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Enzyme Nomenclature
Information on EC 3.4.14.9 - tripeptidyl-peptidase I
for references in articles please use BRENDA:EC3.4.14.9
Word Map on EC 3.4.14.9
- 3.4.14.9
-
ceroid
- lipofuscinosis
-
infantile
-
lincl
- neurodegenerative
-
late-infantile
- tripeptides
-
exopeptidase
-
curvilinear
- palmitoyl-protein
-
autofluorescent
-
serine-carboxyl
- batten
-
pepstatin-insensitive
- molecular biology
- diagnostics
- medicine
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The enzyme appears in viruses and cellular organisms
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EC NUMBER 
COMMENTARY 
3.4.14.9
-
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RECOMMENDED NAME
GeneOntology No.
tripeptidyl-peptidase I
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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.
-
-
-
-
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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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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
physiological function
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
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
-
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
-
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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
(pGlu)LYENKPRRRPYIL + H2O
(pGlu)L + YENKPRRRPYIL
-
i.e. neurotensin, 15.0% degradation after 16 h
-
?
Ala-Ala-Phe-7-amido-4-carbamoylmethylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-carbamoylmethylcoumarin
-
-
-
-
?
Ala-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
-
-
-
-
?
Ala-Ala-Pro-4-nitroanilide + H2O
Ala-Ala-Pro + 4-nitroaniline
-
-
-
-
?
Ala-Arg-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-Arg-Phe + p-nitrophenylalanyl-Arg-Leu
-
-
-
-
?
Ala-Asp-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-Asp-Phe + p-nitrophenylalanyl-Arg-Leu
-
-
-
-
?
Ala-His-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-His-Phe + p-nitrophenylalanyl-Arg-Leu
-
-
-
-
?
Ala-Nle-Leu-7-amido-4-carbamoylmethylcoumarin + H2O
Ala-Nle-Leu + 7-amino-4-carbamoylmethylcoumarin
-
-
-
-
?
Ala-Nle-Nle-7-amido-4-carbamoylmethylcoumarin + H2O
Ala-Nle-Nle + 7-amino-4-carbamoylmethylcoumarin
-
-
-
-
?
Ala-Nva-Nle-7-amido-4-carbamoylmethylcoumarin + H2O
Ala-Nva-Nle + 7-amino-4-carbamoylmethylcoumarin
-
-
-
-
?
Ala-Phe-Pro-4-nitroanilide + H2O
Ala-Phe-Pro + 4-nitroaniline
-
-
-
-
?
Ala-Pro-Gly-Asp-Arg-Ile-Tyr-Val-His-Pro-Phe + H2O
Ala-Pro-Gly + Asp-Arg-Ile + Tyr-Val-His-Pro-Phe
SedB
-
-
?
Ala-Ser-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ala-Ser-Phe + p-nitrophenylalanyl-Arg-Leu
-
-
-
-
?
Arg-Ala-Phe-7-amido-4-methylcoumarin + H2O
Arg-Ala-Phe + 7-amino-4-methylcoumarin
-
-
-
-
?
Arg-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Arg-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
-
-
-
-
?
Arg-Pro-Phe-7-amido-4-carbamoylmethylcoumarin + H2O
Arg-Pro-Phe + 7-amino-4-carbamoylmethylcoumarin
-
-
-
-
?
Asp-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Asp-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
-
-
-
-
?
DRVYIHPFHL + H2O
DRV + YIHPFHL
-
i.e. angiotensin I, 11.3% degradation after 16 h
-
?
GKPIPFFRLK + H2O
GKPIP + FFRLK
-
endo-type substrate, 24.5% degradation after 16 h
-
?
Gly-L-Pro-L-Met-2-anthraquinonyl hydrazide + H2O
Gly-L-Pro-L-Met + 2-anthraquinonyl hydrazine
-
-
-
-
?
