Cathepsin X

 

Cathepsin X is a widespread, abundantly expressed papain-like mammalian lysosomal cysteine protease. It exhibits carboxy-monopeptidase as well as carboxy-dipeptidase activity and shares a similar activity profile with cathepsin B. Atypically, the mature enzyme is primarily a carboxypeptidase and has extremely poor endopeptidase activity. Cathepsin X is synthesised as an inactive zymogen, but the propeptide lacks the ERFNIN motif characteristic of lysosomal cysteine peptidases. A novel disulfide bridge can be formed between the proregion and the enzyme active site (Cys10p and Cys31) which leads to inactivation of the zymogen by the formation of a reversible covalent bond with the active site residue [PMID:10656802]. Cathepsin X deficiency leads to accelerated cell senescence [PMID:21616554] and it also regulates the immune response to Helicobacter pylori infection [PMID:16025436, PMID:19446361].

 

Reference Protein and Structure

Sequence
Q9UBR2 UniProt (3.4.18.1) IPR033157 (Sequence Homologues) (PDB Homologues)
Biological species
Homo sapiens (Human) Uniprot
PDB
1deu - CRYSTAL STRUCTURE OF HUMAN PROCATHEPSIN X: A CYSTEINE PROTEASE WITH THE PROREGION COVALENTLY LINKED TO THE ACTIVE SITE CYSTEINE (1.7 Å) PDBe PDBsum 1deu
Catalytic CATH Domains
3.90.70.10 CATHdb (see all for 1deu)
Click To Show Structure

Enzyme Reaction (EC:3.4.18.1)

dipeptide zwitterion
CHEBI:90799ChEBI
+
water
CHEBI:15377ChEBI
→
L-alpha-amino acid zwitterion
CHEBI:59869ChEBI
+
L-alpha-amino acid zwitterion
CHEBI:59869ChEBI
Alternative enzyme names: Acid carboxypeptidase, Cathepsin B(2), Cathepsin IV, Cathepsin Z, Cysteine-type carboxypeptidase, Lysosomal carboxypeptidase B,

Enzyme Mechanism

Introduction

This enzyme is thought to follow a similar mechanism to other cysteine proteases in which the catalytic cysteine residue acts as a nucleophile, activated by the histidine residue.

Catalytic Residues Roles

UniProt PDB* (1deu)
Gln83 Gln22(57)A Forms part of the oxyanion hole that stabilises the reactive intermediates and transition states formed during the course of the reaction. electrostatic stabiliser
Cys92 Cys31(66)A Acts as a general acid/base and catalytic nucleophile. covalent catalysis, proton shuttle (general acid/base)
Asn261 Asn200(235)A Modifies the pKa of the catalytic histidine. modifies pKa, electrostatic stabiliser
His241 His180(215)A Acts as a general acid/base. proton shuttle (general acid/base)
*PDB label guide - RESx(y)B(C) - RES: Residue Name; x: Residue ID in PDB file; y: Residue ID in PDB sequence if different from PDB file; B: PDB Chain; C: Biological Assembly Chain if different from PDB. If label is "Not Found" it means this residue is not found in the reference PDB.

Chemical Components

References

  1. Sivaraman J et al. (2000), J Mol Biol, 295, 939-951. Crystal structure of human procathepsin X: a cysteine protease with the proregion covalently linked to the active site cysteine. DOI:10.1006/jmbi.1999.3410. PMID:10656802.
  2. Kraus S et al. (2011), Eur J Cell Biol, 90, 678-686. Cellular senescence induced by cathepsin X downregulation. DOI:10.1016/j.ejcb.2011.03.008. PMID:21616554.
  3. Kos J et al. (2009), Cell Adh Migr, 3, 164-166. The role of cathepsin X in cell signaling. PMID:19262176.
  4. Obermajer N et al. (2009), Eur J Cell Biol, 88, 461-471. Cathepsin X prevents an effective immune response against Helicobacter pylori infection. DOI:10.1016/j.ejcb.2009.03.003. PMID:19446361.
  5. Krueger S et al. (2005), J Pathol, 207, 32-42. Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer. DOI:10.1002/path.1820. PMID:16025436.
  6. Guncar G et al. (2000), Structure, 8, 305-313. Crystal structure of cathepsin X: a flip-flop of the ring of His23 allows carboxy-monopeptidase and carboxy-dipeptidase activity of the protease. PMID:10745011.
  7. Klemencic I et al. (2000), Eur J Biochem, 267, 5404-5412. Biochemical characterization of human cathepsin X revealed that the enzyme is an exopeptidase, acting as carboxymonopeptidase or carboxydipeptidase. PMID:10951198.
  8. Nägler DK et al. (1999), Biochemistry, 38, 12648-12654. Human cathepsin X: A cysteine protease with unique carboxypeptidase activity. PMID:10504234.

Step 1.

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Catalytic Residues Roles

Residue Roles
Gln22(57)A electrostatic stabiliser
Asn200(235)A electrostatic stabiliser, modifies pKa
His180(215)A proton shuttle (general acid/base)
Cys31(66)A proton shuttle (general acid/base), covalent catalysis

Chemical Components

Step 1.

Contributors

Gemma L. Holliday