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Information on EC 3.4.14.9 - tripeptidyl-peptidase I
for references in articles please use BRENDA:EC3.4.14.9
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EC Tree 3 Hydrolases
3.4 Acting on peptide bonds (peptidases)
3.4.14 Dipeptidyl-peptidases and tripeptidyl-peptidases
3.4.14.9 tripeptidyl-peptidase I
IUBMB Comments
A lysosomal enzyme that is active at acidic pH. Deficient in classical late-infantile neuronal ceroid lipofuscinosis brain tissue. Belongs in peptidase family S53. Formerly included in EC 3.4.14.8.
The enzyme appears in viruses and cellular organisms
- 3.4.14.9
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infantile
- neurodegenerative
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lincl
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late-infantile
- lipofuscinoses
- batten
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curvilinear
- palmitoyl-protein
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pepstatin-insensitive
- cdc28p
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serine-carboxyl
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lipopigments
- molecular biology
- diagnostics
- medicine
- analysis
Reaction Schemes
showRelease of an N-terminal tripeptide from a polypeptide, but also has endopeptidase activity
Synonyms
tpp-i, tripeptidyl peptidase 1, cln2p, tripeptidyl peptidase i, tripeptidyl-peptidase i, cln2 protein, tripeptidyl-peptidase 1, tripeptidyl peptidase-i, tpp1f, ttp-i, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
aminopeptidase, tripeptidyl, I
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AO090166000084
ceroid lipofuscinosis 2 protease
CLN2
CLN2p
EC 3.4.14.8
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formerly, part transferred
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LPIC
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lysosomal pepstatin insensitive protease
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SedD
TPP I
TPP-I
Tpp1
TPPI
tripeptidyl aminopeptidase
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tripeptidyl aminopeptidase I
tripeptidyl peptidase
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tripeptidyl peptidase 1
tripeptidyl peptidase I
tripeptidyl-peptidase 1
TTP-I
TPP I
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prefers Leu, Phe and Nle at the P1 position, whereas Asn, His, Lys, Arg, Ser, Val, Ile, Thr, Gly and Pro are highly unfavored in this position, showing less than 1% of the activity of the best substrates
Tpp1
TPP1 is a serine protease that possesses two catalytic functions, a primary tripeptidyl exopeptidase activity with a pH optimum of about 5.0 that catalyzes the sequential release of tripeptides from the unsubstituted N termini of substrates and a much weaker endoproteolytic activity with a pH optimum of about 3.0
tripeptidyl aminopeptidase I
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tripeptidyl peptidase I
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tripeptidyl peptidase I
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shows tripeptidyl peptidase activity and pepstatin insensitive carboxyl endopeptidase activity
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Release of an N-terminal tripeptide from a polypeptide, but also has endopeptidase activity
Release of an N-terminal tripeptide from a polypeptide, but also has endopeptidase activity
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Release of an N-terminal tripeptide from a polypeptide, but also has endopeptidase activity
the S4 subsite of TPP-I is occluded and there is an electrostatic interaction of the positively charged substrate N-terminus amino group and a negative locus in the region of the enzyme active site
Release of an N-terminal tripeptide from a polypeptide, but also has endopeptidase activity
the S4 subsite of TPP-I is occluded and there is an electrostatic interaction of the positively charged substrate N-terminus amino group and a negative locus in the region of the enzyme active site
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
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CAS REGISTRY NUMBER
COMMENTARY
151662-36-1
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
(pGlu)LYENKPRRRPYIL + H2O
(pGlu)L + YENKPRRRPYIL
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Substrates: i.e. neurotensin, 15.0% degradation after 16 h
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-carbamoylmethylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-carbamoylmethylcoumarin
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Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
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Substrates: -
Products: -
Products: -
?
Ala-Ala-Pro-4-nitroanilide + H2O
Ala-Ala-Pro + 4-nitroaniline
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Substrates: -
Products: -
Products: -
?
Ala-Arg-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-Arg-Phe + p-nitrophenylalanyl-Arg-Leu
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Substrates: -
Products: -
Products: -
?
Ala-Asp-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-Asp-Phe + p-nitrophenylalanyl-Arg-Leu
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Substrates: -
Products: -
Products: -
?
Ala-His-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-His-Phe + p-nitrophenylalanyl-Arg-Leu
-
Substrates: -
Products: -
Products: -
?
Ala-Nle-Leu-7-amido-4-carbamoylmethylcoumarin + H2O
Ala-Nle-Leu + 7-amino-4-carbamoylmethylcoumarin
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Substrates: -
Products: -
Products: -
?
Ala-Nle-Nle-7-amido-4-carbamoylmethylcoumarin + H2O
Ala-Nle-Nle + 7-amino-4-carbamoylmethylcoumarin
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Substrates: -
Products: -
Products: -
?
Ala-Nva-Nle-7-amido-4-carbamoylmethylcoumarin + H2O
Ala-Nva-Nle + 7-amino-4-carbamoylmethylcoumarin
-
Substrates: -
Products: -
Products: -
?
Ala-Phe-Pro-4-nitroanilide + H2O
Ala-Phe-Pro + 4-nitroaniline
-
Substrates: -
Products: -
Products: -
?
Ala-Pro-Gly-Asp-Arg-Ile-Tyr-Val-His-Pro-Phe + H2O
Ala-Pro-Gly + Asp-Arg-Ile + Tyr-Val-His-Pro-Phe
Substrates: SedB
Products: -
Products: -
?
Ala-Ser-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-Ser-Phe + p-nitrophenylalanyl-Arg-Leu
-
Substrates: -
Products: -
Products: -
?
amyloid-beta + H2O
?
Substrates: AbetaCy3 peptides are released from the nanofibrils due to TPP1 activity
Products: -
Products: -
?
amyloid-beta1-42 + H2O
?
Substrates: the 34 Abeta end of the substrate shows integrated peak areas for peptide fragments 21-34, 22-34, and 23-34, indicative of cleavage after residue L34. The most abundant cleavages occur after residues Y10, G33, L34, and A30, and these cleavages occur more rapidly at pH 3.0 than at pH 4.5, consistent with endopeptidase activity. Peptides ending at residues E11, L17, F20, G37, and G38, are detected with lower abundances. At later times, the abundance of some of the peptides may decrease due to further proteolysis by TPP1. TPP1 can proteolyze monomeric Abeta1-42 efficiently at acidic pH
Products: -
Products: -
?
Arg-Ala-Phe-7-amido-4-methylcoumarin + H2O
Arg-Ala-Phe + 7-amino-4-methylcoumarin
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Substrates: -
Products: -
Products: -
?
Arg-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Arg-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
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Substrates: -
Products: -
Products: -
?
Arg-Pro-Phe-7-amido-4-carbamoylmethylcoumarin + H2O
Arg-Pro-Phe + 7-amino-4-carbamoylmethylcoumarin
-
Substrates: -
Products: -
Products: -
?
Asp-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Asp-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
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Substrates: -
Products: -
Products: -
?
DRVYIHPFHL + H2O
DRV + YIHPFHL
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Substrates: i.e. angiotensin I, 11.3% degradation after 16 h
Products: -
Products: -
?
epsilon-aminocaproyl-WFFIQ-[N-(2,4-dinitrophenyl)-ethylenediamine] + H2O
epsilon-aminocaproyl-WF + FIQ-[N-(2,4-dinitrophenyl)-ethylenediamine]
Substrates: -
Products: -
Products: -
?
GKPIPFFRLK + H2O
GKPIP + FFRLK
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Substrates: endo-type substrate, 24.5% degradation after 16 h
Products: -
Products: -
?
Gly-L-Pro-L-Ala-4-nitroanilide + H2O
Gly-L-Pro-L-Ala + 4-nitroaniline
Substrates: -
Products: -
Products: -
?
Gly-L-Pro-L-Met-2-anthraquinonyl hydrazide + H2O
Gly-L-Pro-L-Met + 2-anthraquinonyl hydrazine
-
Substrates: -
Products: -
Products: -
?
Gly-L-Pro-L-Met-5-chloro-1-anthraquinonyl hydrazide + H2O
Gly-L-Pro-L-Met + 5-chloro-1-anthraquinonyl hydrazine
-
Substrates: -
Products: -
Products: -
?
Gly-L-Pro-L-Met-L-anthraquinonyl hydrazide + H2O
?
Substrates: -
Products: -
Products: -
?
Gly-Lys-Pro-Ile-Pro-Phe-Phe-Arg-Leu-Lys + H2O
Gly-Lys-Pro-Ile-Pro-Phe + Phe-Arg-Leu-Lys
-
Substrates: -
Products: -
Products: -
?
Gly-Pro-Ala 4-nitroanilide + H2O
Gly-Pro-Ala + 4-nitroaniline
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Substrates: at 20% the rate of Gly-Pro-Met 4-nitroanilide hydrolysis
Products: -
Products: -
?
Gly-Pro-Arg-7-amido-4-methylcoumarin + H2O
?
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Substrates: at 10% the rate of Gly-Pro-Met 4-methylcoumarin 7-amide hydrolysis
Products: -
Products: -
?
Gly-Pro-Met 4-nitroanilide + H2O
Gly-Pro-Met + 4-nitroaniline
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Substrates: -
Products: -
Products: -
?
Gly-Pro-Met-7-amido-4-methylcoumarin + H2O
Gly-Pro-Met + 7-amino-4-methylcoumarin
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Substrates: -
Products: -
Products: -
?
GNLWATGHFM-NH2 + H2O
GNL + WATGHFM-NH2
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Substrates: i.e. neuromedin B, complete degradation after 16 h
Products: -
Products: -
?
His-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
His-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
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Substrates: -
Products: -
Products: -
?
KWFFIQ-[N-(2,4-dinitrophenyl)-ethylenediamine] + H2O
KWF + FIQ-[N-(2,4-dinitrophenyl)-ethylenediamine]
Substrates: -
Products: -
Products: -
?
L-Ala-L-Ala-L-Phe-7-amido-4-methylcoumarin + H2O
L-Ala-L-Ala-L-Phe + 7-amino-4-methylcoumarin
L-Arg-L-Nle-L-Nle-7-amido-4-methylcoumarin + H2O
L-Arg-L-Nle-L-Nle + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
L-Asp-L-Ala-L-Phe-4-nitroanilide + H2O
L-Asp-L-Ala-L-Phe + 4-nitroaniline
Substrates: -
Products: -
Products: -
?
