Information on EC 3.1.2.22 - palmitoyl[protein] hydrolase

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The expected taxonomic range for this enzyme is: Opisthokonta

EC NUMBER
COMMENTARY
3.1.2.22
-
RECOMMENDED NAME
GeneOntology No.
palmitoyl[protein] hydrolase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
palmitoyl[protein] + H2O = palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl[protein] + H2O = palmitate + protein
show the reaction diagram
specific for long-chain thioesters of fatty acids from S-acylated residues in proteins, palmitoyl cysteine and palmitoyl-CoA
O59747, -
palmitoyl[protein] + H2O = palmitate + protein
show the reaction diagram
specific for long-chain thioesters of fatty acids from S-acylated residues in proteins, palmitoyl cysteine and palmitoyl-CoA, catalytic triad of PPT2 consists of Ser111, His283, and Asp228, mechanism, both PPT1 and PPT2 have lipid-binding grooves leading away from the active site
-
palmitoyl[protein] + H2O = palmitate + protein
show the reaction diagram
specific for long-chain thioesters of fatty acids from S-acylated residues in proteins, palmitoyl cysteine and palmitoyl-CoA
-
palmitoyl[protein] + H2O = palmitate + protein
show the reaction diagram
specific for long-chain thioesters of fatty acids from S-acylated residues in proteins, palmitoyl cysteine and palmitoyl-CoA
-
palmitoyl[protein] + H2O = palmitate + protein
show the reaction diagram
specific for long-chain thioesters of fatty acids from S-acylated residues in proteins, palmitoyl cysteine and palmitoyl-CoA
-
palmitoyl[protein] + H2O = palmitate + protein
show the reaction diagram
specific for long-chain thioesters of fatty acids from S-acylated residues in proteins, palmitoyl cysteine and palmitoyl-CoA, catalytic triad consists of Ser115, His289, and Asp233
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
hydrolysis of thioester
-
-
-
-
hydrolysis of thioester
O59747, -
-
hydrolysis of thioester
-
-
hydrolysis of thioester
-
-
hydrolysis of thioester
-
-
PATHWAY
KEGG Link
MetaCyc Link
Fatty acid elongation
-
Metabolic pathways
-
SYSTEMATIC NAME
IUBMB Comments
palmitoyl[protein] hydrolase
Specific for long-chain thioesters of fatty acids. Hydrolyses fatty acids from S-acylated cysteine residues in proteins, palmitoyl cysteine and palmitoyl-CoA.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
Acyl protein thioester hydrolase
-
-
-
-
acylprotein thioesterase 1
O75608
-
CLN1
-
gene name
G14
-
-
-
-
GenBank AF020543-derived protein GI 2501961
-
-
-
-
GenBank L42809-derived protein GI 1160967
-
-
-
-
Hydrolase, acyl protein thioester
-
-
-
-
Hydrolase, acyl protein thioester (cattle clone pBovPPT-18 precursor reduced)
-
-
-
-
Hydrolase, acyl protein thioester (cattle pBovPPT-25 precursor reduced)
-
-
-
-
Hydrolase, acyl protein thioester (human clone B lysosome-associated isoenzyme 2)
-
-
-
-
Hydrolase, acyl protein thioester (human clone pHuPPT-5')
-
-
-
-
Hydrolase, acyl protein thioester (ox clone pBovPPT-18 precursor reduced)
-
-
-
-
Hydrolase, acyl protein thioester (ox pBovPPT-25 precursor reduced)
-
-
-
-
Hydrolase, acyl protein thioester (rat clone pRatPPT-44 precursor reduced)
-
-
-
-
lysophospholipase 1
O75608
-
palmitoyl protein thioesterase
-
-
palmitoyl protein thioesterase
-
-
palmitoyl protein thioesterase 1
Q5JZR0
-
palmitoyl protein thioesterase 1
-
-
palmitoyl protein thioesterase 1
-
-
palmitoyl protein thioesterase 1
P50897
-
palmitoyl protein thioesterase 1
-
-
palmitoyl protein thioesterase 1
O59747
-
palmitoyl protein thioesterase-1
-
-
palmitoyl protein thioesterase-1
-
-
palmitoyl protein thioesterase-2
-
-
palmitoyl-protein hydrolase
-
-
Palmitoyl-protein thioesterase
-
-
-
-
Palmitoyl-protein thioesterase
-
-
Palmitoyl-protein thioesterase
-
-
Palmitoyl-protein thioesterase (bovine clone pBovPPT-17 precursor)
-
-
-
-
Palmitoyl-protein thioesterase (bovine clone pBovPPT-25 precursor)
-
-
-
-
Palmitoyl-protein thioesterase (human clone pHuPPT-5')
-
-
-
-
Palmitoyl-protein thioesterase (rat clone pRatPPT-44 precursor)
-
-
-
-
palmitoyl-protein thioesterase 1
-
-
palmitoyl-protein thioesterase 1
-
-
palmitoyl-protein thioesterase 1
-
-
Palmitoyl-protein thioesterase PPT2 (human clone B lysosome associated)
-
-
-
-
palmitoyl-protein thioesterase-1
-
-
palmitoyl-protein thioesterase-1
-
-
palmitoyl-thioesterase
-
-
PPT
-
-
-
-
PPT1
-
-
-
-
PPT1
P50897
-
PPT2
-
-
CAS REGISTRY NUMBER
COMMENTARY
150605-49-5
-
158210-90-3
hydrolase, acyl protein thioester (rat clone pRatPPT-44 precursor reduced) /palmitoyl-protein thioesterase (rat clone pRatPPT-44 precursor)
158210-92-5
hydrolase, acyl protein thioester (cattle clone pBovPPT-18 precursor reduced) /hydrolase, acyl protein thioester (ox clone pBovPPT-18 precursor reduced) /palmitoyl-protein thioesterase (bovine clone pBovPPT-17 precursor)
