D00423
type: Enzyme
rlcp: p966
cath: Cathepsin D, subunit A; domain 1
ec: https://purl.uniprot.org/enzyme/3.4.23.4
csa: 1cms
uniprot: P00794
kegg enzyme: chymosin
kegg enzyme: rennin (but this should be avoided since it leads to confusion withrenin)
kegg substrate: Protein
kegg substrate: Peptide
kegg substrate: Casein K
kegg substrate: H2O
kegg product: Protein
kegg product: Peptide
kegg intermediate: Amino-diol-tetrahedral intermediate
pdb: 1cmsA01
pdb: 1cziE01
pdb: 3cmsA01
pdb: 4cmsA01
pdb: 1cmsA02
pdb: 1cziE02
pdb: 3cmsA02
pdb: 4cmsA02
pdb bound state: Unbound
  compound: Protein
  pdb: 1cmsA01
pdb bound state: Unbound
  compound: Protein
  pdb: 1cziE01
pdb bound state: Unbound
  compound: Protein
  pdb: 3cmsA01
pdb bound state: Unbound
  compound: Protein
  pdb: 4cmsA01
pdb bound state: Unbound
  compound: Protein
  pdb: 1cmsA02
pdb bound state: Unbound
  compound: Protein
  pdb: 1cziE02
pdb bound state: Unbound
  compound: Protein
  pdb: 3cmsA02
pdb bound state: Unbound
  compound: Protein
  pdb: 4cmsA02
pdb bound state: Unbound
  compound: Peptide
  pdb: 1cmsA01
pdb bound state: Unbound
  compound: Peptide
  pdb: 1cziE01
pdb bound state: Unbound
  compound: Peptide
  pdb: 3cmsA01
pdb bound state: Unbound
  compound: Peptide
  pdb: 4cmsA01
pdb bound state: Unbound
  compound: Peptide
  pdb: 1cmsA02
pdb bound state: Unbound
  compound: Peptide
  pdb: 1cziE02
pdb bound state: Unbound
  compound: Peptide
  pdb: 3cmsA02
pdb bound state: Unbound
  compound: Peptide
  pdb: 4cmsA02
pdb bound state: Unbound
  compound: Casein K
  pdb: 1cmsA01
pdb bound state: Unbound
  compound: Casein K
  pdb: 1cziE01
pdb bound state: Unbound
  compound: Casein K
  pdb: 3cmsA01
pdb bound state: Unbound
  compound: Casein K
  pdb: 4cmsA01
pdb bound state: Unbound
  compound: Casein K
  pdb: 1cmsA02
pdb bound state: Unbound
  compound: Casein K
  pdb: 1cziE02
pdb bound state: Unbound
  compound: Casein K
  pdb: 3cmsA02
pdb bound state: Unbound
  compound: Casein K
  pdb: 4cmsA02
pdb bound state: Unbound
  compound: Protein
  pdb: 1cmsA01
pdb bound state: Unbound
  compound: Protein
  pdb: 1cziE01
pdb bound state: Unbound
  compound: Protein
  pdb: 3cmsA01
pdb bound state: Unbound
  compound: Protein
  pdb: 4cmsA01
pdb bound state: Unbound
  compound: Protein
  pdb: 1cmsA02
pdb bound state: Unbound
  compound: Protein
  pdb: 1cziE02
active site residues resources: P00794
references: The structure and function of acid proteases. III. Isolation and characterization of the active-site peptides from bovine rennin.
references: Alteration of catalytic properties of chymosin by site-directed mutagenesis.
references: Engineering enzyme subsite specificity: preparation, kinetic characterization, and X-ray analysis at 2.0-A resolution of Val111Phe site-mutated calf chymosin.
references: Protein engineering of chymosin; modification of the optimum pH of enzyme catalysis.
references: The three-dimensional structure of recombinant bovine chymosin at 2.3 A resolution.
references: X-ray structural studies of mammalian aspartic proteinases.
references: Functional implications of the three-dimensional structure of bovine chymosin.
references: Chymosin-catalyzed peptide synthesis.
references: X-ray analyses of aspartic proteinases. IV. Structure and refinement at 2.2 A resolution of bovine chymosin.
references: Can enzymes adopt a self-inhibited form? Results of x-ray crystallographic studies of chymosin.
references: Functional implication of disulfide bond, Cys250 -Cys283, in bovine chymosin.
references: Domain flexibility in aspartic proteinases.
references: Protein engineering of surface loops: preliminary X-ray analysis of the CHY155-165RHI mutant.
references: Restrained molecular dynamics study of the interaction between bovine kappa-casein peptide 98-111 and bovine chymosin and porcine pepsin.
references: Post X-ray crystallographic studies of chymosin: the existence of two structural forms and the regulation of activity by the interaction with the histidine-proline cluster of kappa-casein.
references: Protein engineering loops in aspartic proteinases: site-directed mutagenesis, biochemical characterization and X-ray analysis of chymosin with a replaced loop from rhizopuspepsin.
references: Functional implications of disulfide bond, Cys45-Cys50, in recombinant prochymosin.
references: Mutagenesis, biochemical characterization and X-ray structural analysis of point mutants of bovine chymosin.
references: http://ezcatdb.cbrc.jp/EzCatDB/reference/D00423#19
references: Post X-ray crystallographic studies of chymosin specificity. The role of histidine-proline cluster of kappa-casein in catalytic reactions.
references: Mechanism of activation of the gastric aspartic proteinases: pepsinogen, progastricsin and prochymosin.
references: A 2.3 A resolution structure of chymosin complexed with a reduced bond inhibitor shows that the active site beta-hairpin flap is rearranged when compared with the native crystal structure.
references: Functional implications of disulfide bond, Cys206-Cys210, in recombinant prochymosin (chymosin).
references: A basic residue at position 36p of the propeptide is not essential for the correct folding and subsequent autocatalytic activation of prochymosin.
references: Role of S'1 loop residues in the substrate specificities of pepsin A and chymosin.
comment: This enzyme belongs to the peptidase family-A1. This enzyme has got a catalytic dyad, composed of two aspartic acid residues, which are conserved among other aspartate proteases such as pepsin (D00436 in EzCatDB). Thus, its catalytic mechanism must be similar to those.