Phe-Pro-Ala 2-naphthylamide + H2O
Phe-Pro-Ala + 2-naphthylamine
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Substrates: synthetic peptide modeled after NH2-terminal tripeptide sequence of the phenylalanyl monomer of bovine or rat growth hormone, fluorogenic substrate
Products: -
Products: -
?
phenylalanyl monomer of bovine growth hormone + H2O
?
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Substrates: cleaves 11 tripeptides sequentially from the NH2-terminus
Products: -
Products: -
?
RVYIHPF + H2O
RVY + IHPF
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Substrates: i.e. angiotensin III, 95.0% degradation after 15 min
Products: -
Products: -
?
RWFFIQ-[N-(2,4-dinitrophenyl)-ethylenediamine] + H2O
RWF + FIQ-[N-(2,4-dinitrophenyl)-ethylenediamine]
Substrates: FRET substrate
Products: -
Products: -
?
RWFVIQ-[N-(2,4-dinitrophenyl)-ethylenediamine] + H2O
RWF + VIQ-[N-(2,4-dinitrophenyl)-ethylenediamine]
Substrates: -
Products: -
Products: -
?
Ser-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ser-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
-
Substrates: -
Products: -
Products: -
?
synthetic collagen-like polypetides + H2O
Gly-Pro-Xaa tripeptides
-
Substrates: -
Products: -
Products: -
?
Val-Pro-Arg 4-nitroanilide + H2O
Val-Pro-Arg + 4-nitroaniline
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Substrates: at 11% the rate of Gly-Pro-Met 4-nitroanilide hydrolysis
Products: -
Products: -
?
YGGFLRKYP + H2O
YGG + FLRKYP
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Substrates: i.e. beta-neo-endorphin, 28% degradation after 16 h
Products: -
Products: -
?
[Ala-Ala-Phe]2-rhodamine 110 + H2O
[Ala-Ala-Phe]2 + rhodamine 110
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Substrates: specific substrate for determining TPP-I activity and intracellular localization in living cells
Products: -
Products: -
?
[Arg-Nle-Nle]2-rhodamine 110 + H2O
[Ala-Ala-Phe]2 + rhodamine 110
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Substrates: specific substrate for determining TPP-I activity and intracellular localization in living cells
Products: -
Products: -
?
Ala-Ala-Ala-4-nitroanilide + H2O
Ala-Ala-Ala + 4-nitroaniline
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Ala-4-nitroanilide + H2O
Ala-Ala-Ala + 4-nitroaniline
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-4-nitroanilide + H2O
Ala-Ala-Phe + 4-nitroaniline
Substrates: SedB
Products: -
Products: -
?
Ala-Ala-Phe-4-nitroanilide + H2O
Ala-Ala-Phe + 4-nitroaniline
Substrates: SedC
Products: -
Products: -
?
Ala-Ala-Phe-4-nitroanilide + H2O
Ala-Ala-Phe + 4-nitroaniline
Substrates: SedD
Products: -
Products: -
?
Ala-Ala-Phe-4-nitroanilide + H2O
Ala-Ala-Phe + 4-nitroaniline
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-4-nitroanilide + H2O
Ala-Ala-Phe + 4-nitroaniline
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
Substrates: 33.8% degradation within 60 min
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
DRVYIHPF + H2O
DRV + YIHPF
-
Substrates: i.e. angiotensin II, 18.2% degradation after 16 h
Products: -
Products: -
?
Gly-L-Pro-L-Met-4-hydrazino-N-hexyl-1,8-naphthalimide + H2O
?
-
Substrates: -
Products: -
Products: -
?
Gly-L-Pro-L-Met-4-hydrazino-N-hexyl-1,8-naphthalimide + H2O
?
-
Substrates: -
Products: -
Products: -
?
Gly-Pro-Leu 2-naphthylamide + H2O
Gly-Pro-Leu + 2-naphthylamine
-
Substrates: 25% of the activity with Gly-Pro-Met 2-naphthylamide, Ala-Ala-Phe-4-nitroanilide or Ala-Ala-Phe-7-amido-4-methylcoumarin
Products: -
Products: -
?
Gly-Pro-Leu 2-naphthylamide + H2O
Gly-Pro-Leu + 2-naphthylamine
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Substrates: at 30% the rate of Gly-Pro-Met 2-naphthylamide hydrolysis
Products: -
Products: -
?
Gly-Pro-Met 2-naphthylamide + H2O
Gly-Pro-Met + 2-naphthylamine
-
Substrates: -
Products: -
Products: -
?
Gly-Pro-Met 2-naphthylamide + H2O
Gly-Pro-Met + 2-naphthylamine
-
Substrates: -
Products: -
Products: -
?
Gly-Pro-Met 2-naphthylamide + H2O
Gly-Pro-Met + 2-naphthylamine
-
Substrates: -
Products: -
Products: -
?
KWFFIQ-EDDnp + H2O
KWF + FIQ-EDDnp
Substrates: rat spleen and kidney homogenates cleave only at F-F bond
Products: -
Products: -
?
KWFFIQ-EDDnp + H2O
KWF + FIQ-EDDnp
Substrates: rat spleen and kidney homogenates cleave only at F-F bond
Products: -
Products: -
?
L-Ala-L-Ala-L-Phe-4-hydrazino-N-hexyl-1,8-naphthalimide + H2O
?
-
Substrates: -
Products: -
Products: -
?
L-Ala-L-Ala-L-Phe-4-hydrazino-N-hexyl-1,8-naphthalimide + H2O
?
-
Substrates: -
Products: -
Products: -
?
L-Ala-L-Ala-L-Phe-7-amido-4-methylcoumarin + H2O
L-Ala-L-Ala-L-Phe + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
L-Ala-L-Ala-L-Phe-7-amido-4-methylcoumarin + H2O
L-Ala-L-Ala-L-Phe + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
L-Ala-L-Ala-L-Phe-7-amido-4-methylcoumarin + H2O
L-Ala-L-Ala-L-Phe + 7-amino-4-methylcoumarin
-
Substrates: -
Products: -
Products: -
?
L-Ala-L-Ala-L-Phe-7-amido-4-methylcoumarin + H2O
L-Ala-L-Ala-L-Phe + 7-amino-4-methylcoumarin
Substrates: -
Products: -
Products: -
?
Phe-Pro-Ala-4-nitroanilide + H2O
Phe-Pro-Ala + 4-nitroaniline
Substrates: SedB
Products: -
Products: -
?
Phe-Pro-Ala-4-nitroanilide + H2O
Phe-Pro-Ala + 4-nitroaniline
Substrates: SedC
Products: -
Products: -
?
Phe-Pro-Ala-4-nitroanilide + H2O
Phe-Pro-Ala + 4-nitroaniline
Substrates: SedD
Products: -
Products: -
?
RWFFIQ-EDDnp + H2O
RWF + FIQ-EDDnp
Substrates: best substrate, rat spleen and kidney homogenates cleave only at F-F bond
Products: -
Products: -
?
RWFFIQ-EDDnp + H2O
RWF + FIQ-EDDnp
Substrates: best substrate, rat spleen and kidney homogenates cleave only at F-F bond
Products: -
Products: -
?
RWFVIQ-EDDnp + H2O
RWF + VIQ-EDDnp
Substrates: rat spleen and kidney homogenates cleave only at F-V bond
Products: -
Products: -
?
RWFVIQ-EDDnp + H2O
RWF + VIQ-EDDnp
Substrates: rat spleen and kidney homogenates cleave only at F-V bond
Products: -
Products: -
?
glucagon + H2O
additional information
-
-
Substrates: -
Products: all nine tripeptides and the C-terminal pentapeptide are identified
Products: all nine tripeptides and the C-terminal pentapeptide are identified
?
additional information
?
-
-
Substrates: no substrates are Ala-Phe-Pro-beta-naphthylamide (modeled after NH2-terminal tripeptide sequence of the alanyl monomer of bovine growth hormone), alanyl monomer of bovine growth hormone
Products: -
Products: -
?
additional information
?
-
-
Substrates: no significant aminopeptidase activity
Products: -
Products: -
?
additional information
?
-
Substrates: TPP1F is binding partner of Dictyostelium discoideum intracellular transmembrane protein GPHR, i.e. Golgi pH regulator. A region encompassing the DUF3735 (GPHR_N) domain of GPHR is responsible for the interaction. In TPP1F, the binding site is located in the prodomain of the protein. GPHR is present in subcellular membranous compartments reaching from endoplasmic reticulum membranes to membranes of the endo-lysosomal system
Products: -
Products: -
?
additional information
?
-
-
Substrates: TPP1F is binding partner of Dictyostelium discoideum intracellular transmembrane protein GPHR, i.e. Golgi pH regulator. A region encompassing the DUF3735 (GPHR_N) domain of GPHR is responsible for the interaction. In TPP1F, the binding site is located in the prodomain of the protein. GPHR is present in subcellular membranous compartments reaching from endoplasmic reticulum membranes to membranes of the endo-lysosomal system
Products: -
Products: -
?
additional information
?
-
-
Substrates: succinyl-Ala-Ala-Phe-7-amido-4-methylcoumarin, succinyl-Gly-Pro-Leu 4-methylcoumarin 7-amide, Gly-Pro-7-amido-4-methylcoumarin, Gly-7-amido-4-methylcoumarin, Pro-7-amido-4-methylcoumarin, Met-7-amido-4-methylcoumarin, Ala 7-amido-4-methylcoumarin, Phe-7-amido-4-methylcoumarin, or Leu-7-amido-4-methylcoumarin
Products: -
Products: -
?
additional information
?
-
-
Substrates: the enzyme removes tripeptides from the free N-termini of small polypeptides and also shows a minor endoprotease activity
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?
additional information
?
-
-
Substrates: absolute requirement for unsubstituted amino-terminus
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?
additional information
?
-
-
Substrates: involved in degradation of bone collagen
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?
additional information
?
-
-
Substrates: elevated enzyme activity of tripeptidyl peptidase I and other lysosomal enzymes in Sjoegren's syndrome patients may play a role in tissue damage by accelerated breakdown of glycoproteins in lysosomes
Products: -
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?
additional information
?