158210-93-6
hydrolase, acyl protein thioester (cattle pBovPPT-25 precursor reduced) /hydrolase, acyl protein thioester (ox pBovPPT-25 precursor reduced) /palmitoyl-protein thioesterase (bovine clone pBovPPT-25 precursor)
179801-10-6
hydrolase, acyl protein thioester (human clone pHuPPT-5') /GenBank L42809-derived protein GI 1160967 /palmitoyl-protein thioesterase (human clone pHuPPT-5')
199619-79-9
hydrolase, acyl protein thioester (human clone B lysosome-associated isoenzyme 2) /genBank AF020543-derived protein GI 2501961 /palmitoyl-protein thioesterase PPT2 (human clone B lysosome associated)
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
strain deleted for ppt-1, potentially provides a model system for the study of human infantile neuronal ceroid lipofuscinosis
-
-
Manually annotated by BRENDA team
Miniature Dachshund
UniProt
Manually annotated by BRENDA team
2 lysosomal enzyme forms PPT1 and PPT2
-
-
Manually annotated by BRENDA team
lysosomal enzyme forms PPT1
-
-
Manually annotated by BRENDA team
precursor
UniProt
Manually annotated by BRENDA team
PPT1
-
-
Manually annotated by BRENDA team
gene ppt
-
-
Manually annotated by BRENDA team
cosmid; isozyme PPT1. gene pdf1
UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
PPT1 deficient cells are partially resistant to tumor necrosis factor-induced cell death (57-75% cell viability versus 15-30% for control fibroblasts), tumor necrosis factor-initiated proteolytic cleavage of caspase-8, Bid and caspase-3, as well as cytochrome c release is strongly attenuated. Activation of p42/p44 mitogen-activated protein kinase and of transcription factor NF-kappaB by tumor necrosis factor, and induction of cell death by staurosporine or chemotherapeutic drugs in infantile neuronal ceroid lipofuscinosis cells are unaffected by PPT1 deficiency
malfunction
-
resistance to tumor necrosis factor-induced apoptosis in embryonic fibroblasts derived from Ppt1/Cln1-deficient mice but not from mice with a targeted deletion of Cln3 or Cln5 (murine models of ceroid lipofuscinosis)
malfunction
-
first case of infantile neuronal ceroid lipofuscinosis in 37 month old Japanese boy diagnosed by enzyme activity deficiency of palmitoyl-protein thioesterase, displaying symptoms of severe deterioration beginning in his 14th month
malfunction
-
PPT1-deficient mouse (PPT1-/-) mimics the clinical symptoms and underlying pathology of infantile neuronal ceroid lipofuscinosis: Purkinje cell loss beginning at 3 months, which correlates with changes in rotarod performance, an early stage reactive gliosis and a primary pathology in astrocytes, including changes in S100beta and GLAST expression, a late stage granule cell loss, microglial activation, and demyelination. Neuronal–glial interactions are the core pathology in the PPT1-/- cerebellum
malfunction
-
Garland cells from Ppt1 loss-of-function mutants have defects in endocytic trafficking
malfunction
-, Q5JZR0
neuronal ceroid lipofuscinoses-like signs caused by single nucleotide insertion in exon 8 (homozygous)
physiological function
-
role of PPT1 and, likely, protein depalmitoylation in the regulation of tumor necrosis factor-induced apoptosis. PPT1 is involved in cell death triggered by death receptors but not receptor-independent cytotoxic agents. Expression of PPT1 cDNA in infantile neuronal ceroid lipofuscinosis cells restores the tumor necrosis factor sensitivity
physiological function
-
role of PPT1 and, likely, protein depalmitoylation in the regulation of tumor necrosis factor-induced apoptosis
physiological function
-
when injected intravenously into PPT1-deficient mice, the clearance of recombinant PPT1 from plasma is rapid, with a half-life of 10 min. Most of the injected dose is distributed to the kidney and liver and potentially corrective levels are also observed in heart, lung and spleen. Brain uptake is minimal. The enzyme is largely mannose 6-phosphorylated and takes up rapidly by PPT1-deficient immortalized lymphoblasts derived from infantile neuronal ceroid lipofuscinosis patients
physiological function
-
Ppt1 plays a role in modulating the early stages of vesicle formation. There may be a connection between Ppt1 and bone morphogenetic protein signaling at the cellular level. Expression of wild-type Ppt1 in the adult visual system using GMR-Gal4 alters the external and internal organization of the adult retina. When co-expressed UAS-dynamin with Ppt1 there is a significant enhancement of the rough eye phenotype
physiological function
-
essential for proper neuronal cell fates and organization, ortholog to the human Batten disease palmitoyl protein thioesterase 1
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
1-palmitoyl lysophosphatidylcholine + H2O
glycerophosphocholine + palmitate
show the reaction diagram
O75608
-
-
-
?
