DB code: S00445

RLCP classification 1.13.30000.44 : Hydrolysis
CATH domain 3.90.70.10 : Cathepsin B; Chain A Catalytic domain
E.C. 3.4.22.1
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
3.90.70.10 : Cathepsin B; Chain A S00444 S00447 S00448 S00449 S00450 S00451 S00446 S00518

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Contains MEROPS Pfam RefSeq
P00787 Cathepsin B
EC 3.4.22.1
Cathepsin B1
RSG-2
Cathepsin B light chain
Cathepsin B heavy chain
C01.060 (Cysteine)
PF00112 (Peptidase_C1)
PF08127 (Propeptide_C1)
[Graphical View]
P07858 Cathepsin B
EC 3.4.22.1
Cathepsin B1
APP secretase
APPS
Cathepsin B light chain
Cathepsin B heavy chain
C01.060 (Cysteine)
PF00112 (Peptidase_C1)
PF08127 (Propeptide_C1)
[Graphical View] 		NP_001899.1 (Protein)
NM_001908.3 (DNA/RNA sequence)
NP_680090.1 (Protein)
NM_147780.2 (DNA/RNA sequence)
NP_680091.1 (Protein)
NM_147781.2 (DNA/RNA sequence)
NP_680092.1 (Protein)
NM_147782.2 (DNA/RNA sequence)
NP_680093.1 (Protein)
NM_147783.2 (DNA/RNA sequence)

KEGG enzyme name
cathepsin B
cathepsin B1 (obsolete)
cathepsin II

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P00787 CATB_RAT Hydrolysis of proteins with broad specificity for peptide bonds. Preferentially cleaves -Arg-Arg-|-Xaa bonds in small molecule substrates (thus differing from cathepsin L). In addition to being an endopeptidase, shows peptidyl-dipeptidase activity, liberating C-terminal dipeptides. Dimer of a heavy chain and a light chain cross-linked by a disulfide bond. Lysosome. Melanosome (By similarity).
P07858 CATB_HUMAN Hydrolysis of proteins with broad specificity for peptide bonds. Preferentially cleaves -Arg-Arg-|-Xaa bonds in small molecule substrates (thus differing from cathepsin L). In addition to being an endopeptidase, shows peptidyl-dipeptidase activity, liberating C-terminal dipeptides. Dimer of a heavy chain and a light chain cross-linked by a disulfide bond. Lysosome. Melanosome. Note=Identified by mass spectrometry in melanosome fractions from stage I to stage IV.

KEGG Pathways
Map code Pathways E.C.

Compound table
Substrates Products Intermediates
KEGG-id C00017 C00012 C00001 C00017 C00012 I00153 I00154 I00155
E.C.
Compound Protein Peptide H2O Protein Peptide Peptidyl-Cys-tetrahedral-intermediate (with previous peptide) Acyl-enzyme(Peptidyl-Cys-acyl group) Peptidyl-Cys-tetrahedral-intermediate
Type peptide/protein peptide/protein H2O peptide/protein peptide/protein
ChEBI 15377
 15377
PubChem 22247451
 962
 22247451
 962
1cpjA Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1cpjB Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1csbA Unbound Unbound Unbound Unbound Intermediate-analogue:EP0 Unbound Unbound
1csbB Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1csbD Unbound Unbound Unbound Unbound Intermediate-analogue:EP0 Unbound Unbound
1csbE Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1cteA Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:PYS Unbound
1cteB Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:PYS Unbound
1hucA Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1hucB Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1hucC Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1hucD Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1mirA Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1mirB Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1qdqA Unbound Unbound Unbound Unbound Intermediate-analogue:074 Unbound
1theA Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:0E6 Unbound
1theB Unbound Unbound Unbound Unbound Unbound Intermediate-analogue:0E6 Unbound
3pbhA Unbound Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1cpjA GLN 23;CYS 29;HIS 199;ASN 219 CYS 29
1cpjB GLN 23;CYS 29;HIS 199;ASN 219 CYS 29
1csbA GLN 23;CYS 29 CYS 29
1csbB HIS 199;ASN 219
1csbD GLN 23;CYS 29 CYS 29
1csbE HIS 199;ASN 219
1cteA GLN 23;CYS 29;HIS 199;ASN 219 CYS 29
1cteB GLN 23;CYS 29;HIS 199;ASN 219 CYS 29
1hucA GLN 23;CYS 29 CYS 29
1hucB HIS 199;ASN 219
1hucC GLN 23;CYS 29 CYS 29
1hucD HIS 199;ASN 219
1mirA GLN 23; ;HIS 199;ASN 219 mutant C29S
1mirB GLN 23; ;HIS 199;ASN 219 mutant C29S
1qdqA GLN 23;CYS 29;HIS 199;ASN 219 CYS 29
1theA GLN 23;CYS 29;HIS 199;ASN 219 CYS 29
1theB GLN 23;CYS 29;HIS 199;ASN 219 CYS 29
3pbhA GLN 23;CYS 29;HIS 199;ASN 219 CYS 29

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
p.2327-2328
[2]
p.4720-4721
[4]
p.5530-5532, Fig.7
[8]
p.781