-
-
Substrates: TPP I is the predominant proteolytic enzyme responsible for the intracellular degradation of neuromedin B. The inability of cells from patients with late-infantile neuronal ceroid lipofuscinosis (CNL2) to degrade neuromedin B and other neuropeptides may contribute to the pathogenesis of the disease
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?
additional information
?
-
-
Substrates: classical late infantile neuronal ceroid lipofuscinosis is an autosomal recessive disease caused by mutations in the CLN2 gene resulting in functional defects of the gene product tripeptidyl-peptidase I. This disease is associated with a progressive neurodegenerative course beginning at the age of two years with developmental stagnation, finally leading to a complete loss of motor function, vision and speech by the age of 10 years
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?
additional information
?
-
-
Substrates: determination of the substrate specificity of tripeptidyl-peptidase I using combinatorial peptide libraries and development of improved fluorogenic substrates
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?
additional information
?
-
-
Substrates: prefers Leu, Phe and Nle at the P1 position, whereas Asn, His, Lys, Arg, Ser, Val, Ile, Thr, Gly and Pro are highly unfavored in this position, showing less than 1% of the activity of the best substrates
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?
additional information
?
-
-
Substrates: TPP I acts preferentially on small, unstructured oligopeptides of less than 5 kDa
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?
additional information
?
-
Substrates: validation and evaluation of a rapid and simple fluorometric tripeptidyl peptidase 1 (TPP1) assay using dried blood specimens to diagnose CLN2 disease
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?
additional information
?
-
-
Substrates: validation and evaluation of a rapid and simple fluorometric tripeptidyl peptidase 1 (TPP1) assay using dried blood specimens to diagnose CLN2 disease
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?
additional information
?
-
-
Substrates: dipeptidyl-peptidase I cannot functionally compensate for the loss of tripeptidyl-peptidase I
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?
additional information
?
-
-
Substrates: substrates not cleaved after 24 h of digestion: dynorphin, beta-casomorphin-7, Leu-enkephalin, Met-enkephalin, neurokinin-A, LVV-hemorphin, bradykinin
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?
additional information
?
-
-
Substrates: the enzymne cleaves tripeptides from synthetic substrates provided that the N-terminus is unsubstituted and the amino acid in the P1 position is not charged. The enzyme also cleaves small peptides, angiotensin II and glucagon, releasing tripeptides but does not appear to demonstrate any preference for amino acids on either side of the cleavage site. Substrates with a charged amino acid in the P1 position appear to be resistant to hydrolysis
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?
additional information
?
-
-
Substrates: an inherited deficiency of tripeptidyl peptidase I activity causes a fatal lysosomal storage disorder, classic late infantile neuronal ceroid lipofuscinosis, CLN2
Products: -
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?
additional information
?
-
Substrates: development of fluorescence resonance energy transfer (FRET) peptides using tryptophan as the fluorophore to study TPP-I hydrolytic properties. Solvent kinetic isotope effects show the importance of the free N-terminus amino group of the substrates, whose absence results in a more complex solvent-dependent enzyme-substrate interaction and catalytic process. To investigate the exopeptidase activity of TPP-I, the randomized sequence MCA-GXXFXXQ-EDDnp is assayed and the products of hydrolysis analyzed by Edman degradation. TTP-I retains its N-terminus tripeptidase character even in randomized sequences and the preferences at the prime sites are similar to those reported for tripeptidyl amino peptidase
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?
additional information
?
-
Substrates: development of fluorescence resonance energy transfer (FRET) peptides using tryptophan as the fluorophore to study TPP-I hydrolytic properties. Solvent kinetic isotope effects show the importance of the free N-terminus amino group of the substrates, whose absence results in a more complex solvent-dependent enzyme-substrate interaction and catalytic process. To investigate the exopeptidase activity of TPP-I, the randomized sequence MCA-GXXFXXQ-EDDnp is assayed and the products of hydrolysis analyzed by Edman degradation. TTP-I retains its N-terminus tripeptidase character even in randomized sequences and the preferences at the prime sites are similar to those reported for tripeptidyl amino peptidase
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?
additional information
?
-
-
Substrates: N-terminal exopeptidase that removes tripeptide units provided the P3 residue is unsubstituted
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?
additional information
?
-
-
Substrates: Met-2-naphthylamide, succinyl-Gly-Pro-Met 2-naphthylamide, Pro-Met-7-amido-4-methylcoumarin, Met-7-amido-4-methylcoumarin, methoxysuccinyl-Gly-Pro-Met-7-amido-4-methylcoumarin, benzyloxy-Arg-Arg-7-amido-4-methylcoumarin, Arg-7-amido-4-methylcoumarin, Pro-Ala-4-nitroanilide, Ala 4-nitroanilide, tert-butyloxycarbonyl-Gly-Pro-Ala 4-nitroanilide, benzoyl-Val-Pro-Arg 4-nitroanilide
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?
additional information
?
-
-
Substrates: exopeptidase involved in intracellular (lysosomal) degradation of collagen fibrils
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?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
amyloid-beta + H2O
?
Substrates: AbetaCy3 peptides are released from the nanofibrils due to TPP1 activity
Products: -
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?
additional information
?
-
Substrates: TPP1F is binding partner of Dictyostelium discoideum intracellular transmembrane protein GPHR, i.e. Golgi pH regulator. A region encompassing the DUF3735 (GPHR_N) domain of GPHR is responsible for the interaction. In TPP1F, the binding site is located in the prodomain of the protein. GPHR is present in subcellular membranous compartments reaching from endoplasmic reticulum membranes to membranes of the endo-lysosomal system
Products: -
Products: -
?
additional information
?
-
-
Substrates: TPP1F is binding partner of Dictyostelium discoideum intracellular transmembrane protein GPHR, i.e. Golgi pH regulator. A region encompassing the DUF3735 (GPHR_N) domain of GPHR is responsible for the interaction. In TPP1F, the binding site is located in the prodomain of the protein. GPHR is present in subcellular membranous compartments reaching from endoplasmic reticulum membranes to membranes of the endo-lysosomal system
Products: -
Products: -
?
additional information
?
-
-
Substrates: involved in degradation of bone collagen
Products: -
Products: -
?
additional information
?
-
-
Substrates: elevated enzyme activity of tripeptidyl peptidase I and other lysosomal enzymes in Sjoegren's syndrome patients may play a role in tissue damage by accelerated breakdown of glycoproteins in lysosomes
Products: -
Products: -
?
additional information
?
-
-
Substrates: TPP I is the predominant proteolytic enzyme responsible for the intracellular degradation of neuromedin B. The inability of cells from patients with late-infantile neuronal ceroid lipofuscinosis (CNL2) to degrade neuromedin B and other neuropeptides may contribute to the pathogenesis of the disease
Products: -
Products: -
?
additional information
?
-
-
Substrates: classical late infantile neuronal ceroid lipofuscinosis is an autosomal recessive disease caused by mutations in the CLN2 gene resulting in functional defects of the gene product tripeptidyl-peptidase I. This disease is associated with a progressive neurodegenerative course beginning at the age of two years with developmental stagnation, finally leading to a complete loss of motor function, vision and speech by the age of 10 years
Products: -
Products: -
?
additional information
?
-
-
Substrates: dipeptidyl-peptidase I cannot functionally compensate for the loss of tripeptidyl-peptidase I
Products: -
Products: -
?
additional information
?
-
-
Substrates: an inherited deficiency of tripeptidyl peptidase I activity causes a fatal lysosomal storage disorder, classic late infantile neuronal ceroid lipofuscinosis, CLN2
Products: -
Products: -
?
additional information
?