Cathepsin D, subunit A; domain 1
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/2.40.70.10
catalytic domain: index.html

Protein
type: KeggSubstrate
references: KEGG:C00017
compound type: peptide/protein
type: KeggProduct

Peptide
type: KeggSubstrate
references: KEGG:C00012
compound type: peptide/protein
type: KeggProduct

Casein K
type: KeggSubstrate
references: KEGG:C01483
compound type: peptide/protein
references: CHEBI:74101
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

H2O
type: KeggSubstrate
references: KEGG:C00001
compound type: H2O
references: CHEBI:15377
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

Amino-diol-tetrahedral intermediate
type: KeggIntermediate
references: KEGG:I00136

1cmsA01
type: Pdb
references: 1cms
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1cms
catalytic residue: ASP 34

1cziE01
type: Pdb
references: 1czi
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1czi
catalytic residue: ASP 32

3cmsA01
type: Pdb
references: 3cms
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:3cms
catalytic residue: ASP 32

4cmsA01
type: Pdb
references: 4cms
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:4cms
catalytic residue: ASP 32

1cmsA02
type: Pdb
references: 1cms
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1cms
catalytic residue: ASP 216

1cziE02
type: Pdb
references: 1czi
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1czi
catalytic residue: ASP 215

3cmsA02
type: Pdb
references: 3cms
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:3cms
catalytic residue: ASP 215

4cmsA02
type: Pdb
references: 4cms
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:4cms
catalytic residue: ASP 215

The structure and function of acid proteases. III. Isolation and characterization of the active-site peptides from bovine rennin.
type: BibliographicResource
comment: ACTIVE SITE PEPTIDES OF CHYMOSIN B.
medline id: 75060332
references: http://www.ncbi.nlm.nih.gov/pubmed/4612029
journal: J Biochem (Tokyo)
volume: 76
pages: 467-74
published year: 1974
authors:
  item: Chang WJ
  item: Takahashi K
references: P00794

Alteration of catalytic properties of chymosin by site-directed mutagenesis.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/2501781
journal: Protein Eng
volume: 2
pages: 563-9
published year: 1989
authors:
  item: Suzuki J
  item: Sasaki K
  item: Sasao Y
  item: Hamu A
  item: Kawasaki H
  item: Nishiyama M
  item: Horinouchi S
  item: Beppu T