4-methylumbelliferyl 6-deoxy-6-thiopalmitoyl-beta-D-glucopyranoside + H2O
4-methylumbelliferyl 6-deoxy-6-thio-beta-D-glucopyranoside + palmitate
show the reaction diagram
-, Q5JZR0
-
-
-
?
4-methylumbelliferyl-6-S-palmitoyl-beta-D-glucoside + H2O
4-methylumbelliferol + palmitate + beta-D-glucose
show the reaction diagram
-
-
-
?
4-methylumbelliferyl-6-thiopalmitoyl-beta-D-glucoside + H2O
4-methylumbelliferol + palmitate + beta-D-glucose
show the reaction diagram
-
-
-
?
4-methylumbelliferyl-6-thiopalmitoyl-beta-D-glucoside + H2O
4-methylumbelliferol + palmitate + beta-D-glucose
show the reaction diagram
-
artificial substrate
-
?
4-methylumbelliferyl-6-thiopalmitoyl-beta-D-glucoside + H2O
4-methylumbelliferol + palmitate + beta-D-glucose
show the reaction diagram
O59747, -
artificial substrate
-
?
4-methylumbelliferyl-6-thiopalmitoyl-beta-D-glucoside + H2O
?
show the reaction diagram
-
-
-
-
?
4-methylumbelliferyl-6-thiopalmitoyl-beta-D-glucoside + H2O
?
show the reaction diagram
-
-
-
-
?
4-methylumbelliferyl-6-thiopalmitoyl-beta-D-glucoside + H2O
?
show the reaction diagram
-
-
-
-
?
Myristoyl-CoA + H2O
Myristate + CoA
show the reaction diagram
-
-
-
-
-
Palmitoyl-(alpha-subunit of the heterotrimeric G protein) + H2O
?
show the reaction diagram
-
-
-
-
-
Palmitoyl-CoA + H2O
Palmitate + CoA
show the reaction diagram
-
-
-
?
Palmitoyl-CoA + H2O
Palmitate + CoA
show the reaction diagram
-
-
-
-
-
Palmitoyl-CoA + H2O
Palmitate + CoA
show the reaction diagram
-
preferred substrate of PPT2
-
?
Palmitoyl-H-Ras + H2O
Palmitate + Ha-Ras
show the reaction diagram
-
-
-
-
-
Palmitoyl-H-Ras + H2O
Palmitate + Ha-Ras
show the reaction diagram
-
the enzyme recognizes H-Ras as substrate only when H-Ras is in its native conformation
-
-
-
Palmitoyl-H-Ras + H2O
Palmitate + Ha-Ras
show the reaction diagram
-
palmitate-labeled, histidine-tagged H-Ras
-
-
-
palmitoyl-peptide + H2O
palmitate + peptide
show the reaction diagram
O75608
residue 3 to 14 of RGS4 protein with palmitoyl group attached at Cys12 of RGS4 protein
-
-
?
palmitoyl-protein + H2O
palmitate + protein
show the reaction diagram
-
palmitoylation plays critical roles in diverse biological functions, including membrane anchorage, vesicular transport, signal transduction and the maintenance of cellular architecture
-
-
r
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
P50897
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
-
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
various S-acylated proteins
-
-
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
hydrolysis of long-chain fatty acids from S-acylated proteins and CoA
-
?
palmitoyl-[protein] + H2O
palmitate + protein
show the reaction diagram
-
hydrolysis of long-chain fatty acids from S-acylated proteins and CoA
-
?
palmitoylthio-beta-glucoside + H2O
palmitate + thio-beta-glucoside
show the reaction diagram
-
-
-
?
S-palmitoyl-N-acetyl-O-carboxymethyl-cysteine + H2O
N-acetyl-O-carboxymethyl-cysteine + palmitate
show the reaction diagram
-
enzyme form PPT1, not PPT2
-
?
S-palmitoyl-N-acetylcysteamine + H2O
N-acetylcysteamine + palmitate
show the reaction diagram
-
enzyme form PPT1, not PPT2
-
?
4-methylumbelliferyl-6-thiopalmitoyl-beta-D-glucoside + H2O
?
show the reaction diagram
-
4MU-6S-palm-beta-Glc
-
-
?
additional information
?
-
-
enzyme assay development
-
?
additional information
?
-
-
structural differences in the 2 enzyme fomrs PPT1 and PPT2, PPT2 does not hydrolyze substrates with bulky head groups
-
?
additional information
?
-
-
no effect on palmitoylation of endothelial nitric oxide synthase
-
-
-
additional information
?