Gly-Lys-Pro-Ile-Pro-Phe-Phe-Arg-Leu-Lys + H2O
Gly-Lys-Pro-Ile-Pro-Phe + Phe-Arg-Leu-Lys
-
-
-
-
?
Gly-Pro-Ala 4-nitroanilide + H2O
Gly-Pro-Ala + 4-nitroaniline
-
at 20% the rate of Gly-Pro-Met 4-nitroanilide hydrolysis
-
-
?
Gly-Pro-Arg-7-amido-4-methylcoumarin + H2O
?
-
at 10% the rate of Gly-Pro-Met 4-methylcoumarin 7-amide hydrolysis
-
-
?
Gly-Pro-Met-7-amido-4-methylcoumarin + H2O
Gly-Pro-Met + 7-amino-4-methylcoumarin
-
-
-
-
?
GNLWATGHFM-NH2 + H2O
GNL + WATGHFM-NH2
-
i.e. neuromedin B, complete degradation after 16 h
-
?
His-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
His-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
-
-
-
-
?
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
-
-
-
-
?
Phe-Pro-Ala 2-naphthylamide + H2O
Phe-Pro-Ala + 2-naphthylamine
-
synthetic peptide modeled after NH2-terminal tripeptide sequence of the phenylalanyl monomer of bovine or rat growth hormone, fluorogenic substrate
-
?
phenylalanyl monomer of bovine growth hormone + H2O
?
-
cleaves 11 tripeptides sequentially from the NH2-terminus
-
-
?
RVYIHPF + H2O
RVY + IHPF
-
i.e. angiotensin III, 95.0% degradation after 15 min
-
?
Ser-Ala-Phe-p-nitrophenylalanyl-Arg-Leu + H2O
Ser-Ala-Phe + p-nitrophenylalanyl-Arg-Leu
-
-
-
-
?
synthetic collagen-like polypetides + H2O
Gly-Pro-Xaa tripeptides
-
-
-
?
Val-Pro-Arg 4-nitroanilide + H2O
Val-Pro-Arg + 4-nitroaniline
-
at 11% the rate of Gly-Pro-Met 4-nitroanilide hydrolysis
-
-
?
YGGFLRKYP + H2O
YGG + FLRKYP
-
i.e. beta-neo-endorphin, 28% degradation after 16 h
-
?
[Ala-Ala-Phe]2-rhodamine 110 + H2O
[Ala-Ala-Phe]2 + rhodamine 110
-
specific substrate for determining TPP-I activity and intracellular localization in living cells
-
-
?
[Arg-Nle-Nle]2-rhodamine 110 + H2O
[Ala-Ala-Phe]2 + rhodamine 110
-
specific substrate for determining TPP-I activity and intracellular localization in living cells
-
-
?
Ala-Ala-Ala-4-nitroanilide + H2O
Ala-Ala-Ala + 4-nitroaniline
-
-
-
-
?
Ala-Ala-Phe-4-nitroanilide + H2O
Ala-Ala-Phe + 4-nitroaniline
SedB
-
-
?
Ala-Ala-Phe-4-nitroanilide + H2O
Ala-Ala-Phe + 4-nitroaniline
SedC
-
-
?
Ala-Ala-Phe-4-nitroanilide + H2O
Ala-Ala-Phe + 4-nitroaniline
SedD
-
-
?
Ala-Ala-Phe-4-nitroanilide + H2O
Ala-Ala-Phe + 4-nitroaniline
-
-
-
-
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
-
-
-
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
-
-
-
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
-
-
-
?
Ala-Ala-Phe-7-amido-4-methylcoumarin + H2O
Ala-Ala-Phe + 7-amino-4-methylcoumarin
-
33.8% degradation within 60 min
-
-
?
DRVYIHPF + H2O
DRV + YIHPF
-
i.e. angiotensin II, 18.2% degradation after 16 h
-
?
Gly-Pro-Leu 2-naphthylamide + H2O
Gly-Pro-Leu + 2-naphthylamine
-
25% of the activity with Gly-Pro-Met 2-naphthylamide, Ala-Ala-Phe-4-nitroanilide or Ala-Ala-Phe-7-amido-4-methylcoumarin
-
-
?
