Cathepsin H

 

Cathepsin H is a lysosomal cysteine protease, involved in intracellular protein degradation. It is the only known mono-aminopeptidase in the papain-like family and is reported to be involved in tumor metastasis. The enzyme is a relatively abundant protease involved in intracellular protein degradation. It has been proposed that the levels of Cathepsin increase during disease states. Cathepsin H is an aminopeptidase, cleaving a single N-terminal residue from a polypeptide chain. It has been shown that Cathepsin H also exhibits endopeptidase activity. The mature protein consists of three fragments; the N-terminal heavy and C-terminal light chains, and an octapeptide called the mini-chain.

 

Reference Protein and Structure

Sequence
O46427 UniProt (3.4.22.16) IPR013128 (Sequence Homologues) (PDB Homologues)
Biological species
Sus scrofa (pig) Uniprot
PDB
8pch - CRYSTAL STRUCTURE OF PORCINE CATHEPSIN H DETERMINED AT 2.1 ANGSTROM RESOLUTION: LOCATION OF THE MINI-CHAIN C-TERMINAL CARBOXYL GROUP DEFINES CATHEPSIN H AMINOPEPTIDASE FUNCTION (2.1 Å) PDBe PDBsum 8pch
Catalytic CATH Domains
3.90.70.10 CATHdb (see all for 8pch)
Click To Show Structure

Enzyme Reaction (EC:3.4.22.16)

water
CHEBI:15377ChEBI
+
dipeptide zwitterion
CHEBI:90799ChEBI
→
L-alpha-amino acid zwitterion
CHEBI:59869ChEBI
Alternative enzyme names: N-benzoylarginine-beta-naphthylamide hydrolase, Aleurain, Benzoylarginine-naphthylamide (BANA) hydrolase, Cathepsin B(3), Cathepsin Ba, Cathepsin BA, Cathepsin B3,

Enzyme Mechanism

Introduction

The active site triad ( CYS 25, HIS 159, GLN 19) is found in a cleft found running across the top of the molecule. The backbone and sidechains of the catalytic residues are found at positions usual for a papain-like enzyme. The only exception is the HIS 159 imidazole ring which in contrasts to all other known structures of cysteine proteases - does not form a thiolate-imidazolium ion pair with CYS 25.

Catalytic Residues Roles

UniProt PDB* (8pch)
Gln135 Gln19(20)A Forms part of a Cys-His-Gln catalytic triad. Activates the histidine residue. electrostatic stabiliser
Cys141 Cys25(26)A Forms part of a Cys-His-Gln catalytic triad. Acts as a catalytic nucleophile. covalent catalysis, proton shuttle (general acid/base)
His281 His159(166)A Forms part of a Cys-His-Gln catalytic triad. Acts as a general acid/base. proton shuttle (general acid/base), electrostatic stabiliser
*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. Guncar G et al. (1998), Structure, 6, 51-61. Crystal structure of porcine cathepsin H determined at 2.1 å resolution: location of the mini-chain C-terminal carboxyl group defines cathepsin H aminopeptidase function. DOI:10.1016/s0969-2126(98)00007-0. PMID:9493267.
  2. Turk V et al. (2012), Biochim Biophys Acta, 1824, 68-88. Cysteine cathepsins: from structure, function and regulation to new frontiers. DOI:10.1016/j.bbapap.2011.10.002. PMID:22024571.
  3. Jenko S et al. (2003), J Mol Biol, 326, 875-885. Crystal Structure of Stefin A in Complex with Cathepsin H: N-terminal Residues of Inhibitors can Adapt to the Active Sites of Endo- and Exopeptidases. DOI:10.1016/S0022-2836(02)01432-8.

Step 1.

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Catalytic Residues Roles

Residue Roles
Cys25(26)A proton shuttle (general acid/base)
His159(166)A proton shuttle (general acid/base)
Gln19(20)A electrostatic stabiliser
His159(166)A electrostatic stabiliser
Cys25(26)A covalent catalysis

Chemical Components

Step 1.

Contributors

Craig Porter, Gemma L. Holliday, Charity Hornby