-
-
mutations in the enzyme protein cause the neurodegenerative disorder infantile neuronal ceroid lipofuscinosis
-
-
-
additional information
?
-
-
defect in the palmitoyl-(protein) hydrolase gene causes a neurodegenerative disorder. Depalmitoylation of the still uncharacterized substrate(s) of the enzyme is critical for postnatal development or maintainance of cortical neurons
-
-
-
additional information
?
-
-
the enzyme is required for the efficient lysosomal degradation of thioesters derived from S-acylated proteins
-
-
-
additional information
?
-
-
enzyme deficiency causes infantile neuronal ceroid lipofuscinosis, the enzyme plays an important role in the development of the CNS
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological and granular osmiophilic deposits, GROD, and infantile neuronal ceroid lipofuscinosis
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL, a lysosomal storage disorder
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL, molecular basis
-
?
additional information
?
-
-
enzyme deficiency causes the infantile form of neuronal ceroid lipofuscinosis INCL, a progressive encephalopathyof children
-
?
additional information
?
-
-
epileptic seizures in adult rats lead to progressive and remarkable increase in enzyme activity inlimbic areas of the brain, the enzyme may protect neurons from excitotoxicity and have a role in synaptic plasticity, enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
PPT1 deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
PPT1 deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, only in neurons of the cerebral and cerbellar cortexes and retina not in other cell types, characterized by early loss of vision and massiv neuronal death
-
?
additional information
?
-
-
PPT1 deficiency causes, together with tripeptidyl peptidase 1 deficiency, progressive neurological disorder infantile neuronal ceroid lipofuscinosis, a group of at least 8 inherited, progressive encephalopathies that are characterized by lipofuscin-like inclusions in various tissues and have been classified as CNL1-CNL8
-
?
additional information
?
-
O59747, -
PPT1 mutations cause severe neurodegenerative storage disorder, termed infantile Batten, in humans, Schizosaccharomyces pombe is a genetically tractable model for the sutdy of this disease due to evolutionary highly conserved gene and function
-
?
additional information
?
-
-
the enzyme has a role outside the lysosome in the brain and might be associated with synaptic functioning
-
?
additional information
?
-
-
the enzyme is essential for both development and maintenance of cortical neurons, enzyme deficiency causes severe neurodegenerative disorders by loss of cortical neurons
-
?
additional information
?
-
-
altough the ppt-1 gene is not essential for the animal‘s survival, its mutation results in a mild developmental and reproductive phenotype, affects the number and size of mitochondria and results in an abnormality in mitochondrial morphology
-
-
-
additional information
?
-
-
in palmitoyl-protein thioesterase-1-knockout mice (that mimic human infantile neuronal ceroid lipofuscinosis) the endoplasmic reticulum in the brain cells is structurally abnormal. Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in human infantile neuronal ceroid lipofuscinosis
-
-
-
additional information
?
-
-
Ppt1 modulates the activity of several pathways known to play a role in synaptic development either directly through its depalmitoylation activity or indirectly through effects on general endocytic mechanisms
-
-
-
additional information
?
-
P50897
the most severe form of neuronal ceroid lipofuscinoses, infantile neuronal ceroid lipofuscinosis (INCL), is caused by mutations in the CLN1 gene, resulting in a deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1
-
-
-
additional information
?
-
-
depalmitoylation reaction, palmitoylation is the post-translational addition of a palmitate moiety to a cysteine residue through a covalent thioester bond
-
-
-
additional information
?
-
-
PPT1 deficiency leads to abnormally low levels of soluble synaptic vesicle proteins like synaptobrevin 2 and SNAP25, that are known to undergo palmitoylation and are critical for fusion, exocytosis, recycling, and regeneration of fresh synaptic vesicles
-
-
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
palmitoyl-protein + H2O
palmitate + protein
show the reaction diagram
-
palmitoylation plays critical roles in diverse biological functions, including membrane anchorage, vesicular transport, signal transduction and the maintenance of cellular architecture
-
-
r
additional information
?
-
-
no effect on palmitoylation of endothelial nitric oxide synthase
-
-
-
additional information
?
-
-
mutations in the enzyme protein cause the neurodegenerative disorder infantile neuronal ceroid lipofuscinosis
-
-
-
additional information
?
-
-
defect in the palmitoyl-(protein) hydrolase gene causes a neurodegenerative disorder. Depalmitoylation of the still uncharacterized substrate(s) of the enzyme is critical for postnatal development or maintainance of cortical neurons
-
-
-
additional information
?
-
-
the enzyme is required for the efficient lysosomal degradation of thioesters derived from S-acylated proteins
-
-
-
additional information
?
-
-
enzyme deficiency causes infantile neuronal ceroid lipofuscinosis, the enzyme plays an important role in the development of the CNS
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological and granular osmiophilic deposits, GROD, and infantile neuronal ceroid lipofuscinosis
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL, a lysosomal storage disorder
-
?
additional information
?
-
-
enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL, molecular basis
-
?
additional information
?
-
-
enzyme deficiency causes the infantile form of neuronal ceroid lipofuscinosis INCL, a progressive encephalopathyof children
-
?
additional information
?