-
-
Substrates: exopeptidase involved in intracellular (lysosomal) degradation of collagen fibrils
Products: -
Products: -
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Dextran sulfate
-
initially, as the glycosaminoglycan concentration progressed from 0 to about 100 ng/ml, the activity of TPP I falls down rapidly to reach a plateau with saturable inhibition at about 100 ng-0.1 mg/ml and then it gradually increases with increased glycosaminoglycan concentration. The maximal percent inhibition is 50%
-
heparin
-
initially, as the glycosaminoglycan concentration progressed from 0 to about 100 ng/ml, the activity of TPP I falls down rapidly to reach a plateau with saturable inhibition at about 100 ng-0.1 mg/ml and then it gradually increases with increased glycosaminoglycan concentration. The maximal percent inhibition is 50%
prosegment of tripeptidyl peptidase I
-
wild type prosegment of tripeptidyl peptidase I (176 amino acid residues) is a potent, slow-binding inhibitor of its parent enzyme with an overall inhibition constant in the low nanomolar range, in the presence of the prosegment (at 0.001 mM) leads from a significant to complete inhibition of TPP I activity at pH between 3.5 and 5.5 with IC 50 ranging from more than 0.016 mM to 0.000043 mM at pH from 3.5 to 5.5
-
Ala-Ala-Phe-chloromethylketone
AAF-CMK, inhibits both the endoproteolytic and tripeptidyl peptidase activities of TPP1
additional information
-
no inhibition by pepstatin; no inhibition: EDTA; no inhibition: Phe-Pro-Arg chloromethylketone, inhibitors of cysteine proteinases or metalloproteinases, iodoacetamide, trans-epoxysuccinyl-L-leucinamido(4-guanidino)butane (i.e. E-64), mercaptoethanol, bestatin, soybean trypsin inhibitor, phenylchloromethyl ketone
-
additional information
-
resistant to inhibition by diisopropylfluorophosphate
-
additional information
the enzyme is not inhibited by pepstatin, E-64, EDTA or PMSF. The enzyme shows resistance to hydrolysis by cathepsin D
-
additional information
-
no inhibition by pepstatin; no inhibition: EDTA; no inhibition: alkali-inactivated diisopropylfluoride, leupeptin
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
neonatally treated mice display high levels of TPP-I activity in the CNS 1 year after administration of AAVrh.10hCLN2 vector directly to the neonatal brain of CLN2 knockout mice at 2 days, 3 weeks, and 7 weeks of age, the AAVrh.10hCLN2 vector contains an expression cassette consisting of the human CLN2 cDNA driven by a CMV/beta-actin hybrid promoter consisting of the enhancer from the cytomegalovirus immediate early gene, the promoter, splice donor and intron from the chicken beta-actin gene, the splice acceptor from the rabbit beta-globin gene followed by a CLN2 cDNA with an optimized Kozak translation initiation sequence, the cDNA is followed by the polyadenylation sequence from rabbit beta-globin, the expression cassette is surrounded by the inverted terminal repeats of adeno-associated virus 2
-
additional information
tripeptidylamino peptidase activity is enhanced by the presence of amino acids in the prime side
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00509
Ala-Asp-Phe-p-nitrophenylalanyl-Arg-Leu
-
pH 4.0, 37°C, wild-type enzyme
0.0625
Phe-Pro-Ala-4-nitroanilide
pH 6.0, 20°C, SedB
0.076
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme S475L
0.098
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, wild-type enzyme
0.105
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme D276A
0.111
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme D360A
0.118
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme E272A
0.164
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme D327A
0.00402
Ala-Arg-Phe-p-nitrophenylalanyl-Arg-Leu
-
pH 4.0, 37°C, wild-type enzyme
0.123
Ala-Arg-Phe-p-nitrophenylalanyl-Arg-Leu
-
pH 4.0, 37°C, mutant enzyme E77A
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.04 - 1.97
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme D276A
0.12
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme S475L
1.52
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme D360A
1.54
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme E272A
4.22
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme D327A
9.36
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, mutant enzyme D276A
41.66
Ala-Ala-Phe-7-amido-4-methylcoumarin
pH 5.0, 37°C, wild-type enzyme
0.0124
Ala-Arg-Phe-p-nitrophenylalanyl-Arg-Leu
-
pH 4.0, 378°C, mutant enzyme E77A
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0001581
prosegment of tripeptidyl peptidase I
-
in sodium acetate buffer (50 mM, pH 5.0), 0.05% Triton X-100
-
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0001292
prosegment of tripeptidyl peptidase I
Homo sapiens
-
in sodium acetate buffer (50 mM, pH 5.0), 0.05% Triton X-100
-
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4.5
5 - 5.5
-
hydrolysis of Gly-Pro-Met 2-naphthylamide or Ala-Ala-Phe 4-methylcoumarin 7-amide
5.9
-
and a second optimum at pH 4.5, at pH 5.9 70% of the activity at pH 4.5
additional information
-
the optimum pH of TPP 1 is dependent on the substrate used
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
3 - 4.8
-
pH 3.0: about 30% of maximal activity, pH 4.8: about 50% of maximal activity
3 - 7
3 - 8
-
about half-maximal activity at pH 3 and 8, hydrolysis of Gly-Pro-Met 2-naphthylamide
3.5 - 5
-
pH 3.5: about 25% of maximal activity, pH 5.0: about 45% of maximal activity, hydrolysis of Ala-Ala-Phe-7-amido-4-methylcoumarin
3.5 - 6.5
-
about half-maximal activity at pH 3.5 and 6.5, hydrolysis of Ala-Ala-Phe 4-methylcoumarin 7-amide
4 - 5.5
about 55% of maximal activity at pH 4.0 and at pH 5.5, hydrolysis of Ala-Ala-Phe-7-amido-4-methylcoumarin
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5.12
calculated from sequence, mature domain, SedD
5.17
calculated from sequence, mature domain, SedB
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
enzyme histochemistry show high activity of TPP I in carotid body glomeruli. The glomus cells contain many TPP I-positive granules, while the glial-like sustentacular cells display a slightly fainter reaction
brenda
-
activity in neuroglia cells, no activity in small granule cells, Purkinje cells, remified dendrites and myelinated fibers
brenda
-
activity in ducts, no activity in acinar cells and islets of Langerhans
brenda
-
activity in excretory duct and stereocilia, no activity in glandular acinus and intercalated portion
brenda
-
activity in spermatogonia, spermatozoa, Sertoli cells and Leygig cells, no activity in basement cells
brenda
additional information
-
TPPI is expressed ubiquitously throughout the body but disease appears restricted to the brain
brenda
presence of recombinant fusion protein with enhanced green fluorescent protein
brenda
-
presence of recombinant fusion protein with enhanced green fluorescent protein
-
brenda
-
activity in proximal tubules, distal tubules, collecting tubules and transitional cells, no activity in glomerulus and Bowmans capsule
brenda
-
enzyme activity is elevated during the first 5 years of Sjoegren's syndrome, and it increases further between 5 and 10 years after diagnosis
brenda
-
activity in corpus luteum and corpus albicus, no activity in follicles
brenda
-
heterogenous distribution of TPP I positive macrophages, leukocytes and reticular fibroblasts in the red and white pulp
brenda
additional information
Dictyostelium discoideum harbors at least six genes encoding TPP1, tpp1A to tpp1F. The tpp1F gene is transcribed throughout development and translated into a polypeptide. TPPIF transcript is very abundant throughout development and is particularly high at the vegetative stage, but the amounts of the protein are lower during growth (t0) than during development
brenda
additional information
-
Dictyostelium discoideum harbors at least six genes encoding TPP1, tpp1A to tpp1F. The tpp1F gene is transcribed throughout development and translated into a polypeptide. TPPIF transcript is very abundant throughout development and is particularly high at the vegetative stage, but the amounts of the protein are lower during growth (t0) than during development
brenda
additional information
-
morphological changes in the studied brain parts at different time periods following a single i.p. injection of sodium nitrite and altered TPPI activity in the brain, immunohistochemic analysis of the enzyme in brain regions and different neurons, overview
brenda
additional information
morphological changes in the studied brain parts at different time periods following a single i.p. injection of sodium nitrite and altered TPPI activity in the brain, immunohistochemic analysis of the enzyme in brain regions and different neurons, overview
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
presence of recombinant fusion protein with enhanced green fluorescent protein
brenda
-
presence of recombinant fusion protein with enhanced green fluorescent protein
-
brenda
-
the conversion of the proenzyme into the mature form takes place in lysosomal compartment
brenda
additional information
TPP1F contains an N-terminal hydrophobic sequence, which is predicted as a signal sequence. The N-terminal signal sequence is essential for transport of the protein across the endoplasmic reticulum membrane and is presumably cleaved off
-
brenda
additional information
-
TPP1F contains an N-terminal hydrophobic sequence, which is predicted as a signal sequence. The N-terminal signal sequence is essential for transport of the protein across the endoplasmic reticulum membrane and is presumably cleaved off
-
brenda
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
TPPI is conserved in mammals, amphibians, fish and the amoeba Dictyostelium discoideum. Tripeptidyl peptidase 1 (TPP1) enzymes belong to the group of sedolisins, serine peptidases that are present in organisms ranging from bacteria to mammals. High homology to tripeptidyl peptidase 1 (TPP) from various organisms
malfunction
physiological function
additional information
malfunction
-
TPP1 knockout mice which serve as a mouse model for classical late-infantile neuronal ceroid lipofuscinosis (LINCL) are analysed in terms of storage material present in the brain of the mouse model. It is shown that a number of protein constituents including glial fibrillary acidic protein are elevated
malfunction
-
TPP1 knockout mice providing a mouse model for late-infantile neuronal ceroid lipofuscinosis (LINCL) generated that either lack the pro-apoptotic p53 or have increased levels of anti-apoptotic Bcl-2. Neither modification affects the shortened life-span of the LINCL mouse. These findings suggest that targeting pathways of cell death involving p53 or Bcl-2 do not represent useful directions for developing effective treatment
malfunction
CLN2 disease is a genetic disorder caused by dysfunction of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1) that belongs to the neuronal ceroid lipofuscinoses (NCL) and leads to epilepsy, dementia, and death in young persons. CLN2 disease has become treatable by enzyme replacement, which can only be effective when the disease is diagnosed early. Analysis of reliability of a test for TPP1 deficiency in dried blood specimens (DBS) to detect CLN2 disease, overview. Diminished TTP1 activity is carefully checked for clinical information compatible with the diagnosis of CLN2 disease, and respective patients are subject to molecular genetic testing and confirmation of CLN2 disease by detection of known variants within the CLN2 gene, phenotypes, overview
malfunction
knockout tpp1F mutants do not display any particular phenotype, and TPP1 activity is not abrogated, presumably because tpp1B compensates as it has the highest expression level of all the TPP1 genes during growth. The majority of the TPP1 mutations in NCL results in reduction or loss of enzyme activity
malfunction
late-infantile neuronal ceroid lipofuscinosis is a fatal neurodegenerative disease of children caused by mutations resulting in loss of activity of the lysosomal protease, tripeptidyl peptidase 1 (TPP1), gene therapy studies on the LINCL mouse using Tpp1-targeted mouse models for LINCL that accurately recapitulate the human disease with locomotor deficits and a reduced lifespan. Tpp1-/- mice show signs of disease progression but death typically occurs suddenly (possibly from disease-related seizures) when feeding and grooming behaviors remained normal and before they become moribund. No gender-specific effects in life-span or other phenotypes of the LINCL mouse model are observed
