Dipeptidyl peptidase-4 (revision 1)

Dipeptidyl peptidase-4 (DPP-4), also known as CD26, is a serine exopeptidase that removes the N-terminal two residues from peptides presenting proline or alanine in the second position. Both incretin hormones — Glucagon-like peptide-1 and Glucose-dependent insulinotropic polypeptide — carry alanine at position 2 and are therefore inactivated within minutes of secretion.^[1]

The enzyme exists as a type II membrane protein on endothelial cells, epithelial cells and lymphocytes, and as a catalytically active soluble form in plasma. Cleavage of GLP-1 begins in the capillaries of the intestinal lamina propria, before the hormone reaches the portal vein, so that only a minority of secreted GLP-1 arrives at the systemic circulation intact.^[2]

DPP-4 cleaves the dipeptide His-Ala from the N-terminus of GLP-1(7–36)amide to yield GLP-1(9–36)amide. The truncated product binds the GLP-1 receptor with roughly two orders of magnitude lower affinity and behaves as a weak antagonist at pharmacological concentrations; whether it has independent cardiovascular activity remains an open question in the literature.^[2]

The substrate range is wide. Substance P, neuropeptide Y, several chemokines and the incretins are all cleaved, and the enzyme also has non-catalytic functions as a co-stimulatory molecule on T cells and as a binding partner for adenosine deaminase. The breadth of this range is the reason inhibitor development required careful selectivity against the related enzymes DPP-8 and DPP-9.^[1]