-
-
epileptic seizures in adult rats lead to progressive and remarkable increase in enzyme activity inlimbic areas of the brain, the enzyme may protect neurons from excitotoxicity and have a role in synaptic plasticity, enzyme deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
PPT1 deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, INCL
-
?
additional information
?
-
-
PPT1 deficiency causes progressive neurological disorder infantile neuronal ceroid lipofuscinosis, only in neurons of the cerebral and cerbellar cortexes and retina not in other cell types, characterized by early loss of vision and massiv neuronal death
-
?
additional information
?
-
-
PPT1 deficiency causes, together with tripeptidyl peptidase 1 deficiency, progressive neurological disorder infantile neuronal ceroid lipofuscinosis, a group of at least 8 inherited, progressive encephalopathies that are characterized by lipofuscin-like inclusions in various tissues and have been classified as CNL1-CNL8
-
?
additional information
?
-
O59747, -
PPT1 mutations cause severe neurodegenerative storage disorder, termed infantile Batten, in humans, Schizosaccharomyces pombe is a genetically tractable model for the sutdy of this disease due to evolutionary highly conserved gene and function
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additional information
?
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the enzyme has a role outside the lysosome in the brain and might be associated with synaptic functioning
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?
additional information
?
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the enzyme is essential for both development and maintenance of cortical neurons, enzyme deficiency causes severe neurodegenerative disorders by loss of cortical neurons
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additional information
?
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altough the ppt-1 gene is not essential for the animal‘s survival, its mutation results in a mild developmental and reproductive phenotype, affects the number and size of mitochondria and results in an abnormality in mitochondrial morphology
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additional information
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in palmitoyl-protein thioesterase-1-knockout mice (that mimic human infantile neuronal ceroid lipofuscinosis) the endoplasmic reticulum in the brain cells is structurally abnormal. Palmitoyl-protein thioesterase-1 deficiency mediates the activation of the unfolded protein response and neuronal apoptosis in human infantile neuronal ceroid lipofuscinosis
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additional information
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Ppt1 modulates the activity of several pathways known to play a role in synaptic development either directly through its depalmitoylation activity or indirectly through effects on general endocytic mechanisms
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additional information
?
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P50897
the most severe form of neuronal ceroid lipofuscinoses, infantile neuronal ceroid lipofuscinosis (INCL), is caused by mutations in the CLN1 gene, resulting in a deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1
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additional information
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depalmitoylation reaction, palmitoylation is the post-translational addition of a palmitate moiety to a cysteine residue through a covalent thioester bond
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additional information
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PPT1 deficiency leads to abnormally low levels of soluble synaptic vesicle proteins like synaptobrevin 2 and SNAP25, that are known to undergo palmitoylation and are critical for fusion, exocytosis, recycling, and regeneration of fresh synaptic vesicles
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METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
O75608
activity independent of Ca2+ and Mg2+
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
1-palmitoyl lysophosphatidylcholine
O75608
competitive inhibitor for acylprotein thioesterase activity
Chloroquine
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inhibits the hydrolysis and leads to accumulation of lipid cysteine thioesters in the lysosomes of treated cells
Didemnin B
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diethyl dicarbonate
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dithiothreitol
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palmitoyl-peptide
O75608
competitive inhibitor for lysophospholipase activity
Sodium vanadate
O59747, -
pdf1 mutant
Leupeptin
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inhibits the hydrolysis and leads to accumulation of lipid cysteine thioesters in the lysosomes of treated cells but has no direct inhibitory effect on the enzyme
additional information
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no inhibition by EDTA
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additional information
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dSmt3 mutations are the lone suppressor modifiers
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ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
additional information
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Drosophila C-terminal Src kinase is an enhancer of the Ppt1 phenotype. Mutations in the fear of intimacy gene are also identified as enhancers. Mutations in zipper or mutations at the Drosophila IGF-II mRNA-binding protein locus enhance the degenerative phenotype. The tsg alleles tsg2 and tsg4 both enhance the rough eye phenotype produced by Ppt1 expression
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KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0273
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1-palmitoyl lysophosphatidylcholine
O75608
-
0.091
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myristoyl-CoA
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-
0.227
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palmitoyl-beta-D-thioglucoside
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-
0.017
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palmitoyl-CoA
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-
0.039
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palmitoyl-CoA
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-
0.01
0.02
palmitoyl-H-Ras
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-
0.00349
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palmitoyl-peptide
O75608
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Ki VALUE [mM]
Ki VALUE [mM] Maximum
INHIBITOR
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.0222
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1-palmitoyl lysophosphatidylcholine
O75608
for acylprotein thioesterase activity
0.0323
-
palmitoyl-peptide
O75608
for lysophospholipase activity
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.0055
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-, Q5JZR0
substrate 4-methylumbelliferyl 6-deoxy-6-thiopalmitoyl-beta-D-glucopyranoside, cerebral cortex gray matter lysate, pH not specified in the publication, temperature not specified in the publication