Gly-Pro-Leu 2-naphthylamide + H2O
Gly-Pro-Leu + 2-naphthylamine
-
at 30% the rate of Gly-Pro-Met 2-naphthylamide hydrolysis
-
-
?
L-Ala-L-Ala-L-Phe-7-amido-4-methylcoumarin + H2O
L-Ala-L-Ala-L-Phe + 7-amino-4-methylcoumarin
-
-
-
-
?
L-Ala-L-Ala-L-Phe-7-amido-4-methylcoumarin + H2O
L-Ala-L-Ala-L-Phe + 7-amino-4-methylcoumarin
-
-
-
-
?
Phe-Pro-Ala-4-nitroanilide + H2O
Phe-Pro-Ala + 4-nitroaniline
SedB
-
-
?
Phe-Pro-Ala-4-nitroanilide + H2O
Phe-Pro-Ala + 4-nitroaniline
SedC
-
-
?
Phe-Pro-Ala-4-nitroanilide + H2O
Phe-Pro-Ala + 4-nitroaniline
SedD
-
-
?
glucagon + H2O
additional information
-
-
-
all nine tripeptides and the C-terminal pentapeptide are identified
?
additional information
?
-
-
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
-
-
-
additional information
?
-
-
no significant aminopeptidase activity
-
-
-
additional information
?
-
-
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
-
-
-
additional information
?
-
-
the enzyme removes tripeptides from the free N-termini of small polypeptides and also shows a minor endoprotease activity
-
-
-
additional information
?
-
-
absolute requirement for unsubstituted amino-terminus
-
-
-
additional information
?
-
-
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
-
-
-
additional information
?
-
-
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
-
-
-
additional information
?
-
-
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
-
-
-
additional information
?
-
-
determination of the substrate specificity of tripeptidyl-peptidase I using combinatorial peptide libraries and development of improved fluorogenic substrates
-
-
-
additional information
?
-
-
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
-
-
-
additional information
?
-
-
TPP I acts preferentially on small, unstructured oligopeptides of less than 5 kDa
-
-
-
additional information
?
-
-
dipeptidyl-peptidase I cannot functionally compensate for the loss of tripeptidyl-peptidase I
-
-
-
additional information
?
-
-
substrates not cleaved after 24 h of digestion: dynorphin, beta-casomorphin-7, Leu-enkephalin, Met-enkephalin, neurokinin-A, LVV-hemorphin, bradykinin
-
-
-
additional information
?
-
-
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
-
-
-
additional information
?
-
-
an inherited deficiency of tripeptidyl peptidase I activity causes a fatal lysosomal storage disorder, classic late infantile neuronal ceroid lipofuscinosis, CLN2
-
-
-
additional information
?
-
-
N-terminal exopeptidase that removes tripeptide units provided the P3 residue is unsubstituted
-
-
-
additional information
?
-
-
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
-
-
-
additional information
?
-
-
exopeptidase involved in intracellular (lysosomal) degradation of collagen fibrils
-
-
-
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NATURAL SUBSTRATES
NATURAL PRODUCTS
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
additional information
?
-
-
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
-
-
-
additional information
?
-
-
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
-
-
-
additional information
?
-
-
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
-
-
-
additional information
?
-
-
dipeptidyl-peptidase I cannot functionally compensate for the loss of tripeptidyl-peptidase I
-
-
-
additional information
?
-
-
an inherited deficiency of tripeptidyl peptidase I activity causes a fatal lysosomal storage disorder, classic late infantile neuronal ceroid lipofuscinosis, CLN2
-
-
-
additional information
?
