Information on EC 2.3.1.24 - sphingosine N-acyltransferase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
2.3.1.24
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RECOMMENDED NAME
GeneOntology No.
sphingosine N-acyltransferase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
acyl-CoA + sphingosine = CoA + a ceramide
show the reaction diagram
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Acyl group transfer
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Metabolic pathways
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sphingolipid biosynthesis (yeast)
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Sphingolipid metabolism
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ceramide biosynthesis
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SYSTEMATIC NAME
IUBMB Comments
acyl-CoA:sphingosine N-acyltransferase
Acts on sphingosine or its 2-epimer.
CAS REGISTRY NUMBER
COMMENTARY hide
37257-09-3
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
isozymes LOH1, LOH2, and LOH3
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
gene cers2
SwissProt
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
Trypanosoma cruzi microsomes harbor a Fumonisin B1-sensitive acyl-CoA-dependent CerS activity that uses both dihydrosphingosine and sphingosine as long-chain sphingoid base acceptors and palmitoyl-CoA as the principal fatty-acyl-CoA substrate donor
UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
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in Arabidopsis thaliana, three distinct ceramide synthases have been identified denoted LOH1, LOH2, and LOH3. These ceramide synthases can be divided into two distinct groups based on sequence alignment and function that appears to be a conserved feature of ceramide synthases within the plant kingdom
malfunction
metabolism
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2-hydroxystearoyl-CoA + dihydrosphingosine
CoA + N-(2-hydroxystearoyl)-dihydrosphingosine
show the reaction diagram
acyl-CoA + sphinganine
CoA + N-acyl-sphinganine
show the reaction diagram
acyl-CoA + sphinganine
CoA + N-acylsphinganine
show the reaction diagram
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-
-
-
?
acyl-CoA + sphingosine
?
show the reaction diagram
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LASS5 is the major ceramide synthase gene product involved in sphingolipid production that may also regulate PtdCho metabolism in pulmonary epithelia
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-
?
acyl-CoA + sphingosine
CoA + N-acylsphingosine
show the reaction diagram
an acyl-CoA + sphingosine
CoA + an N-acylsphingosine
show the reaction diagram
behenoyl-CoA + sphingosine
CoA + behenoylsphingosine
show the reaction diagram
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-
-
?
fatty acid-CoA + dihydrosphingosine
CoA + an N-acylsphingosine
show the reaction diagram
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-
-
-
?
hexacosanoyl-CoA + phytosphingosine
CoA + hexacosanoylphytosphinganine
show the reaction diagram
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-
-
-
?
hexacosanoyl-CoA + sphinganine
CoA + N-hexacosanoylsphinganine
show the reaction diagram
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-
-
-
?
hexanoyl-CoA + sphingosine
CoA + hexanoylsphingosine
show the reaction diagram
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-
-
?
lauroyl-CoA + sphingosine
CoA + lauroylsphingosine
show the reaction diagram
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-
-
?
lignoceroyl-CoA + phytosphingosine
CoA + N-lignoceroylphytosphinganine
show the reaction diagram
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-
-
-
?
lignoceroyl-CoA + sphinganine
CoA + N-lignoceroylsphinganine
show the reaction diagram
lignoceroyl-CoA + sphingosine
CoA + C24:0-ceramide
show the reaction diagram
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reaction of sphingosine (C18:1) and C24:0 fatty acid-coenzyme A
d18:1/24:0 ceramide
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?
nervonoyl-CoA + dihydrosphingosine
CoA + dihydroceramide
show the reaction diagram
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reaction of dihydrosphingosine (C18:0) and C24:1 fatty acid-coenzyme A
d18:0/24:1 ceramide
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?
nervonoyl-CoA + NBD-sphinganine
CoA + ?
show the reaction diagram
oleoyl-CoA + sphingosine
CoA + oleoylsphingosine
show the reaction diagram
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-
-
?
palmitoyl-CoA + dihydrosphingosine
CoA + an N-palmitoyl-dihydrosphingosine
show the reaction diagram
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?
palmitoyl-CoA + dihydrosphingosine
CoA + N-palmitoyldihydrosphingosine
show the reaction diagram
no reverse ceramidase activity is detected in Trypanosoma cruzi microsomal fractions
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-
?