0.067
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-
1.62
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O75608
substrate 1-palmitoyl lysophosphatidylcholine
1.72
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whole cell, wild-type enzyme, substrate palmitoyl-CoA
7.49
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whole cell, wild-type enzyme, substrate S-palmitoyl-beta-glucoside
27.3
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O75608
substrate palmitoyl-peptide
additional information
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pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
4
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assay at
5.2
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assay at
6.5
7
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7
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palmitoyl-H-Ras
7.4
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O75608
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TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
22
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assay at, room temperature
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
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transformed by Epstein-Barr virus
Manually annotated by BRENDA team
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expression of enzyme is developmentally regulated, with increasing expression during maturation of the CNS, reaching the maximum in young adulthood
Manually annotated by BRENDA team
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postmortem from patient with infantile neuronal ceroid lipofuscinosis (INCL) caused by PPT1 deficiency
Manually annotated by BRENDA team
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exclusively localized to the basolateral side of the polarized cells
Manually annotated by BRENDA team
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PPT1-/- cerebella appear smaller than aged matched wild-type littermates
Manually annotated by BRENDA team
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normal fibroblasts and infantile neuronal ceroid lipofuscinosis fibroblasts, deficient of PPT1
Manually annotated by BRENDA team
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enzyme expression slowly decreases during maturation
Manually annotated by BRENDA team
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hippocampal, retinal, and cortical neurons
Manually annotated by BRENDA team
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primary cortical neuron culture from tissue of PPT1 knockout mice that mimic infantile neuronal ceroid lipofuscinosis
Manually annotated by BRENDA team
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very low or no activity
Manually annotated by BRENDA team
additional information
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the most common mutation results in intracellular accumulationof the enzyme polypeptide and undetectable activity in the brain
Manually annotated by BRENDA team
additional information
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activity is increased during neuronal maturation
Manually annotated by BRENDA team
additional information
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the enzyme expression is strictly developmentally regulated in brain and eyes but not in spleen
Manually annotated by BRENDA team
additional information
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Ppt1/Cln1-deficient cells
Manually annotated by BRENDA team
additional information
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lymphoblasts from patients with infantile neuronal ceroid lipofuscinosis, deficient of PPT1
Manually annotated by BRENDA team
additional information
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Garland cell
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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preferably targeted to in mature neurons
Manually annotated by BRENDA team
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in contrast to the wild type enzyme, the mutant polypeptides are retained in the endoplasmic reticulum, most probably due to the misfolding of the mutant polypeptide
Manually annotated by BRENDA team
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the most common mutation results in intracellular accumulation of the enzyme polypeptide and undetectable activity in the brain
Manually annotated by BRENDA team
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infantile neuronal ceroid lipofuscinosis is a lysosomal storage disease
Manually annotated by BRENDA team
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the glycoslated enzyme is recognized by the mannose 6-phosphate receptor and routed to the lysosome
Manually annotated by BRENDA team
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enzyme is recognized by the mannose 6-phosphate receptor and routed to the lysosome
Manually annotated by BRENDA team
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PPT1 and PPT2
Manually annotated by BRENDA team
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cortical, in synaptic junctions of epileptic rats, nearly not in non-epileptic ones
Manually annotated by BRENDA team
additional information
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not in lysosomes of mouse brain or neurons
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Manually annotated by BRENDA team
additional information
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colocalization of the enzyme with the synaptic membrane marker is enhanced after epileptic seizures
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Manually annotated by BRENDA team
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
37000
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gel filtration
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
O59747, -
x * 31000, processed enzyme, SDS-PAGE, x * 101000, unprocessed enzyme, SDS-PAGE
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x * 37000, SDS-PAGE
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x * 35000-37000, SDS-PAGE
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O75608
x * 25000, SDS-PAGE (52000 for GST-fusion protein)
monomer
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1 * 37000, SDS-PAGE
additional information
P50897
PPT1 forms oligomers
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
glycoprotein
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heterogenous glycosylation is the major cause of multiple bands observed in SDS-PAGE
glycoprotein
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three potential asparagine-linked glycosylation sites are found near the carboxyl terminus of the protein at positions 199, 214, and 234. Glycosylation of the amino acid 234 demonstrated experimentally
glycoprotein
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glycoprotein
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N-glycosylation at Asn232, Asn197, and Asn212, essential for activity
glycoprotein
P50897
N-glycosylation of N197 and N232, but not N212, is essential for enzyme activity and intracellular transport. Deglycosylation of overexpressed PPT1 produced in neurons and fibroblasts demonstrates differentially modified PPT1 in different cell types
