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Information on EC 3.4.21.2 - chymotrypsin C and Organism(s) Homo sapiens and UniProt Accession Q99895
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3.4.21.2 chymotrypsin CSpecify your search results
Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
chymotrypsin c, caldecrin, chymotrypsinogen c, serum calcium-decreasing factor, enzyme y, elastase-like chymotrypsin, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
enzyme Y
chymotrypsin C is identical to enzyme Y, the trypsinogen-degrading enzymatic activity isolated from human pancreatic juice
Serum calcium-decreasing factor
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CAS REGISTRY NUMBER
COMMENTARY
9036-09-3
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
cationic trypsin + H2O
?
-
selectively cleaves the Leu81-Glu82 peptide bond within the Ca2-binding loop
-
?
N-succinyl-Ala-Ala-Pro-Phe-4-nitroanilide + H2O
N-succinyl-Ala-Ala-Pro-Phe + 4-nitroaniline
-
-
-
?
N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide + H2O
N-succinyl-Ala-Ala-Pro-Phe + p-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Ala 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Ala + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Asn 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Asn + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Gln 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Gln + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Ile 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Ile + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Leu 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Leu + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Met 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Met + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Phe + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Trp 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Trp + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Tyr 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Tyr + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Val 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Val + 4-nitroaniline
-
-
-
?
cationic trypsinogen + H2O
?
-
chymotrypsin activates trypsinogen by cleaving the N-terminal tripeptide of the protein
-
-
?
cationic trypsinogen A16V + H2O
?
-
the A16V mutation of trypsinogen is processed 4fold more rapidly compared to wild-type trypsiongen
-
-
?
N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide + H2O
N-succinyl-Ala-Ala-Pro-Phe + p-nitroaniline
-
-
-
-
?
human cationic trypsinogen + H2O
?
-
enzyme cleaves the Leu81-Glu82 peptide bond in the calcium-binding loop. Chymotrypsin C-mediated cleavage is stimulated threefold by mutation E82A and unaffected by mutations E79A and N84A in human cationic trypsinogen. Specific cleavage of the Leu81-Glu82 peptide bond is primarily determined by the enzymes' distinctively high activity on leucyl peptide bonds, with the P1' Glu82, P3' Asn84 and P4' Glu85 residues serving as additional specificity determinants
-
?
succinyl-Ala-Ala-Pro-Phe 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Phe + 4-nitroaniline
-
-
-
?
succinyl-Ala-Ala-Pro-Phe 4-nitroanilide + H2O
succinyl-Ala-Ala-Pro-Phe + 4-nitroaniline
-
-
-
-
?
Trypsinogen + H2O
?
chymotrypsin C protects against pancreatitis by degrading trypsinogen and thereby curtailing harmful intrapancreatic trypsinogen activation
-
-
?
additional information
?
-
CTRC cleaves after a P1 Leu with at least tenfold higher catalytic efficiency than other enzymes tested
-
-
?
additional information
?
-
-
CTRC cleaves after a P1 Leu with at least tenfold higher catalytic efficiency than other enzymes tested
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
Trypsinogen + H2O
?
chymotrypsin C protects against pancreatitis by degrading trypsinogen and thereby curtailing harmful intrapancreatic trypsinogen activation
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ca2+
increasing the Ca2+ concentration from 0.025 mM to 1 mM progressively inhibits the degradation of cationic trypsin by chymotrypsin C, with essentially complete protection observed at 1 mM Ca2+
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.392
succinyl-Ala-Ala-Pro-Ala 4-nitroanilide
pH 8.0, temperature not specified in the publication
3.452
succinyl-Ala-Ala-Pro-Asn 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.738
succinyl-Ala-Ala-Pro-Gln 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.0605
succinyl-Ala-Ala-Pro-Ile 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.0118
succinyl-Ala-Ala-Pro-Leu 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.0304
succinyl-Ala-Ala-Pro-Met 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.0277
succinyl-Ala-Ala-Pro-Trp 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.0196
succinyl-Ala-Ala-Pro-Tyr 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.1504
succinyl-Ala-Ala-Pro-Val 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.0105
N-succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
mutant enzyme T58M, pH and temperature not specified in the publication
0.0134
N-succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
wild-type enzyme, pH and temperature not specified in the publication
0.022
succinyl-Ala-Ala-Pro-Phe 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.0153
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, wild-type enzyme
0.0157
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme I209M
0.0167
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme K247E
0.019
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme S239A