malfunction
-
enzyme knockdown in HTR8/SVneo cells by 95% significantly impairs cell adhesion and proliferation without affecting cell migration and invasion
malfunction
enzyme variants c.544_545del and c.230-3C>G are associated with neuronal ceroid lipofuscinosis type 2
malfunction
enzyme mutations affect the late-infantile onset form of neuronal ceroid lipofuscinosis
malfunction
-
late-infantile neuronal ceroid lipofuscinosis is a fatal neurodegenerative disease of children caused by mutations resulting in loss of activity of the lysosomal protease, tripeptidyl peptidase 1 (TPP1), gene therapy studies on the LINCL mouse using Tpp1-targeted mouse models for LINCL that accurately recapitulate the human disease with locomotor deficits and a reduced lifespan. Tpp1-/- mice show signs of disease progression but death typically occurs suddenly (possibly from disease-related seizures) when feeding and grooming behaviors remained normal and before they become moribund. No gender-specific effects in life-span or other phenotypes of the LINCL mouse model are observed
-
physiological function
both the total protease and tripeptidyl peptidase activities in the culture medium of a gene disruptant strain are decreased as compared to those of the control strain. The maximum yields of recombinant bovine chymosin and human lysozyme produced by the disruptants show approximately 2.9- and 1.7fold increases, respectively, as compared to their control strains. Tripeptidyl peptidase activity in the culture medium of the disruptant is decreased
physiological function
tripeptidyl peptidase 1 (TPP1) is a lysosomal serine protease, that possesses endopeptidase activity and cleaves peptides between hydrophobic residues. TPP1 is able to proteolyze fibrillar amyloid-beta efficiently. Mass spectrometry analysis of peptides released from fibrillar amyloid-beta digested with TPP1 reveals several endoproteolytic cleavages including some within beta-sheet regions that are important for fibril formation. These cleavages destabilize fibrillar beta-sheet structure. N-terminal tripeptidyl exopeptidase activity with a pH optimum of 5 that catalyzes the sequential release of tripeptides from the unsubstituted N termini of proteins
physiological function
upon hypoxic shock, the studied brain areas show different histopathological changes, such as neuronal loss and tissue vacuolization, dilatation of the smallest capillaries and impairment of neuronal processes. TPPI activity is strictly regulated following the hypoxic stress. TPPI activity increases 12-24 h post-treatment, then decreases followed by a slow process of recovery. There is a temporary enzyme deficiency in all types of neurons
physiological function
in sodium nitrite-induced acute hypoxic shocked rat brain, morphological changes in cerebral cortex, cerebellum, medulla oblongata, thalamus,mesencephalon and pons are assessed using silver-copper impregnation for neurodegeneration. TPPI activity on these brains leads to less vulnerable to oxidative stress, the studied brain areas show different histopathological changes, such as neuronal loss and tissue vacuolization, dilatation of the smallest capillaries and impairment of neuronal processes. TPPI activity is strictly regulated following the hypoxic stress. The involvement of the enzyme in rat brain response to hypoxic stress causes a temporary enzyme deficiency in all types of neurons
physiological function
tripeptidyl peptidase 1, TPP1, is a lysosomal serine protease, which removes tripeptides from the N-terminus of proteins and is composed of an N-terminal prodomain and a catalytic domain. Isozyme TPP1F is a binding partner of the Golgi pH regulator (GPHR), an evolutionarily highly conserved intracellular transmembrane protein, in Dictyostelium discoideum. The GPHR interaction is not restricted to TPP1F but occurs also with isozyme TPP1B
physiological function
-
the enzyme regulates trophoblast cell proliferation implying a role in placentation
physiological function
-
the enzyme actively participates in the functions of all the neuronal structures in porcine lumbar spinal ganglia
physiological function
-
both the total protease and tripeptidyl peptidase activities in the culture medium of a gene disruptant strain are decreased as compared to those of the control strain. The maximum yields of recombinant bovine chymosin and human lysozyme produced by the disruptants show approximately 2.9- and 1.7fold increases, respectively, as compared to their control strains. Tripeptidyl peptidase activity in the culture medium of the disruptant is decreased
-
additional information
molecular dynamics (MD) simulations are used to analyze the effects of each cleavage on beta-sheet and fibril stability of amyloid-beta, eight cleavage sites are selected to be simulated, namely after residues K16, F20, G33, L34, M35, V36, G38, and V40, stability of hydrogen bonds following selected TPP1 cleavages and peptide release from the fibril, molecular modeling, detailed overview
additional information
the enzyme has a prodomain (residues 25-182) and a catalytic domain (peptidases S53 domain), which extends from residue 197 to the end. In TPP1F, the catalytic domain is interrupted by a stretch of amino acids (residues 370-499). The catalytic triad, a Ca2+ binding site and a particular sequence of amino acids (S611, E272, D369 in TPP1F), which represent the catalytic residues and are highly conserved in the S53 sedolisin family of peptidases, to which TPP1 proteins belong, are also present
additional information
-
the enzyme has a prodomain (residues 25-182) and a catalytic domain (peptidases S53 domain), which extends from residue 197 to the end. In TPP1F, the catalytic domain is interrupted by a stretch of amino acids (residues 370-499). The catalytic triad, a Ca2+ binding site and a particular sequence of amino acids (S611, E272, D369 in TPP1F), which represent the catalytic residues and are highly conserved in the S53 sedolisin family of peptidases, to which TPP1 proteins belong, are also present
additional information
tripeptidyl peptidase I (TPP-I), also named ceroid lipofuscinosis 2 protease (CLN2p), is a serine carboxyllysosomal protease involved in neurodegenerative diseases, and has both tripeptidyl amino- and endo-peptidase activities under different pH conditions. The enzyme shows resistance to hydrolysis by cathepsin D
additional information
-
the elevation of enzyme activity by either transgenic overexpression or a pharmacological approach fails to have any measurable beneficial effect on Alzheimer disease phenotype
additional information
-
tripeptidyl peptidase I (TPP-I), also named ceroid lipofuscinosis 2 protease (CLN2p), is a serine carboxyllysosomal protease involved in neurodegenerative diseases, and has both tripeptidyl amino- and endo-peptidase activities under different pH conditions. The enzyme shows resistance to hydrolysis by cathepsin D
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Show AA Sequence and Transmembrane Helices (832 entries)
Please use the AA Sequence and Transmembrane Helices Search for a specific query.
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
46000
48000
68000
89000
x * 89000, fusion protein with enhanced green fluorescent protein, SDS-PAGE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
?
x * 89000, fusion protein with enhanced green fluorescent protein, SDS-PAGE
?
-
x * 89000, fusion protein with enhanced green fluorescent protein, SDS-PAGE
-
?
x * 65000, TPPIF, SDS-PAGE, x * 75780, sequence calculation, x * 105000, recombinant GFP-tagged TPPIF, SDS-PAGE
additional information
the enzyme has a prodomain (residues 25-182) and a catalytic domain (peptidases S53 domain), which extends from residue 197 to the end. In TPP1F, the catalytic domain is interrupted by a stretch of amino acids (residues 370-499). The catalytic triad, a particular sequence of amino acids (S611, E272, D369 in TPP1F), which represent the catalytic residues and are highly conserved in the S53 sedolisin family of peptidases, to which TPP1 proteins belong, and a Ca2+ binding site are also present
additional information
-
the enzyme has a prodomain (residues 25-182) and a catalytic domain (peptidases S53 domain), which extends from residue 197 to the end. In TPP1F, the catalytic domain is interrupted by a stretch of amino acids (residues 370-499). The catalytic triad, a particular sequence of amino acids (S611, E272, D369 in TPP1F), which represent the catalytic residues and are highly conserved in the S53 sedolisin family of peptidases, to which TPP1 proteins belong, and a Ca2+ binding site are also present
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
proteolytic modification
glycoprotein
TPPIs are N-glycosylated and become mannosylated during passage through the Golgi complex. TPP1F does not have N-glycosylation sites, but Ser95 and Ser201 are predicted as potential O-glycosylation sites
glycoprotein
-
all five potential N-glycosylation sites in the enzyme are utilized, some of its N-linked oligosaccharides are of the complex/hybrid type
glycoprotein
-
TPP I in vivo utilizes all five N-glycosylation sites (Asn210, Asn222, Asn286, Asn313 and Asn443). Mutation of N286Q dramatically affects the folding of the enzyme and partially arrests TPP I in the endoplasmic reticulum. N-glycans at Asn210, Asn222, Asn313, and Asn443 contribute slightly to the specific activity of the enzyme
glycoprotein
-
TPP 1 is glycosylatd at most or all of five asparagin-linked glycosylation sites
glycoprotein
TPP1 requires at least partial glycosylation for in vitro autoprocessing and proteolytic activity
proteolytic modification
the preproprotein SedB is composed of 602 amino acids, the signal peptide contains 24 amino acids
proteolytic modification
the preproprotein SedC is composed of 596 amino acids, the signal peptide contains 24 amino acids
proteolytic modification
the preproprotein SedD is composed of 568 amino acids, the signal peptide contains 20 amino acids
proteolytic modification
the enzyme is synthesized as precursor with an N-terminal signal sequence, a prodomain and a catalytic domain ( peptidases S53 domain). The cleavage of the signal sequence occurs between residues 21 and 22
proteolytic modification
the protein is synthesized as an inactive zymogen that is autocatalytically converted to an active serine protease at acidic pH, removal of a 19-residue signal peptide
proteolytic modification
-
the 68000 Da precursor polypeptide is converted to the mature enzyme of 48000 Da. Although tripeptidyl-peptidase I zymogen is capable of autoactivation in vitro, a serine protease that is sensitive to 4-(2-aminoethyl)-benzene-sulfonamide participates in processing of the proenzyme to the mature, active form in vivo
proteolytic modification
-
TPP I activity is not involved in the major proteolytic step leading to generation of the mature enzyme, indicating that autoactivation of human pro-TTP I in vitro occurs by intramolecular mechanisms
proteolytic modification
-
TPP-I is synthesized as a 66000 Da inactive precursor consisting of a 195 residue prepro-peptide and 368 residue mature enzyme. Most of the precursor proteins are converted to a 46000 Da form by post-translational proteolysis
proteolytic modification
-
autoactivation of pro-TPP I is fully activated at pH 3.5 after only 15 min of activation in 50 mM sodium acetate buffer, independent of NaCl concentration. In presence of 1 M NaCl (but not 150 mM NaCl) significant activation also is observed at pH 4.0. Ionic strength affects the yield but not the rates or the mechanism of pro-TPP I activation in vitro
proteolytic modification
-
proenzyme, the N-linked glycan at Asn286 is involved in maturation of the enzyme
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
deglycosylated inactive proenzyme pro-TPP1, hanging drop vapour diffusion method, using 0.1 M citrate, 4-7% polyethylene glycol 6000, at pH 5.0
fully-glycosylated TPP1 precursor, hanging drop vapour diffusion method, using 7% PEG4000, 0.02 M zinc sulfate, 0.1 M sodium acetate, pH 5.0, and 0.1 M ammonium sulfate
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C365R
D360A
E343K
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, no enzymatic activity
E490K
the mutation causes enzyme deficiency, which may lead to spinocerebellar ataxia recessive type 7
G284V
G473R
G501C
the mutation loses the chaperone binding tendency of the enzyme and severely reduces protein stability
G77R
I287N
K428N
no apparent conformational destabilization is observed for the missense mutation