References
[1]
Resource
Comments X-ray crystallography (2.15 Angstroms)
Medline ID
PubMed ID 1868826
Journal EMBO J
Year 1991
Volume 10
Pages 2321-30
Authors Musil D, Zucic D, Turk D, Engh RA, Mayr I, Huber R, Popovic T, Turk V, Towatari T, Katunuma N, et al
Title The refined 2.15 A X-ray crystal structure of human liver cathepsin B: the structural basis for its specificity.
Related PDB 1huc
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 1537854
Journal J Biol Chem
Year 1992
Volume 267
Pages 4713-21
Authors Hasnain S, Hirama T, Tam A, Mort JS
Title Characterization of recombinant rat cathepsin B and nonglycosylated mutants expressed in yeast. New insights into the pH dependence of cathepsin B-catalyzed hydrolyses.
Related PDB
Related UniProtKB
[3]
Resource
Comments X-ray crystallography (2.0 Angstroms, with inhibitor)
Medline ID
PubMed ID 7718586
Journal Biochemistry
Year 1995
Volume 34
Pages 4791-7
Authors Turk D, Podobnik M, Popovic T, Katunuma N, Bode W, Huber R, Turk V
Title Crystal structure of cathepsin B inhibited with CA030 at 2.0-A resolution: A basis for the design of specific epoxysuccinyl inhibitors.
Related PDB 1csb
Related UniProtKB
[4]
Resource
Comments X-ray crystallography
Medline ID
PubMed ID 7890671
Journal J Biol Chem, Erratum in:J Biol Chem 1995 Nov 24;270(47):28494
Year 1995
Volume 270
Pages 5527-33
Authors Jia Z, Hasnain S, Hirama T, Lee X, Mort JS, To R, Huber CP
Title Crystal structures of recombinant rat cathepsin B and a cathepsin B-inhibitor complex. Implications for structure-based inhibitor design.
Related PDB 1cpj 1cte 1the
Related UniProtKB
[5]
Resource
Comments X-ray crystallography (3.2-3.3 Angstroms)
Medline ID
PubMed ID 8617355
Journal FEBS Lett
Year 1996
Volume 384
Pages 211-4
Authors Turk D, Podobnik M, Kuhelj R, Dolinar M, Turk V
Title Crystal structures of human procathepsin B at 3.2 and 3.3 Angstroms resolution reveal an interaction motif between a papain-like cysteine protease and its propeptide.
Related PDB 3pbh
Related UniProtKB
[6]
Resource
Comments X-ray crystallography (2.8 Angstroms)
Medline ID
PubMed ID 8740363
Journal Structure
Year 1996
Volume 4
Pages 405-16
Authors Cygler M, Sivaraman J, Grochulski P, Coulombe R, Storer AC, Mort JS
Title Structure of rat procathepsin B: model for inhibition of cysteine protease activity by the proregion.
Related PDB 1mir
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 9233788
Journal EMBO J
Year 1997
Volume 16
Pages 3787-96
Authors Johnston SC, Larsen CN, Cook WJ, Wilkinson KD, Hill CP
Title Crystal structure of a deubiquitinating enzyme (human UCH-L3) at 1.8 A resolution.
Related PDB
Related UniProtKB
[8]
Resource
Comments X-ray crystallography (2.5 Angstroms)
Medline ID 97446326
PubMed ID 9299326
Journal J Mol Biol
Year 1997
Volume 271
Pages 774-788
Authors Podobnik M., Kuhelj R., Turk V., Turk D
Title Crystal structure of the wild-type human procathepsin B at 2.5-A resolution reveals the native active site of a papain-like cysteine protease zymogen.
Related PDB
Related UniProtKB P07858
[9]
Resource
Comments (catalysis)
Medline ID
PubMed ID 10213604
Journal Biochemistry
Year 1999
Volume 38
Pages 5017-23
Authors Quraishi O, Nagler DK, Fox T, Sivaraman J, Cygler M, Mort JS, Storer AC
Title The occluding loop in cathepsin B defines the pH dependence of inhibition by its propeptide.
Related PDB
Related UniProtKB
[10]
Resource
Comments catalysis
Medline ID
PubMed ID 9890884
Journal Biochemistry
Year 1999
Volume 38
Pages 73-80
Authors Lukong KE, Elsliger MA, Mort JS, Potier M, Pshezhetsky AV
Title Identification of UDP-N-acetylglucosamine-phosphotransferase-binding sites on the lysosomal proteases, cathepsins A, B, and D.
Related PDB
Related UniProtKB
[11]
Resource
Comments X-ray crystallography (2.18 Angstroms)
Medline ID
PubMed ID 10739956
Journal J Biochem (Tokyo)
Year 2000
Volume 127
Pages 635-43
Authors Yamamoto A, Tomoo K, Hara T, Murata M, Kitamura K, Ishida T
Title Substrate specificity of bovine cathepsin B and its inhibition by CA074, based on crystal structure refinement of the complex.
Related PDB 1qdq
Related UniProtKB

Comments
This enzyme belongs to the peptidase family-C1.
According to the literature [1], the sidechain of Cys29 is reactive, with pKa 3.4, to form covalent bond with substrate during the first acylation step. This residue is positioned to form a hydrogen bond with the imidazole ring of the catalytic His199, which, in turn, forms a hydrogen bond with Asn219 [1]. The biochemical data [2] indicated that the pKa of His199 is 8.6, which is comparable to that of about 8.3 for the acitive site His159 of papain. Thus, this histidine residue must stabilize the thiolate anion with its positive charge [2].
The oxyanion hole, composed of Gln23 sidechain and Cys29 mainchain amide groups, is thought to stabilize the tetrahedral intermediate (see [4] & [8]).

Created Updated
2002-07-01 2012-10-23