Peptidases (Molecular Biology)

Peptidases are enzymes that catalyze the hydrolysis of peptide bonds—that is, the -CONH- bonds that link amino acids in peptides, polypeptides, and proteins. According to the Enzyme Commission of the International Union of Biochemistry and Molecular Biology, they are Class 3, subgroup 4 (peptide hydrolase) enzymes (E.C. 3.4). Some peptidases only act on small substrates—di-, tri-, or oligopeptides—while others act preferentially on protein substrates. The latter are more properly referred to as proteinases (also known as proteases, proteolytic enzymes). Some peptidases cleave peptide bonds involving the amino acids at either the beginning or end, i.e., the amino terminal (N-terminal) or carboxy terminal (C-terminal)—of a peptide chain. They are therefore called exopeptidases and, depending on their particular specificity, are either aminopeptidases or carboxypeptidases. Other peptidases cleave internal bonds in a polypeptide chain and are called endopeptidases. Most peptidases are relatively specific and will only act at peptide bonds in which a particular amino acid or type of amino acid (acidic, basic, neutral, hydrophobic, etc.) contributes either the -CO or -NH group. Some have broad specificity, especially when acting on unfolded, denatured proteins, but they can be highly specific or not active at all with folded, native proteins.

Figure 1. Chemical structure of pepstatin [isovaleryl-valyl-valyl-(3S, 4S)4-amino-3-hydroxy-6-methylheptanoyl-alanyl-i amino-3-hydroxy-6-methylheptanoic acid], a transition-state analogue inhibitor of certain carboxyl proteinases, such as \ cathepsin D, and many microbial carboxyl proteinases. Because its structure resembles the tetrahedral intermediate that f substrate hydrolysis, it forms a tightly bound complex with the active site of each of these enzymes.

Peptidases have myriad functions. They activate or inactivate peptide hormones; they degrade dietary proteins and peptides; they participate in structural growth and remodeling by degrading collagen and other structural proteins; they protect against infectious agents; and they induce blood clotting. They regulate blood pressure, play an important role in fertilization, and control the cell cycle. They are ubiquitous and enormously diverse. As might be expected, inappropriate peptidase activity could have devastating consequences, so there are numerous peptidase inhibitors and other biological means of curtailing peptidase activity (see Proteinase Inhibitors).

While all peptidases catalyze peptide bond hydrolysis, they do not all do this the same way. In order to act under various conditions, four different mechanisms have evolved, and peptidases are classified as carboxyl proteinase, thiol proteinase, serine proteinase, and metalloproteinase, depending on the particular mechanism they employ. Even within these classes, there are many thematic variations such that it seems that there are almost as many peptidases as there are peptides.

Peptidases have a host of commercially significant uses ranging from "clot busters" (both in blood vessels and in drain pipes) to meat tenderizers. Peptidase inhibitors represent a multibillion dollar pharmaceutical market where they are important for controlling high blood pressure, as well as preventing the progress of acquired immune deficiency syndrome (AIDS).