N286Q
-
the secreted proenzyme formes non-native, interchain disulfide bridges and displays only residual TPP I activity upon acidification. A small portion of the mutant enzyme reaches the lysosome and is processed to an active species, however, it shows low thermal and pH stability
N286S
P202L
P544S
Q248P
the mutation probably compromises the active center and results in loss of proteolytic activity
Q422H
Q442H
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, no enzymatic activity
R127Q
R206C
R208X
-
mutation is identified in patients with late infantile ceroid lipofuscinosis, no detection of any translational product for the mutant
R266Q
no apparent conformational destabilization is observed for the missense mutation
R447H
S475L
T353P
-
mutation is identified in patients with late infantile ceroid lipofuscinosis, enzyme shows 5.5% of wild-type enzyme when expressed in HEK cells, blocked processing to mature size peptidase leads to protein retention in the endoplasmic reticulum and rapid degradation in non-lysosomal compartments
V216M
no apparent conformational destabilization is observed for the missense mutation
V227M
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, no enzymatic activity
V277M
R446H
additional information
C365R
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, no enzymatic activity
G284V
the mutation probably compromises the active center and results in loss of proteolytic activity
G284V
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, no enzymatic activity
G473R
the mutation probably compromises the active center and results in loss of proteolytic activity
G473R
the mutation causes enzyme deficiency, which may lead to spinocerebellar ataxia recessive type 7
G77R
-
the mutation is associated with classic late infantile neuronal ceroid lipofuscinosis
G77R
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, 1% of wild-type activity
I287N
-
mutation is identified in patients with late infantile ceroid lipofuscinosis, enzyme shows 4.1% of wild-type enzyme when expressed in HEK cells, blocked processing to mature size peptidase leads to protein retention in the endoplasmic reticulum and rapid degradation in non-lysosomal compartments
I287N
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, no enzymatic activity
N286S
-
mutation is identified in patients with late infantile ceroid lipofuscinosis, enzyme shows 5.8% of wild-type enzyme when expressed in HEK cells, blocked processing to mature size peptidase leads to protein retention in the endoplasmic reticulum and rapid degradation in non-lysosomal compartments
N286S
the substitution results in loss of one glycosylation site, which leads to almost complete loss of protease activity
N286S
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, no enzymatic activity
P202L
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, no enzymatic activity
P544S
-
demonstrates a normal polypeptide pattern on Western blots, enzyme activity, and lysosomal localization
P544S
protein processing similar to wild-type, lysosomal localisation, 32.8% of wild-type activity
Q422H
-
mutation is identified in patients with late infantile ceroid lipofuscinosis, enzyme shows 4.7% of wild-type enzyme when expressed in HEK cells, blocked processing to mature size peptidase leads to protein retention in the endoplasmic reticulum and rapid degradation in non-lysosomal compartments
R127Q
-
mutation is identified in patients with late infantile ceroid lipofuscinosis, enzyme shows 74.3% of wild-type enzyme when expressed in HEK cells
R127Q
-
demonstrates a normal polypeptide pattern on Western blots, enzyme activity, and lysosomal localization
R127Q
protein processing similar to wild-type,lysosomal localization, 43% of wild-type activity
R206C
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, 0.7% of wild-type activity
R447H
protein processing different from wild-type, mutant is not localized in lysosomes, intracellular trafficking of mutant is altered compared to wild-type, 1.8% of wild-type activity
S475L
the mutation probably compromises the active center and results in loss of proteolytic activity
S475L
protein processing similar to wild-type, lysosomal localization, no enzymatic activity
V277M
the mutation probably compromises the active center and results in loss of proteolytic activity
R446H
the Tpp1f allele produces normal levels of properly spliced transcript, albeit with the Arg446His mutation
R446H
-
the Tpp1f allele produces normal levels of properly spliced transcript, albeit with the Arg446His mutation
-
additional information
knockout mice containing the LSL-TPP1 transgene in the ROSA26 locus are referred to as TgLSL-TPP1, 5'-integration of TgLSL-TPP1 into the ROSA26 locus. A cloned PCR-amplified region of ROSA26 corresponds to nucleotides 113076032 to 113077227 of Mus musculus strain C57BL/6J chromosome 6 (GRCm38.p4). Method development for creation of mice expressing cre/ERT2 transgenes, transgenic mouse with inducible TPP1 to benchmark treatment approaches, evaluation of treatment at different stages of disease. A construct containing a loxP-flanked stop cassette inserted between the chicken-actin promoter and a sequence encoding murine TPP1 (TgLSL-TPP1) is integrated into the ROSA26 locus in mice by homologous recombination. Tested in both transfected CHO cells and in transgenic mice, the TgLSL-TPP1 does not express TPP1 until cre-mediated removal of the LSL cassette, which results in supraphysiological levels of TPP1 activity. Two of the four cre/ERT2 driver transgenes have significant cre activity in the absence of tamoxifen, while cre-mediated recombination cannot be induced by tamoxifen by two others. The germline-recombined mouse transgenic that constitutively overexpresses TPP1 allow long-term evaluation of overexposure to the enzyme and in cell culture, the inducible transgene may be a useful tool in biomarker discovery projects
additional information
-
knockout mice containing the LSL-TPP1 transgene in the ROSA26 locus are referred to as TgLSL-TPP1, 5'-integration of TgLSL-TPP1 into the ROSA26 locus. A cloned PCR-amplified region of ROSA26 corresponds to nucleotides 113076032 to 113077227 of Mus musculus strain C57BL/6J chromosome 6 (GRCm38.p4). Method development for creation of mice expressing cre/ERT2 transgenes, transgenic mouse with inducible TPP1 to benchmark treatment approaches, evaluation of treatment at different stages of disease. A construct containing a loxP-flanked stop cassette inserted between the chicken-actin promoter and a sequence encoding murine TPP1 (TgLSL-TPP1) is integrated into the ROSA26 locus in mice by homologous recombination. Tested in both transfected CHO cells and in transgenic mice, the TgLSL-TPP1 does not express TPP1 until cre-mediated removal of the LSL cassette, which results in supraphysiological levels of TPP1 activity. Two of the four cre/ERT2 driver transgenes have significant cre activity in the absence of tamoxifen, while cre-mediated recombination cannot be induced by tamoxifen by two others. The germline-recombined mouse transgenic that constitutively overexpresses TPP1 allow long-term evaluation of overexposure to the enzyme and in cell culture, the inducible transgene may be a useful tool in biomarker discovery projects
additional information
-
knockout mice containing the LSL-TPP1 transgene in the ROSA26 locus are referred to as TgLSL-TPP1, 5'-integration of TgLSL-TPP1 into the ROSA26 locus. A cloned PCR-amplified region of ROSA26 corresponds to nucleotides 113076032 to 113077227 of Mus musculus strain C57BL/6J chromosome 6 (GRCm38.p4). Method development for creation of mice expressing cre/ERT2 transgenes, transgenic mouse with inducible TPP1 to benchmark treatment approaches, evaluation of treatment at different stages of disease. A construct containing a loxP-flanked stop cassette inserted between the chicken-actin promoter and a sequence encoding murine TPP1 (TgLSL-TPP1) is integrated into the ROSA26 locus in mice by homologous recombination. Tested in both transfected CHO cells and in transgenic mice, the TgLSL-TPP1 does not express TPP1 until cre-mediated removal of the LSL cassette, which results in supraphysiological levels of TPP1 activity. Two of the four cre/ERT2 driver transgenes have significant cre activity in the absence of tamoxifen, while cre-mediated recombination cannot be induced by tamoxifen by two others. The germline-recombined mouse transgenic that constitutively overexpresses TPP1 allow long-term evaluation of overexposure to the enzyme and in cell culture, the inducible transgene may be a useful tool in biomarker discovery projects
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
2 - 5
-
optimal activation occurs in the range pH 3.0-4.0, the proteolytic processing takes place in a wider pH range (2.0-5.0), at pH 3.0 and lower, TPP I is quickly inactivated, whereas the polypeptide generated at higher pH (4.5-5.0) possesses 6- and 13-aa N-terminal extensions and is inactive, the enzyme is unstable at alkaline and neutral pH
3 - 6
-
at pH 3.0 the activity of TPP I is less than 75% of its maximal activity at pH 4.5, most stable at pH 3-4, no activity at pH above 6.0
3.5
-
TPP I is an acidic protease that is quickly inactivated under alkaline pH conditions, in the absence of prosegment, the enzyme is quickly denatured with a rate constant of around 0.107/min, amounting to a half-life of 6.472 min, whereas in the presence of the prosegment, the inactivation rate is reduced to about 0.035/min, and approximately 84% of the activity is preserved after over 2 h of incubation
7.4
-
37°C, half-life: of mature enzyme in absence of heparin is 2.5 min, of mature enzyme in presence of heparin is 21.5 min
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
binding to glycosaminoglycans improves the thermal stability of TPP I
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
butyl-Sepharose 4 column chromatography, Mono Q12 column chromatography, and Superdex 75 gel filtration
Ni2+ affinity resin chromatography and heparin agarose affinity chromatography
-
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
C-terminal hexahistidine-tagged human CLN2p/tripeptidyl-peptidase I produced from insect cells transfected with a baculovirus vector
expressed in CHO cells
expression as fusion protein with enhanced green fluorescent protein, in Aspergillus oryzae
expression in Chinese hamster ovary cells under the control of the cytomegalovirus promoter
-
expression of mutant enzymes N210Q, N222Q, N286Q, N313Q and N443N in Chinese hamster overy cells and human embryonic kidney 293 cells
-
expression of wild-type and mutant enzymes (E272A, D276A, D327A, D360A and S475L) in CHO cells
gene v4-7 or tpp1F, vegetative stage-specific mRNA 4-7, located on chromosome 3, recombinant expression of C-terminally GFP-tagged isozyme TPPIF(1-702) in Dictyostelium discoideum strain AX2
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
3-hydroxy-(2,2)-dimethyl butyrate -activated peroxisome proliferator-activated receptor-alpha transcriptionally upregulates the enzyme gene. Oral administration of 3-hydroxy-(2,2)-dimethyl butyrate to Cln2 heterozygous mice leads to a marked upregulation of enzyme expression
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
development of fluorescence resonance energy transfer peptides using tryptophan as the fluorophore to study TPP-I hydrolytic properties. Assay can be applied to spleen and kidney homogenate
diagnostics
medicine
molecular biology
-
fluorescent method for the histochemical detection of tripeptidyl peptidase I using glycyl-L-prolyl-L-Met-2-anthraquinonyl hydrazide as substrate
diagnostics
-
saliva is a reliable and non-invasive source for the diagnosis of infantile (CLN1) and late infantile (CLN2) neuronal ceroid lipofuscinoses
medicine
-
adeno-associated virus 2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for late infantile neuronal ceroid lipofuscinosis
medicine
-
[Ala-Ala-Phe]2-rhodamine 110 and [Arg-Nle-Nle]2-rhodamine 110 are specific substrate for determining TPP-I activity and intracellular localization in living cells. These substrates can be a valuable tool for studying the neuronal pathology underlying classical late-infantile neuronal ceroid lipofuscinosis
medicine
-
mutations in tripeptidyl-peptidase I underlie the classic late-infantile form of neuronal ceroid lipofuscinoses (CLN2), the most common neurodegenerative disorders of childhood
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Doebber, T.W.; Divor, A.R.; Ellis, S.