0.0194
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme R80W
0.0221
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme G214M
0.0221
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme G214R
0.0226
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme R80Q
0.0331
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme S239C
0.0472
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme G214A
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.3
succinyl-Ala-Ala-Pro-Ala 4-nitroanilide
pH 8.0, temperature not specified in the publication
3.6
succinyl-Ala-Ala-Pro-Asn 4-nitroanilide
pH 8.0, temperature not specified in the publication
1.1
succinyl-Ala-Ala-Pro-Gln 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.03
succinyl-Ala-Ala-Pro-Ile 4-nitroanilide
pH 8.0, temperature not specified in the publication
9.2
succinyl-Ala-Ala-Pro-Leu 4-nitroanilide
pH 8.0, temperature not specified in the publication
14.9
succinyl-Ala-Ala-Pro-Met 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.1
succinyl-Ala-Ala-Pro-Trp 4-nitroanilide
pH 8.0, temperature not specified in the publication
16.6
succinyl-Ala-Ala-Pro-Tyr 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.05
succinyl-Ala-Ala-Pro-Val 4-nitroanilide
pH 8.0, temperature not specified in the publication
11.7
N-succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
wild-type enzyme, pH and temperature not specified in the publication
24
N-succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
mutant enzyme T58M, pH and temperature not specified in the publication
13.2
succinyl-Ala-Ala-Pro-Phe 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.6
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme S239C
10.3
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme I209M
11.7
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme S239A
14.1
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme G214A
14.7
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme K247E
15.1
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme R80W
15.4
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, wild-type enzyme
16.5
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme R80Q
23.6
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme G214M
42.2
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme G214R
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.77
succinyl-Ala-Ala-Pro-Ala 4-nitroanilide
pH 8.0, temperature not specified in the publication
1
succinyl-Ala-Ala-Pro-Asn 4-nitroanilide
pH 8.0, temperature not specified in the publication
1.5
succinyl-Ala-Ala-Pro-Gln 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.5
succinyl-Ala-Ala-Pro-Ile 4-nitroanilide
pH 8.0, temperature not specified in the publication
780
succinyl-Ala-Ala-Pro-Leu 4-nitroanilide
pH 8.0, temperature not specified in the publication
490
succinyl-Ala-Ala-Pro-Met 4-nitroanilide
pH 8.0, temperature not specified in the publication
3.6
succinyl-Ala-Ala-Pro-Trp 4-nitroanilide
pH 8.0, temperature not specified in the publication
850
succinyl-Ala-Ala-Pro-Tyr 4-nitroanilide
pH 8.0, temperature not specified in the publication
0.33
succinyl-Ala-Ala-Pro-Val 4-nitroanilide
pH 8.0, temperature not specified in the publication
600
succinyl-Ala-Ala-Pro-Phe 4-nitroanilide
pH 8.0, temperature not specified in the publication
18
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme S239C
300
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme G214A
620
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme S239A
660
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme I209M
730
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme R80Q
780
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme R80W
880
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme K247E
1000
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, wild-type enzyme
1100
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme G214M
1900
succinyl-Ala-Ala-Pro-Phe-4-nitroanilide
pH 8.0, 22°C, mutant enzyme G214R
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
malfunction
-
pancreatitis-associated CTRC mutations can markedly increase the propensity of chymotrypsinogen C to elicit endoplasmic reticulum stress in pancreatic acinar cells. Diminished secretion and intracellular retention/degradation of the p.A73T CTRC mutant. Endoplasmic reticulum stress in AR42J cells is proportional to intracellular levels of the p.A73T CTRC mutant. No activation of the PERK pathway and NFkappaB in acinar cells expressing the p.A73T CTRC mutant. Apoptotic cell death in AR42J cells expressing the p.A73T CTRC mutant
malfunction
loss-of-function mutations increase the risk for pancreatitis. Variant p.G214R degrades trypsinogen poorly, is resistant to inhibitors and cleaves their reactive sites. Pathogenic variant p.G214R is a functional paralog of mesotrypsin, an inhibitor-degrading trypsin isoform
malfunction
the protective effect of chymotrypsin C against pancreatitis can be compromised by loss-of-function mutations in CTRC, which increase risk for sporadic chronic pancreatitis
physiological function
chymotrypsin C protects against pancreatitis by degrading trypsinogen and thereby curtailing harmful intrapancreatic trypsinogen activation
physiological function
intrapancreatic activation of human anionic trypsinogen is prevented through chymotrypsin-mediated degradation. Chymotrypsin C controls activation of human cationic trypsinogen through proteolytic cleavage of regulatory sites. Chymotrypsin C promotes degradation of anionic trypsinogen more effectively than it does with cationic trypsinogen
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CTRC_HUMAN