Engineering enzyme subsite specificity: preparation, kinetic characterization, and X-ray analysis at 2.0-A resolution of Val111Phe site-mutated calf chymosin.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF MUTANT.
medline id: 91104895
references: http://www.ncbi.nlm.nih.gov/pubmed/2271625
journal: Biochemistry
volume: 29
pages: 9863-71
published year: 1990
authors:
  item: Strop P
  item: Sedlacek J
  item: Stys J
  item: Kaderabkova Z
  item: Blaha I
  item: Pavlickova L
  item: Pohl J
  item: Fabry M
  item: Kostka V
  item: Newman M
  item: et al
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P00794

Protein engineering of chymosin; modification of the optimum pH of enzyme catalysis.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/2217134
journal: Protein Eng
volume: 3
pages: 605-9
published year: 1990
authors:
  item: Mantafounis D
  item: Pitts J

The three-dimensional structure of recombinant bovine chymosin at 2.3 A resolution.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
medline id: 91017501
references: http://www.ncbi.nlm.nih.gov/pubmed/2217166
journal: Proteins
volume: 8
pages: 82-101
published year: 1990
authors:
  item: Gilliland GL
  item: Winborne EL
  item: Nachman J
  item: Wlodawer A
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P00794

X-ray structural studies of mammalian aspartic proteinases.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/1812745
journal: Adv Exp Med Biol
volume: 306
pages: 47-61
published year: 1991
authors:
  item: Cooper JB
  item: Newman MP

Functional implications of the three-dimensional structure of bovine chymosin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/1812710
journal: Adv Exp Med Biol
volume: 306
pages: 23-37
published year: 1991
authors:
  item: Gilliland GL
  item: Oliva MT
  item: Dill J

Chymosin-catalyzed peptide synthesis.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/1820027
journal: Biomed Biochim Acta
volume: 50
pages: S102-5
published year: 1991
authors:
  item: Abdel Malak CA
  item: Lavrenova GI

X-ray analyses of aspartic proteinases. IV. Structure and refinement at 2.2 A resolution of bovine chymosin.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
medline id: 92046065
references: http://www.ncbi.nlm.nih.gov/pubmed/1942052
journal: J Mol Biol
volume: 221
pages: 1295-309
published year: 1991
authors:
  item: Newman M
  item: Safro M
  item: Frazao C
  item: Khan G
  item: Zdanov A
  item: Tickle IJ
  item: Blundell TL
  item: Andreeva N
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P00794

Can enzymes adopt a self-inhibited form? Results of x-ray crystallographic studies of chymosin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/1575726
journal: Biochem Biophys Res Commun
volume: 184
pages: 1074-81
published year: 1992
authors:
  item: Andreeva N
  item: Dill J
  item: Gilliland GL

Functional implication of disulfide bond, Cys250 -Cys283, in bovine chymosin.
type: BibliographicResource
comment: MUTAGENESIS OF CYS-308 AND CYS-341.
medline id: 92412108
references: http://www.ncbi.nlm.nih.gov/pubmed/1530626
journal: Biochem Biophys Res Commun
volume: 187
pages: 692-6
published year: 1992
authors:
  item: Huang K
  item: Zhang Z
  item: Liu N
  item: Zhang Y
  item: Zhang G
  item: Yang K
references: P00794

Domain flexibility in aspartic proteinases.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/1603805
journal: Proteins
volume: 12
pages: 158-70
published year: 1992
authors:
  item: Sali A
  item: Veerapandian B
  item: Cooper JB
  item: Moss DS
  item: Hofmann T
  item: Blundell TL

Protein engineering of surface loops: preliminary X-ray analysis of the CHY155-165RHI mutant.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/8540386
journal: Adv Exp Med Biol
volume: 362
pages: 95-9
published year: 1995
authors:
  item: Dhanaraj RR
  item: Pitts JE
  item: Nugent P
  item: Orprayoon P
  item: Cooper JB
  item: Blundell TL
  item: Uusitalo J
  item: Penttila M

Restrained molecular dynamics study of the interaction between bovine kappa-casein peptide 98-111 and bovine chymosin and porcine pepsin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/7593830
journal: J Dairy Res
volume: 62
pages: 451-67
published year: 1995
authors:
  item: Plowman JE
  item: Creamer LK

Post X-ray crystallographic studies of chymosin: the existence of two structural forms and the regulation of activity by the interaction with the histidine-proline cluster of kappa-casein.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/8566230
journal: FEBS Lett
volume: 379
pages: 60-2
published year: 1996
authors:
  item: Gustchina E
  item: Rumsh L
  item: Ginodman L
  item: Majer P
  item: Andreeva N