Identification of a tripeptidyl aminopeptidase in the anterior pituitary gland: effect on the chemical and biological properties of rat and bovine growth hormones
Endocrinology
103
1794-1804
1978
Bos taurus
brenda
McDonald, J.K.; Hoisington, A.R.; Eisenhauer, D.A.
Partial purification and characterization of an ovarian tripeptidyl peptidase: a lysosomal exopeptidase that sequentially releases collagen-related (Gly-Pro-X) triplets
Biochem. Biophys. Res. Commun.
126
63-71
1985
Sus scrofa
brenda
Page, A.E.; Fuller, K.; Chambers, T.J.; Warburton, M.J.
Purification and characterization of a tripeptidyl peptidase I from human osteoclastomas: evidence for its role in bone resorption
Arch. Biochem. Biophys.
306
354-359
1993
Homo sapiens
brenda
Krimper, R.P.; Jones, T.H.
Purification and characterization of tripeptidyl peptidase I from Dictyostelium discoideum
Biochem. Mol. Biol. Int.
47
1079-1088
1999
Dictyostelium discoideum
brenda
Du, P.G.; Kato, S.; Li, Y.H.; Maeda, T.; Yamane, T.; Yamamoto, S.; Fujiwara, M.; Yamamoto, Y.; Nishi, K.; Ohkubo, I.
Rat tripeptidyl peptidase I: molecular cloning, functional expression, tissue localization and enzymatic characterization
Biol. Chem.
382
1715-1725
2001
Rattus norvegicus
brenda
Golabek, A.A.; Kida, E.; Walus, M.; Wujek, P.; Mehta, P.; Wisniewski, K.E.
Biosynthesis, glycosylation, and enzymatic processing in vivo of human tripeptidyl-peptidase I
J. Biol. Chem.
278
7135-7145
2003
Homo sapiens
brenda
Lin, L.; Sohar, I.; Lackland, H.; Lobel, P.
The human CLN2 protein/tripeptidyl-peptidase I is a serine protease that autoactivates at acidic pH
J. Biol. Chem.
276
2249-2255
2001
Homo sapiens (O14773), Homo sapiens
brenda
Vines, D.; Warburton, M.J.
Purification and characterisation of a tripeptidyl aminopeptidase I from rat spleen
Biochim. Biophys. Acta
1384
233-242
1998
Rattus norvegicus
brenda
Reichard, U.; Lechenne, B.; Asif, A.R.; Streit, F.; Grouzmann, E.; Jousson, O.; Monod, M.
Sedolisins, a new class of secreted proteases from Aspergillus fumigatus with endoprotease or tripeptidyl-peptidase activity at acidic pHs
Appl. Environ. Microbiol.
72
1739-1748
2006
Aspergillus fumigatus (Q70J59), Aspergillus fumigatus (Q70GH4), Aspergillus fumigatus (Q70J58)
brenda
Kopan, S.; Sivasubramaniam, U.; Warburton, M.J.
The lysosomal degradation of neuromedin B is dependent on tripeptidyl peptidase-I: evidence for the impairment of neuropeptide degradation in late-infantile neuronal ceroid lipofuscinosis
Biochem. Biophys. Res. Commun.
319
58-65
2004
Homo sapiens
brenda
Dikov, A.; Dimitrova, M.; Krieg, R.; Halbhuber, K.
New fluorescent method for the histochemical detection of tripeptidyl peptidase I using glycyl-L-prolyl-L-Met-2-anthraquinonyl hydrazide as substrate
Cell. Mol. Biol.
50
OL565-OL568
2004
Rattus norvegicus
brenda
Sohar, N.; Sohar, I.; Hammer, H.
Lysosomal enzyme activities: new potential markers for Sjoegrens syndrome
Clin. Biochem.
38
1120-1126
2005
Homo sapiens
brenda
Kohan, R.; Noher de Halac, I.; Anzolini, V.T.; Cismondi, A.; Oller Ramirez, A.M.; Capra, A.P.; Dodelson de Kremer, R.
Palmitoyl protein thioesterase 1 (PPT1) and tripeptidyl peptidase-I (TPP-I) are expressed in the human saliva. A reliable and non-invasive source for the diagnosis of infantile (CLN1) and late infantile (CLN2) neuronal ceroid lipofuscinoses
Clin. Biochem.
38
492-494
2005
Homo sapiens
brenda
Walus, M.; Kida, E.; Wisniewski, K.E.; Golabek, A.A.
Ser475, Glu272, Asp276, Asp327, and Asp360 are involved in catalytic activity of human tripeptidyl-peptidase I
FEBS Lett.
579
1383-1388
2005
Homo sapiens (O14773), Homo sapiens
brenda
Sondhi, D.; Peterson, D.A.; Giannaris, E.L.; Sanders, C.T.; Mendez, B.S.; De, B.; Rostkowski, A.B.; Blanchard, B.; Bjugstad, K.; Sladek, J.R.; Redmond, D.E.; Leopold, P.L.; Kaminsky, S.M.; Hackett, N.R.; Crystal, R.G.
AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL
Gene Ther.
12
1618-1632
2005
Chlorocebus sabaeus
brenda
Steinfeld, R.; Steinke, H.B.; Isbrandt, D.; Kohlschuetter, A.; Gaertner, J.
Mutations in classical late infantile neuronal ceroid lipofuscinosis disrupt transport of tripeptidyl-peptidase I to lysosomes
Hum. Mol. Genet.
13
2483-2491
2004
Homo sapiens
brenda
Oyama, H.; Fujisawa, T.; Suzuki, T.; Dunn, B.M.; Wlodawer, A.; Oda, K.
Catalytic residues and substrate specificity of recombinant human tripeptidyl peptidase I (CLN2)
J. Biochem.
138
127-134
2005
Homo sapiens
brenda
Wujek, P.; Kida, E.; Walus, M.; Wisniewski, K.E.; Golabek, A.A.
N-glycosylation is crucial for folding, trafficking, and stability of human tripeptidyl-peptidase I
J. Biol. Chem.
279
12827-12839
2004
Homo sapiens
brenda
Golabek, A.A.; Wujek, P.; Walus, M.; Bieler, S.; Soto, C.; Wisniewski, K.E.; Kida, E.
Maturation of human tripeptidyl-peptidase I in vitro
J. Biol. Chem.
279
31058-31067
2004
Homo sapiens
brenda
Golabek, A.A.; Walus, M.; Wisniewski, K.E.; Kida, E.
Glycosaminoglycans modulate activation, activity, and stability of tripeptidyl-peptidase I in vitro and in vivo
J. Biol. Chem.
280
7550-7561
2005
Homo sapiens
brenda
Tian, Y.; Sohar, I.; Taylor, J.W.; Lobel, P.
Determination of the substrate specificity of tripeptidyl-peptidase I using combinatorial peptide libraries and development of improved fluorogenic substrates
J. Biol. Chem.
281
6559-6572
2006
Homo sapiens
brenda
Steinfeld, R.; Fuhrmann, J.C.; Gaertner, J.
Detection of tripeptidyl peptidase I activity in living cells by fluorogenic substrates
J. Histochem. Cytochem.
54
991-996
2006
Homo sapiens
brenda
Kyttaelae, A.; Lahtinen, U.; Braulke, T.; Hofmann, S.L.
Functional biology of the neuronal ceroid lipofuscinoses (NCL) proteins
Biochim. Biophys. Acta
1762
920-933
2006
Homo sapiens
brenda
Golabek, A.A.; Kida, E.
Tripeptidyl-peptidase I in health and disease
Biol. Chem.
387
1091-1099
2006
Homo sapiens
brenda
Du, P.; An, L.; Qiu, F.; Lu, G.
Peptidase activities of tripeptidyl peptidase I (TPP I): exopeptidase and endopeptidase
Chem. Res. Chin. Univ.
22
65-67
2006
Rattus norvegicus
-
brenda
Guo, X.; Deng, Y.; Lin, Y.; Cosme-Blanco, W.; Chan, S.; He, H.; Yuan, G.; Brown, E.J.; Chang, S.
Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis
EMBO J.
26
4709-4719
2007
Mus musculus
brenda
Schroeder, B.; Elsaesser, H.P.; Schmidt, B.; Hasilik, A.
Characterisation of lipofuscin-like lysosomal inclusion bodies from human placenta
FEBS Lett.
581
102-108
2007
Homo sapiens (O14773), Homo sapiens
brenda
Leman, A.R.; Polochock, S.; Mole, S.E.; Pearce, D.A.; Rothberg, P.G.
Homogeneous PCR nucleobase quenching assays to detect four mutations that cause neuronal ceroid lipofuscinosis: T75P and R151X in CLN1, and IVS5-1G>C and R208X in CLN2
J. Neurosci. Methods
157
124-131
2006
Homo sapiens
brenda
Qian, M.; Sleat, D.E.; Zheng, H.; Moore, D.; Lobel, P.
Proteomics analysis of serum from mutant mice reveals lysosomal proteins selectively transported by each of the two mannose 6-phosphate receptors
Mol. Cell. Proteomics
7
58-70
2008
Mus musculus
brenda
Bessa, C.; Teixeira, C.A.; Dias, A.; Alves, M.; Rocha, S.; Lacerda, L.; Loureiro, L.; Guimaraes, A.; Ribeiro, M.G.
CLN2/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype
Mol. Genet. Metab.
93
66-73
2008
Homo sapiens
brenda
Sleat, D.E.; El-Banna, M.; Sohar, I.; Kim, K.H.; Dobrenis, K.; Walkley, S.U.; Lobel, P.
