InterPro domain: IPR033157

Cathepsin Z (also known as Cathepsin X , 3.4.18.1 and MEROPS identifier C01.013) is predominantly a cysteine-type carboxypeptidase with limited endopeptidase or dipeptidyl-peptidase activity, mainly against synthetic substrates [ 1 , 2 ]. The substrate specificity has been examined by peptide scanning and shows that proline is not tolerated in the P1 or P1' positions and poorly accepted in P2, and Tyr, Met and Cys are marginally prefered in P2, P1 and P1' [ 3 , 4 ].

Cathepsin X is synthesized as an inactive zymogen, but the propeptide lacks the ERFNIN motif characteristic of lysosomal cysteine peptidases. A disulfide bridge can be formed between the proregion and the enzyme which leads to inactivation of the zymogen by the formation of a reversible covalent bond with the active site residue [ 5 ]. From the crystal structure of the mature enzyme, a short, five-residue 'mini-loop' which includes the motif His-Xaa-Xaa-Xaa-Tyr restricts access to the S2' binding pocket, and it is the histidine that confers carboxypeptidase activity [ 6 ]. Rotation of the histidine ring permits dipeptidyl-peptidase substrates to bind. The presence of an exposed RGD motif allows binding to beta3-integrin [ 7 ] and the enzyme may have a role in cell signalling. Cathepsin X deficiency leads to accelerated cell senescence [ 8 ]. Cathepsin X also regulates the immune response to Helicobacter pylori infection [ 9 , 10 ].

1. Human cathepsin X: A cysteine protease with unique carboxypeptidase activity. Biochemistry 38, 12648-54
2. Biochemical characterization of human cathepsin X revealed that the enzyme is an exopeptidase, acting as carboxymonopeptidase or carboxydipeptidase. Eur. J. Biochem. 267, 5404-12
3. Carboxy-monopeptidase substrate specificity of human cathepsin X. Biochem. Biophys. Res. Commun. 329, 445-52
4. Recombinant human cathepsin X is a carboxymonopeptidase only: a comparison with cathepsins B and L. Biol. Chem. 386, 1191-5
5. Crystal structure of human procathepsin X: a cysteine protease with the proregion covalently linked to the active site cysteine. J. Mol. Biol. 295, 939-51
6. Crystal structure of cathepsin X: a flip-flop of the ring of His23 allows carboxy-monopeptidase and carboxy-dipeptidase activity of the protease. Structure 8, 305-13
7. Carboxypeptidase cathepsin X mediates beta2-integrin-dependent adhesion of differentiated U-937 cells. Exp. Cell Res. 312, 2515-27
8. Cellular senescence induced by cathepsin X downregulation. Eur. J. Cell Biol. 90, 678-86
9. Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer. J. Pathol. 207, 32-42
10. Cathepsin X prevents an effective immune response against Helicobacter pylori infection. Eur. J. Cell Biol. 88, 461-71