Protein engineering loops in aspartic proteinases: site-directed mutagenesis, biochemical characterization and X-ray analysis of chymosin with a replaced loop from rhizopuspepsin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/8931128
journal: Protein Eng
volume: 9
pages: 885-93
published year: 1996
authors:
  item: Nugent PG
  item: Albert A
  item: Orprayoon P
  item: Wilsher J
  item: Pitts JE
  item: Blundell TL
  item: Dhanaraj V

Functional implications of disulfide bond, Cys45-Cys50, in recombinant prochymosin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9434118
journal: Biochim Biophys Acta
volume: 1343
pages: 278-86
published year: 1997
authors:
  item: Zhang Y
  item: Li H
  item: Wu H
  item: Don Y
  item: Liu N
  item: Yang K

Mutagenesis, biochemical characterization and X-ray structural analysis of point mutants of bovine chymosin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9464563
journal: Protein Eng
volume: 10
pages: 991-7
published year: 1997
authors:
  item: Williams MG
  item: Wilsher J
  item: Nugent P
  item: Mills A
  item: Dhanaraj V
  item: Fabry M
  item: Sedlacek J
  item: Uusitalo JM
  item: Penttila ME
  item: Pitts JE
  item: Blundell TL

http://ezcatdb.cbrc.jp/EzCatDB/reference/D00423#19
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9561215
journal: Adv Exp Med Biol
volume: 436
pages: 169-77
published year: 1998
authors:
  item: Albert A
  item: Blundell TL
  item: Dhanaraj V
  item: Donate LE
  item: Groves M
  item: Guruprasad K
  item: Nugent PG
  item: Orprayoon P
  item: Pitts JE
  item: Rufino S
  item: Srinivasan N
  item: Williams M
  item: Wilsher J
title: Protein engineering aspartic proteinases. Site-directed mutagenesis, biochemical characterisation, and X-ray analysis of chymosins with substituted single amino acid substitutions and loop replacements.

Post X-ray crystallographic studies of chymosin specificity. The role of histidine-proline cluster of kappa-casein in catalytic reactions.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9561216
journal: Adv Exp Med Biol
volume: 436
pages: 179-84
published year: 1998
authors:
  item: Gustchina EA
  item: Majer P
  item: Rumsh LD
  item: Ginodman LM
  item: Andreeva NS

Mechanism of activation of the gastric aspartic proteinases: pepsinogen, progastricsin and prochymosin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/9794784
journal: Biochem J
volume: 335
pages: 481-90
published year: 1998
authors:
  item: Richter C
  item: Tanaka T
  item: Yada RY

A 2.3 A resolution structure of chymosin complexed with a reduced bond inhibitor shows that the active site beta-hairpin flap is rearranged when compared with the native crystal structure.
type: BibliographicResource
comment: X-ray crystallography
references: http://www.ncbi.nlm.nih.gov/pubmed/9862200
journal: Protein Eng
volume: 11
pages: 833-40
published year: 1998
authors:
  item: Groves MR
  item: Dhanaraj V
  item: Badasso M
  item: Nugent P
  item: Pitts JE
  item: Hoover DJ
  item: Blundell TL
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl

Functional implications of disulfide bond, Cys206-Cys210, in recombinant prochymosin (chymosin).
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11015192
journal: Biochemistry
volume: 39
pages: 12140-8
published year: 2000
authors:
  item: Chen H
  item: Zhang G
  item: Zhang Y
  item: Dong Y
  item: Yang K

A basic residue at position 36p of the propeptide is not essential for the correct folding and subsequent autocatalytic activation of prochymosin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11298755
journal: Eur J Biochem
volume: 268
pages: 2362-8
published year: 2001
authors:
  item: Francky A
  item: Francky BM
  item: Strukelj B
  item: Gruden K
  item: Ritonja A
  item: Krizaj I
  item: Kregar I
  item: Pain RH
  item: Pungercar J

Role of S'1 loop residues in the substrate specificities of pepsin A and chymosin.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/15568804
journal: Biochemistry
volume: 43
pages: 15122-30
published year: 2004
authors:
  item: Kageyama T

TransitionStateAnalogue
compound: Amino-diol-tetrahedral intermediate
pdb: 1cziE01
ligand het code: PRO-PHI-SMC-NOR

ReferenceForCatalyticMechanism
reference index: 9
reference section: p.1304-1305