glycoprotein
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mannose-6-phosphorylated glycoprotein
glycoprotein
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proteolytic modification
O59747, -
enzyme contains 2 putative cleavage sites for the kex-related endopeptidase Krp1p, the precursor is proteolytically processed to form distinct Ppt1p and Dolpp1p domains, Arg354 is crucial for the processing
Crystallization/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
purified recombinant enzyme with and without bound palmitate, sitting drop vapor diffusion method, 12 mg/ml enzyme in 20 mM HEPES, pH 7.0, plus 150 mM NaCl, plus reservoir solution, containing 55% PEG 400, 100 mM Bis-Tris, pH 6.5, in a ratio 3:2, equilibrated against a250fold excess, X-ray multiwave length anomalous diffraction phasing for structure determinationand analysis, 2.25 A resolution
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purified recombinant PPT2 15 mg/ml, sitting drop vapour diffusion method, 4°C, with equal volume of precipitant solution conataining 2 M ammonium sulfate, 100 mM sodium cacodylate, pH 5.5-6.5, 8% methyl pentanediol, X-ray diffraction structure determination and analysis at 2.7 A resolution
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GENERAL STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
repeated freeze-thawing decreases activity
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STORAGE STABILITY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
4°C, stable for at least 3 weeks
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-80°C, 50 mM Tris/HCl, pH 7.4, more than one year, stable
O75608
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
by centrifugation, dialysis and gel filtration
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GST affinity chromatography, GST-tag cleaved from GST-fusion protein
O75608
recombinant PPT2 from overexpressing insect cells, recombinant PPT2 mutant from COS cells
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Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
expression in endothelial cells
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overexpressed in Drosophila melanogaster
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construction of a UAS:GFP-Ppt1 transgenic fly line. The pUAST:GFP-Ppt1 vector overexpressed using Act5C-Gal4
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baculovirally expressed
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expressed in COS-1 cells
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expression of enzyme carrying naturally occurring mutations in COS-1 cells
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expression of the enzyme in Caco-2 cells, orientation to the basolateral side, also after endocytosis of the recombinant enzyme into Caco-2 cells
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expression of wild-type and enzymes with naturally occurring mutations in COS cells as His-tagged enzyme, and in Sf9 cells, the latter via baculovirus infection
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expression of wild-type and mutant in COS-1 cells
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fragment corresponding to the entire coding region of PPT1 amplified from pCMV5-hPPT1, and cloned into XhoI sites in the polylinker region of expression vector pMSXND1, overexpressed in CHO cells. PPT1 injected intravenously into PPT1-deficient mice
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gene ppt, DNA sequence determnation and analysis, identification of 8 natural mutations of different origins leading to enzyme deficiency
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GST-fusion protein expressed in Escherichia coli BL21, expressed in HEK-293 cell
O75608
overexpression of PPT2 in an insect-baculovirus expression system, secretion of the recombinant enzyme to the culture medium, expression of mutant PPT2 in COS cells, subcloning in Escherichia coli XL1-blue
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PPT1-deficient fibroblasts stably transfected with cDNA encoding PPT1
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expression as glutathione S-transferase fusion protein in BHK and CHO cells, localization of the recombinant enzyme out side the lysosomes and endosomes
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PPT1-KO mice are generated by gene targeting in ES cells
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DNA sequence determination and analysis, enzyme is encoded in frame with a second gene coding for an indispensable dolichol pyrophosphatase, gene pdf1, strains bearing a deletion of the entire pdf1 open reading frame are nonviable, due to Dolpp1p deficiency, and are rescued by pdf1 expression plasmid, mutations only in the palmitoyl protein thioesterase 1 domain results in cells abnormally sensitive to sodium vanadate and elevated extracellular pH, the pdf1-deficient phenotype is complemented by the human PPT1 gene
O59747, -
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
A179T
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loss-of-function allele
S77F
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loss-of-function allele
A179T
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loss-of-function allele, although endocytosis and endo-lysosomal trafficking does occur in Ppt1 mutant garland cells, there is a reduced level of uptake and a decreased rate of trafficking to the lysosomes
S77F
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loss-of-function allele, although endocytosis and endo-lysosomal trafficking does occur in Ppt1 mutant garland cells, there is a reduced level of uptake and a decreased rate of trafficking to the lysosomes
D233N
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site-directed mutagenesis, inactive mutant
D79G
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naturally occurring mutation, recombinant enzyme shows 32.8% of the wild-type activity, mutation is associated with the juvenile form of neuronal ceroid lipofuscinosis, no binding of mannose 6-phosphate receptor
D79G
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site-directed mutagenesis, highly reduced activity
E184K
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naturally occurring mutation, recombinant enzyme is nearly inactive showing an activity below 2% of the wild-type activity, mutation is associated with the infantile form of neuronal ceroid lipofuscinosis, no binding of mannose 6-phosphate receptor
F84del
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natural deletion mutation in gene ppt1, leading to enzyme deficiency and infantile progressive neurological defects
G118D
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natural mutation in gene ppt1, leading to enzyme deficiency and infantile progressive neurological defects
G250V
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naturally occurring mutation, recombinant enzyme shows 5.9% of the wild-type activity, mutation is associated with the juvenile form of neuronal ceroid lipofuscinosis, no binding of mannose 6-phosphate receptor
G42E
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naturally occurring mutation, recombinant enzyme is nearly inactive showing an activity below 2% of the wild-type activity, mutation is associated with the infantile form of neuronal ceroid lipofuscinosis, no binding of mannose 6-phosphate receptor
