amyloid protein precursor (APP) processing cascades as a well characterized example. The therapeutic significance of modulating (activating or inhibiting) metallopeptidase activity will be a particular focus of this chapter.