Metabolomics cuts to the chase to chase the cuts.

type II diabetes5. However, like most proteases, a complete picture of the targets of DPP4 is lacking, which makes it difficult to anticipate metabolic function has prompted the development of a number of small-molecule inhibitors of DPP4, including sitagliptin (Januvia), which was recently approved by the US Food Proteases are enzymes that perform the basic task of cutting up other proteins and peptides by hydrolysis of amide bonds. In most organisms, proteases make up about 2% of the genome1 and can be grouped into subfamilies based on how and where they carry out cutting of a substrate2. The alternative name, peptidase, is often used to describe proteases that act on small peptide substrates rather than proteins. Though proteases and peptidases were once thought to be the uninteresting “garbage disposal units” of the cell, it is now clear that specific and partial proteolysis of protein and peptide substrates plays a critical role in regulating the function of a large and diverse array of signaling molecules. The process of cutting a protein or peptide into smaller pieces can lead to either a gain or loss of function of the substrate. In addition, most proteases act on more than one substrate, resulting in a complex array of possible outcomes that can be controlled by a single protease. Thus, methods that can be used to globally define all the proteolytic processing events mediated by a given protease are often required to fully understand its true range of biological functions. The need to get such a global picture of proteolytic pathways is heightened in cases where a protease is a target for drugs designed to treat human diseases. Having a complete picture of these regulatory networks is critical to our ability to predict the behavior of a drug when used to treat people. In this issue of Nature Chemical Biology, Tagore et al. profile the levels of peptide metabolites (the ‘metabolome’) that are produced by dipeptidyl peptidase 4 (DPP4)3, which removes the first two amino acids (dipeptides) at the N terminus of a peptide substrate. One of its key metabolic regulatory roles is to cleave the peptide hormone glucagon-like peptide-1 (GLP-1), which in turn leads to a reduction in the secretion of insulin by the beta cells of the pancreas4. The identification of this critical Metabolomics cuts to the chase to chase the cuts