InterPro domain: IPR039461

Peptidase family M49 contains exopeptidases that remove dipeptides from the N terminus of peptides and proteins and are known as dipeptidyl-peptidases (DPP). The best characterized of these is dipeptidyl-peptidase III (DPPIII; 3.4.14.4 ; MEROPS identifier M49.001). The exopeptidases in M49 are metal-dependent, and bind a single zinc ion via the histidines in an HEXXXH motif, in which the distance between the histidines in one residue longer than in the HEXXH zinc-binding motif found in endopeptidases of clan MA. The importance of the histidines and the glutamic acid was identified by site-directed mutagenesis [ 1 ]. Some members of family M49, notably from bacteria such as Colwelia and plants possess the more usual HEXXH motif [ 2 ]. A third zinc ligand occurs within a motif that has been described as EECRAE [ 3 ]. DPPIII releases N-terminal dipeptides sequentially from peptides such as angiotensins II and III, Leu-enkephalin, prolactin and alpha-melanocyte-stimulating hormone, but tripeptides are poor substrates and polypeptides of more than ten residues are not cleaved [ 4 , 5 ]. DPPIII is a soluble, cytosolic enzyme with a housekeeping role, but is elevated in retroplacental serum may participate in the increased angiotensin hydrolysis seen during pregnancy [ 6 ].

This family also includes Nudix hydrolase 3 (NUDT3) from plants, which is thought to hydrolyse nucleoside diphosphate derivatives because of the presence of a Nudix box. Isopentenyl diphosphate (IPP), a universal precursor for the biosynthesis of isoprenoid compounds, is hydrolysed; purine nucleotides such as 8-oxo-dATP are dephosphorylated; and the enzyme acts as a dipeptidyl-peptidase against dipeptidyl-2-arylamide substrates [ 7 ].

1. The HELLGH motif of rat liver dipeptidyl peptidase III is involved in zinc coordination and the catalytic activity of the enzyme. Biochemistry 38, 8299-303
2. A novel plant enzyme with dual activity: an atypical Nudix hydrolase and a dipeptidyl peptidase III. Biol. Chem. 398, 101-112
3. The first structure of dipeptidyl-peptidase III provides insight into the catalytic mechanism and mode of substrate binding. J. Biol. Chem. 283, 22316-24
4. Dipeptidyl-aminopeptidase III of rat brain. Selective affinity for enkephalin and angiotensin. J. Biol. Chem. 257, 12043-50
5. Dipeptidyl peptidase III from human erythrocytes. Biol. Chem. Hoppe-Seyler 369, 29-38
6. Purification and characterization of dipeptidyl aminopeptidase III from human placenta. Chem. Pharm. Bull. 34, 3333-40