H289A
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site-directed mutagenesis, inactive mutant
H39Q
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naturally occurring mutation, recombinant enzyme is nearly inactive showing an activity below 2% of the wild-type activity, mutation is associated with the infantile form of neuronal ceroid lipofuscinosis, no binding of mannose 6-phosphate receptor
N197Q
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site-directed mutagenesis, mutation of a glycosylation site, slightly reduced activity
N197Q/N212Q
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site-directed mutagenesis, mutation of glycosylation sites, slightly reduced activity, mutant shows 10% of the wild-type expression level
N197Q/N212Q/N232Q
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site-directed mutagenesis, mutation of all glycosylation sites, inactive mutant
N197Q/N232Q
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site-directed mutagenesis, mutation of glycosylation sites, reduced activity
N212Q
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site-directed mutagenesis, mutation of a glycosylation site, slightly reduced activity
N212Q/N232Q
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site-directed mutagenesis, mutation of glycosylation sites, highly reduced activity
N232Q
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site-directed mutagenesis, mutation of a glycosylation site, slightly reduced activity
Q177E
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naturally occurring mutation, recombinant enzyme shows 7.3% of the wild-type activity, mutation is associated with the late infantile form of neuronal ceroid lipofuscinosis, no binding of mannose 6-phosphate receptor
Q177E
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natural missense mutation in gene ppt1, leading to enzyme deficiency and progressive neurological defects, late-infantile phenotype
Q291X
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natural mutation in gene ppt1, leading to enzyme deficiency and infantile progressive neurological defects
R122W
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naturally occurring mutation, recombinant enzyme is nearly inactive showing an activity below 2% of the wild-type activity, mutation is associated with the infantile form of neuronal ceroid lipofuscinosis, no binding of mannose 6-phosphate receptor, accumulation of the recombinant mutant enzyme in the endoplamic reticulum due to decreased degradation turnover
R164X
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natural mutation in gene ppt1, leading to enzyme deficiency and infantile progressive neurological defects
S115A
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site-directed mutagenesis, inactive mutant
S119A
O75608
part of the catalytic triad, no activity
S199A
P50897
mutation shows 1-5% of normal activity
S199A/S214A
P50897
mutant enzyme with very low enzyme activity
S214A
P50897
mutant shows 31% of normal activity
S234A
P50897
mutation shows 1-5% of normal activity. Partial localization to lysosomes, although a major proportion is retained in the endoplasmic reticulum
T75P
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naturally occurring mutation, recombinant enzyme shows 6.8% of the wild-type activity, mutation is associated with the juvenile form of neuronal ceroid lipofuscinosis, no binding of mannose 6-phosphate receptor
T75P
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natural mutation in gene ppt1, leading to enzyme deficiency and infantile progressive neurological defects
T75P
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naturally occurring mutation, mutation is associated with the late onset form of infantile neuronal ceroid lipofuscinosis, the mutant enzymes shows minor altered intracellular localization in transfected cells and are localized in the presynaptic space and neuronal shaft, about 10fold reduced activity
T75P
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site-directed mutagenesis, highly reduced activity
V181M
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naturally occurring mutation, recombinant enzyme is nearly inactive showing an activity below 2% of the wild-type activity, mutation is associated with the infantile form of neuronal ceroid lipofuscinosis, no binding of mannose 6-phosphate receptor
V181M
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natural mutation in gene ppt1, leading to enzyme deficiency and infantile progressive neurological defects
Y109D
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naturally occurring mutation, recombinant enzyme is nearly inactive showing an activity below 2% of the wild-type activity, mutation is associated with an unclassified form of neuronal ceroid lipofuscinosis
Y247H
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naturally occurring mutation, recombinant enzyme is nearly inactive showing an activity below 2% of the wild-type activity, mutation is associated with an unclassified form of neuronal ceroid lipofuscinosis
L219Q
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naturally occurring mutation, mutation is associated with the late onset form of infantile neuronal ceroid lipofuscinosis, the mutant enzymes shows minor altered intracellular localization in transfected cells and are localized in the presynaptic space and neuronal shaft, about 10fold reduced activity
additional information
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several naturally occurring mutations of alleles 1 and 2 from enzyme deficient patients shows reduced activity compred with the wild-type, overview
additional information
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residues involved in ligand binding differ between PPT1 and PPT2, exchange by site-directed mutagenesis and functional analysis, overview
additional information
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naturally occurring mutations delPhe84 and insCys45, mutation is associated with the late onset form of infantile neuronal ceroid lipofuscinosis, the mutant enzymes shows severely altered intracellular localization in transfected cells and are targeted to the endoplasmic reticulum, about 10fold reduced activity
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
medicine
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in vitro enzyme assay that can be readily used for the clinical diagnosis of both infantile neuronal ceroid lipofuscinosis patients and carrier
medicine
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palmitoyl protein thioesterase 1, expressed in the human saliva is a reliable and non-invasive source for the diagnosis of infantile neuronal ceroid lipofuscinosis
medicine
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if patients are diagnosed with any type of mental and/or physical retardation accompanied by strong and severe visual impairment, then the case physician may consider the possibility of infantile neuronal ceroid lipofuscinosis and conduct an examination of PPT activity level
medicine
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enzyme may be useful as an adjunct to central nervous system-directed therapies and may be used as a starting point for modifications designed to improve brain delivery