-
-
exopeptidase involved in intracellular (lysosomal) degradation of collagen fibrils
-
-
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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INHIBITORS
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
-
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
-
no inhibition: alkali-inactivated diisopropylfluoride, leupeptin; no inhibition by pepstatin; no inhibition: EDTA
-
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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
-
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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
0.00402
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
35
Phe-Pro-Ala-4-nitroanilide
pH 6.0, 20°C, SedB
0.04 - 1.97
Ala-Ala-Phe-7-amido-4-methylcoumarin
-
pH 5.0, 37°C, mutant enzyme D276A
0.0124
Ala-Arg-Phe-p-nitrophenylalanyl-Arg-Leu
-
pH 4.0, 378°C, mutant enzyme E77A
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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
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 - 7
active between pH 3 and pH 7, SedB; active between pH 3 and pH 7, SedC
3 - 4.8
-
pH 3.0: about 30% of maximal activity, pH 4.8: about 50% of maximal activity
3 - 8
-
about half-maximal activity at pH 3 and 8, hydrolysis of Gly-Pro-Met 2-naphthylamide
3.5 - 6.5
-
about half-maximal activity at pH 3.5 and 6.5, hydrolysis of Ala-Ala-Phe 4-methylcoumarin 7-amide
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
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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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
-
activity in neuroglia cells, no activity in small granule cells, Purkinje cells, remified dendrites and myelinated fibers
-
activity in ducts, no activity in acinar cells and islets of Langerhans
-
activity in excretory duct and stereocilia, no activity in glandular acinus and intercalated portion
-
activity in spermatogonia, spermatozoa, Sertoli cells and Leygig cells, no activity in basement cells
-
TPPI is expressed ubiquitously throughout the body but disease appears restricted to the brain
presence of recombinant fusion protein with enhanced green fluorescent protein
-
presence of recombinant fusion protein with enhanced green fluorescent protein
-
presence of recombinant fusion protein with enhanced green fluorescent protein
-
presence of recombinant fusion protein with enhanced green fluorescent protein
-
-
activity in proximal tubules, distal tubules, collecting tubules and transitional cells, no activity in glomerulus and Bowman‘s capsule
-
enzyme activity is elevated during the first 5 years of Sjoegren's syndrome, and it increases further between 5 and 10 years after diagnosis
-
activity in corpus luteum and corpus albicus, no activity in follicles
-
heterogenous distribution of TPP I positive macrophages, leukocytes and reticular fibroblasts in the red and white pulp
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
presence of recombinant fusion protein with enhanced green fluorescent protein
-
presence of recombinant fusion protein with enhanced green fluorescent protein
-
-
the conversion of the proenzyme into the mature form takes place in lysosomal compartment
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PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
40600
x * 40600, SedD, calculated from sequence
43000
x * 43000, SedB, calculated from sequence
46000
48000
68000
89000
x * 89000, fusion protein with enhanced green fluorescent protein, SDS-PAGE
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SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
x * 40600, SedD, calculated from sequence; x * 43000, SedB, calculated from sequence
?
x * 89000, fusion protein with enhanced green fluorescent protein, SDS-PAGE
?
-
x * 89000, fusion protein with enhanced green fluorescent protein, SDS-PAGE
-
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
proteolytic modification
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; the preproprotein SedC is composed of 596 amino acids, the signal peptide contains 24 amino acids; the preproprotein SedD is composed of 568 amino acids, the signal peptide contains 20 amino acids
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
-
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
-
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
-
proenzyme, the N-linked glycan at Asn286 is involved in maturation of the enzyme
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
-
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
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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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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
678513
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
679200
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
698756
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
665697
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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
-
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 SedB in Pichia pastoris; expression of SedC in Pichia pastoris; expression of SedD in Pichia pastoris
expression of wild-type and mutant enzymes (E272A, D276A, D327A, D360A and S475L) in CHO cells
-
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ENGINEERING
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
G284V
G473R
-
the mutation probably compromises the active center and results in loss of proteolytic activity
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
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
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
-
decreased activity; 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
-
decreased activity; 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
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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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LINKS TO OTHER DATABASES (specific for EC-Number 3.4.14.9)
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