268
0
29484
Swiss-Prot
Secretory Pathway (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in complex with small protease inhibitor eglin C, to 1.9 A resolution. The inhibitor binds in a substrate-like manner filling the S6-S5' subsites of the substrate binding cleft. Significant binding affinity derives from burial of preferred hydrophobic residues at the P1, P4, and P2' positions of chymotrypsin C, although acidic P2' residues can also be accommodated by formation of an interfacial salt bridge. There is a ring of intense positive electrostatic surface potential surrounding the primarily hydrophobic substrate binding site. Long-range electrostatic attraction toward substrates of concentrated negative charge governs substrate discrimination
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
G214R
the mutant has increased activity on a small chromogenic peptide substrate but is markedly defective in cleaving bovine beta-casein or the natural chymotrypsin C substrates human cationic trypsinogen and procarboxypeptidase A1. Mutation p.G214R is analogous to the evolutionary mutation in human mesotrypsin, which renders this trypsin isoform resistant to proteinaceous inhibitors and conferrs its ability to cleave these inhibitors. Similarly to the mesotrypsin phenotype, chymotrypsin C variant p.G214R is inhibited poorly by eglin C, ecotin, or a chymotrypsin C-specific variant of SGPI-2, and it readily cleaves the reactive-site peptide bonds in eglin C and ecotin
mre
None of the mutants examined exhibits a gain of function such as increased secretion or activity. 11 mutants show marked loss of function, 3 mutants have moderate functional defects, whereas 18 mutants are functionally similar to wild-type. The functional deficiencies observed are diminished secretion, impaired catalytic activity and degradation by trypsin. Mutants with a secretion defect cause ER stress that is proportional to the loss in secretion. ER stress is not associated with loss-of-function phenotypes related to catalytic defect or proteolytic instability
T58M
mutation in a late-onset case of recurrent acute pancreatitis. The T58M mutant chymotrypsin C has comparable biochemical characteristics to wild type enzyme on large substrates
R37Q
-
mutant shows essentially normal activity and secretion (about 82-88% activity of the wild type enzyme)
V235I
-
CTRC activity secreted by cells transfected with variant V235I is moderately reduced (about 65% of the wild type enzyme)
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cDNAs for the wild-type CTRC and the p.A73T mutant carrying a Glu-Glu epitope tag excised from pcDNA3.1(-)_CTRC expression plasmids with XhoI and EcoRI and subcloned into the VQ Ad5CMV shuttle vector under the control of a CMV promoter. Dexamethasone-differentiated AR42J rat acinar cells and freshly isolated mouse acini transfected with recombinant adenovirus carrying wild-type CTRC or the p.A73T pancreatitis-associated mutant
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
in AR42J cells and mouse acini, CTRC is transiently expressed in its inactive zymogen form
-
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
carriers of CTRC mutations may be at a higher risk of developing endoplasmic reticulum stress in the exocrine pancreas. Endoplasmic reticulum stress may contribute to parenchymal damage in chronic pancreatitis through acinar cell apoptosis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Nemoda, Z.; Sahin-Toth, M.
Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen
J. Biol. Chem.
281
11879-11886
2006
Homo sapiens
Rosendahl, J.; Witt, H.; Szmola, R.; Bhatia, E.; Ozsvari, B.; Landt, O.; Schulz, H.U.; Gress, T.M.; Pfuetzer, R.; Loehr, M.; Kovacs, P.; Blueher, M.; Stumvoll, M.; Choudhuri, G.; Hegyi, P.; te Morsche, R.H.; Drenth, J.P.; Truninger, K.; Macek, M.; Puhl, G.; Witt, U.; Schmidt, H.; Buening, C.; Ockenga, J.
Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis
Nat. Genet.
40
78-82
2008
Homo sapiens
Szmola, R.; Sahin-Toth, M.
Chymotrypsin C (caldecrin) promotes degradation of human cationic trypsin: identity with Rinderknechts enzyme Y
Proc. Natl. Acad. Sci. USA
104
11227-11232
2007
Homo sapiens (Q99895), Homo sapiens
Szmola, R.; Sahin-Toth, M.
Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells
Gut
59
365-372
2010
Homo sapiens
Szabo, A.; Sahin-Toth, M.
Determinants of chymotrypsin C cleavage specificity in the calcium-binding loop of human cationic trypsinogen
FEBS J.
279
4283-4292
2012
Homo sapiens (Q99895), Homo sapiens
Beer, S.; Zhou, J.; Szabo, A.; Keiles, S.; Chandak, G.R.; Witt, H.; Sahin-Toth, M.
Comprehensive functional analysis of chymotrypsin C (CTRC) variants reveals distinct loss-of-function mechanisms associated with pancreatitis risk
Gut
62
1616-1624
2013
Homo sapiens (Q99895), Homo sapiens
Batra, J.; Szabo, A.; Caulfield, T.R.; Soares, A.S.; Sahin-Toth, M.; Radisky, E.S.
Long-range electrostatic complementarity governs substrate recognition by human chymotrypsin C, a key regulator of digestive enzyme activation
J. Biol. Chem.
288
9848-9859
2013
Homo sapiens (Q99895), Homo sapiens
Szabo, A.; Ludwig, M.; Hegyi, E.; Szepeova, R.; Witt, H.; Sahin-Toth, M.
Mesotrypsin signature mutation in a chymotrypsin C (CTRC) variant associated with chronic pancreatitis
J. Biol. Chem.
290
17282-17292
2015
Homo sapiens (Q99895), Homo sapiens
Jancso, Z.; Sahin-Toth, M.
Tighter control by chymotrypsin C (CTRC) explains lack of association between human anionic trypsinogen and hereditary pancreatitis
J. Biol. Chem.
291
12897-12905
2016
Homo sapiens (Q99895), Homo sapiens
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