Residual levels of tripeptidyl-peptidase I activity dramatically ameliorate disease in late-infantile neuronal ceroid lipofuscinosis
Mol. Genet. Metab.
94
222-233
2008
Mus musculus
brenda
Cabrera-Salazar, M.A.; Roskelley, E.M.; Bu, J.; Hodges, B.L.; Yew, N.; Dodge, J.C.; Shihabuddin, L.S.; Sohar, I.; Sleat, D.E.; Scheule, R.K.; Davidson, B.L.; Cheng, S.H.; Lobel, P.; Passini, M.A.
Timing of therapeutic intervention determines functional and survival outcomes in a mouse model of late infantile batten disease
Mol. Ther.
15
1782-1788
2007
Homo sapiens (O14773), Homo sapiens
brenda
Sondhi, D.; Hackett, N.R.; Peterson, D.A.; Stratton, J.; Baad, M.; Travis, K.M.; Wilson, J.M.; Crystal, R.G.
Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector
Mol. Ther.
15
481-491
2007
Homo sapiens
brenda
Chang, M.; Cooper, J.D.; Sleat, D.E.; Cheng, S.H.; Dodge, J.C.; Passini, M.A.; Lobel, P.; Davidson, B.L.
Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis
Mol. Ther.
16
649-656
2008
Homo sapiens
brenda
Kim, K.H.; Pham, C.T.; Sleat, D.E.; Lobel, P.
Dipeptidyl-peptidase I does not functionally compensate for the loss of tripeptidyl-peptidase I in the neurodegenerative disease late-infantile neuronal ceroid lipofuscinosis
Biochem. J.
415
225-232
2008
Mus musculus
brenda
Tye, C.E.; Lorenz, R.L.; Bartlett, J.D.
Lysosomal protease expression in mature enamel
Cells Tissues Organs
189
111-114
2009
Mus musculus
brenda
Ivanov, I.; Tasheva, D.; Todorova, R.; Dimitrova, M.
Synthesis and use of 4-peptidylhydrazido-N-hexyl-1,8-naphthalimides as fluorogenic histochemical substrates for dipeptidyl peptidase IV and tripeptidyl peptidase I
Eur. J. Med. Chem.
44
384-392
2009
Rattus norvegicus, Mus musculus
brenda
Sondhi, D.; Peterson, D.A.; Edelstein, A.M.; del Fierro, K.; Hackett, N.R.; Crystal, R.G.
Survival advantage of neonatal CNS gene transfer for late infantile neuronal ceroid lipofuscinosis
Exp. Neurol.
213
18-27
2008
Mus musculus
brenda
Golabek, A.A.; Dolzhanskaya, N.; Walus, M.; Wisniewski, K.E.; Kida, E.
Prosegment of tripeptidyl peptidase I is a potent, slow-binding inhibitor of its cognate enzyme
J. Biol. Chem.
283
16497-16504
2008
Homo sapiens
brenda
Pal, A.; Kraetzner, R.; Gruene, T.; Grapp, M.; Schreiber, K.; Gronborg, M.; Urlaub, H.; Becker, S.; Asif, A.R.; Gaertner, J.; Sheldrick, G.M.; Steinfeld, R.
Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis
J. Biol. Chem.
284
3976-3984
2009
Homo sapiens (O14773)
brenda
Guhaniyogi, J.; Sohar, I.; Das, K.; Stock, A.M.; Lobel, P.
Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis
J. Biol. Chem.
284
3985-3997
2009
Homo sapiens (O14773), Homo sapiens
brenda
Xu, S.; Sleat, D.E.; Jadot, M.; Lobel, P.
Glial fibrillary acidic protein is elevated in the lysosomal storage disease classical late-infantile neuronal ceroid lipofuscinosis, but is not a component of the storage material
Biochem. J.
428
355-362
2010
Mus musculus
brenda
Walus, M.; Kida, E.; Golabek, A.A.
Functional consequences and rescue potential of pathogenic missense mutations in tripeptidyl peptidase I
Hum. Mutat.
31
710-721
2010
Homo sapiens (O14773), Homo sapiens
brenda
Kim, K.H.; Sleat, D.E.; Bernard, O.; Lobel, P.
Genetic modulation of apoptotic pathways fails to alter disease course in tripeptidyl-peptidase 1 deficient mice
Neurosci. Lett.
453
27-30
2009
Mus musculus
brenda
Atanasova, D.; Lazarov, N.
Histochemical demonstration of tripeptidyl aminopeptidase I in the rat carotid body
Acta Histochem.
117
219-222
2015
Rattus norvegicus
brenda
Zhu, L.; Nemoto, T.; Yoon, J.; Maruyama, J.; Kitamoto, K.
Improved heterologous protein production by a tripeptidyl peptidase gene (AosedD) disruptant of the filamentous fungus Aspergillus oryzae
J. Gen. Appl. Microbiol.
58
199-209
2012
Aspergillus oryzae (Q2U9N2), Aspergillus oryzae ATCC 42149 (Q2U9N2)
brenda
Petrova, E.B.; Dimitrova, M.B.; Ivanov, I.P.; Pavlova, V.G.; Dimitrova, S.G.; Kadiysky, D.S.
Effect of acute hypoxic shock on the rat brain morphology and tripeptidyl peptidase I activity
Acta Histochem.
118
496-504
2016
Rattus norvegicus, Rattus norvegicus (Q9EQV6)
brenda
Lukacs, Z.; Nickel, M.; Murko, S.; Nieves Cobos, P.; Schulz, A.; Santer, R.; Kohlschuetter, A.
Validity of a rapid and simple fluorometric tripeptidyl peptidase 1 (TPP1) assay using dried blood specimens to diagnose CLN2 disease
Clin. Chim. Acta
492
69-71
2019
Homo sapiens (O14773), Homo sapiens
brenda
Stumpf, M.; Mueller, R.; Gassen, B.; Wehrstedt, R.; Fey, P.; Karow, M.; Eichinger, L.; Gloeckner, G.; Noegel, A.
A tripeptidyl peptidase 1 is a binding partner of the Golgi pH regulator (GPHR) in Dictyostelium
Dis. Model. Mech.
10
897-907
2017
Dictyostelium discoideum (Q54TD0), Dictyostelium discoideum
brenda
Kondo, M.Y.; Gouvea, I.E.; Okamoto, D.N.; Santos, J.A.; Souccar, C.; Oda, K.; Juliano, L.; Juliano, M.A.
Analysis of catalytic properties of tripeptidyl peptidase I (TTP-I), a serine carboxyl lysosomal protease, and its detection in tissue extracts using selective FRET peptide substrate
Peptides
76
80-86
2016
Homo sapiens (O14773), Rattus norvegicus (Q9EQV6), Rattus norvegicus Wistar (Q9EQV6)
brenda
Nemtsova, Y.; Wiseman, J.; El-Banna, M.; Lobel, P.; Sleat, D.
Inducible transgenic expression of tripeptidyl peptidase 1 in a mouse model of late-infantile neuronal ceroid lipofuscinosis
PLoS ONE
13
e0192286
2018
Mus musculus (O89023), Mus musculus, Mus musculus C57BL/6 (O89023)
brenda
Sole-Domenech, S.; Rojas, A.V.; Maisuradze, G.G.; Scheraga, H.A.; Lobel, P.; Maxfield, F.R.
Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar Abeta by multiple endoproteolytic cleavages within the beta-sheet domain
Proc. Natl. Acad. Sci. USA
115
1493-1498
2018
Homo sapiens (O14773)
brenda
Zhou, W.; Dimitriadis, E.
Tripeptidyl peptidase 1 regulates human trophoblast cell proliferation implying a role in placentation
BioMed Res. Int.
2022
6856768
2022
Homo sapiens
brenda
Miao, S.B.; Guo, H.; Kong, D.X.; Zhao, Y.Y.; Pan, S.H.; Jiang, Y.; Gao, X.; Wu, X.H.
Case report Analysis of novel compound heterozygous TPP1 variants in a Chinese patient with neuronal ceroid lipofuscinosis type 2
Front. Genet.
13
937485
2022
Homo sapiens (O14773)
brenda
Baranzehi, T.; Kordi-Tamandani, D.M.; Najafi, M.; Khajeh, A.; Schmidts, M.
Identification of a TPP1 Q278X mutation in an Iranian patient with neuronal ceroid lipofuscinosis 2 Literature review and mutations update
J. Clin. Med.
11
6415
2022
Homo sapiens (O14773)
brenda
K, P.; Madhana, P.N.; Eswaramoorthy, R.; Ramasamy, M.
A computational approach to analyzing the functional and structural impacts of tripeptidyl-peptidase 1 missense mutations in neuronal ceroid lipofuscinosis
Metab. Brain Dis.
39
545-558
2024
Homo sapiens (O14773)
brenda
Sleat, D.E.; Maita, I.; Banach-Petrosky, W.; Larrimore, K.E.; Liu, T.; Cruz, D.; Baker, L.; Maxfield, F.R.; Samuels, B.; Lobel, P.
Elevated levels of tripeptidyl peptidase 1 do not ameliorate pathogenesis in a mouse model of Alzheimer disease
Neurobiol. Aging
118
106-107
2022
Mus musculus
brenda
Chakrabarti, S.; Chandra, S.; Roy, A.; Dasarathi, S.; Kundu, M.; Pahan, K.
Upregulation of tripeptidyl-peptidase 1 by 3-hydroxy-(2,2)-dimethyl butyrate, a brain endogenous ligand of PPARalpha Implications for late-infantile Batten disease therapy
Neurobiol. Dis.
127
362-373
2019
Mus musculus (O89023)
brenda
Vodenicharov, A.P.; Dimitrova, M.; Tsandev, N.S.; Stefanov, I.S.
Tripeptidyl peptidase I activity in porcine lumbar spinal ganglia - a histochemical study
Pol. J. Vet. Sci.
24
409-414
2021
Sus scrofa
brenda
Liu, R.H.; Wang, X.Y.; Jia, Y.Y.; Wang, X.C.; Xia, M.; Nie, Q.; Guo, J.; Kong, Q.X.
Compound heterozygous mutations in tripeptidyl peptidase 1 cause rare autosomal recessive spinocerebellar ataxia type 7 A case report
World J. Clin. Cases
11
6618-6623
2023
Homo sapiens (O14773)
brenda
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