palmitoyl-CoA + phytosphingosine
CoA + N-palmitoylphytosphinganine
show the reaction diagram
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?
palmitoyl-CoA + sphinganine
CoA + dihydroceramide
show the reaction diagram
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-
-
?
palmitoyl-CoA + sphinganine
CoA + N-palmitoylsphinganine
show the reaction diagram
palmitoyl-CoA + sphinganine
CoA + palmitoylsphinganine
show the reaction diagram
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-
-
?
palmitoyl-CoA + sphingosine
CoA + N-palmitoyl-sphingosine
show the reaction diagram
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?
palmitoyl-CoA + sphingosine
CoA + N-palmitoylsphingosine
show the reaction diagram
palmitoyl-CoA + sphingosine
CoA + palmitoylsphingosine
show the reaction diagram
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-
?
stearoyl-CoA + sphingosine
CoA + stearoylsphingosine
show the reaction diagram
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
acyl-CoA + sphingosine
?
show the reaction diagram
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LASS5 is the major ceramide synthase gene product involved in sphingolipid production that may also regulate PtdCho metabolism in pulmonary epithelia
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-
?
acyl-CoA + sphingosine
CoA + N-acylsphingosine
show the reaction diagram
an acyl-CoA + sphingosine
CoA + an N-acylsphingosine
show the reaction diagram
fatty acid-CoA + dihydrosphingosine
CoA + an N-acylsphingosine
show the reaction diagram
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?
additional information
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
4,4'-diisothiocyanostilbene-2,2'-disulfonic acid
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AAL-toxin
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ceramide synthase is a target for a class of fungal toxins called sphinganine-analogue mycotoxins such as fumonisin B1 and AAL-toxin, which probably inhibit ceramide synthases in a competitive manner by mimicking the structure of the long-chain base
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FTY720
fumonisin
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nixtamalization and rinsing with water effectively reduce both the concentration and ceramide synthase inhibitory activity of readily extractable fumonisins in masa and tortilla products prepared using a commercial process. The data provided no evidence for the formation of biologically active fumonisin reaction products during nixtamalization, baking, or frying
fumonisin B1
Fumonisin B2
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mycotoxin produced by Fusarium moniliforme
SP600125
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additional information
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no enzyme inhibition by curcumin
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
daunorubicin
L-alpha-phosphatidyl-L-serine
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6.7fold activation of solubilized enzyme
L-alpha-phosphatidylcholine
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4.3fold activation of solubilized enzyme
L-alpha-phosphatidylinositol
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5.3fold activation of solubilized enzyme
N-(4-hydroxyphenyl)retinamide
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induces enzyme activity in neuroblastoma cell line possibly via a posttranslational mechanism
sphingosine 1-phosphate
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.299
behenoyl-CoA
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0.17
D-Sphingosine
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0.522
Hexanoyl-CoA
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0.358
lauroyl-CoA
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0.18
oleoyl-CoA
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0.0124 - 0.141
palmitoyl-CoA
0.035 - 0.144
sphinganine
0.171
sphingosine
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0.003 - 0.146
stearoyl-CoA
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00215
FTY720
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isoform ceramide synthase 2, pH 7.4, 37C
0.000003 - 0.00097
fumonisin B1
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.0000006 - 0.0000535
pH 7.4, 37C, enzyme activity in mouse tissues, overview
0.000049
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activity in endoplasmic reticulum vesicles from liver
0.0148
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 7.8
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.5 - 9
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more than 70% of maximal activity between pH 7.0 and pH 8.0
6.5 - 8.5
7 - 7.5
optimal pH
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
14 - 28
TcCerS from Y strain has an optimal activity that increases between 14C and 28C, but decreases at 37C and 42C
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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reduced ceramide synthase activity in the inner epidermis of aged skin. Reduced ceramide synthase activity in the inner epidermis correlates with reduced capacity for permeability barrier repair in aging
Manually annotated by BRENDA team
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high expression level
Manually annotated by BRENDA team
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CerS3/LASS3 mRNA is the most predominantly expressed in keratinocytes
Manually annotated by BRENDA team
of cerebrum and cerebellum as well as in the white matter
Manually annotated by BRENDA team
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renal tubular epithelial cells
Manually annotated by BRENDA team
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schlank mRNA and protein are highly abundant in oocytes and during early embryogenesis
Manually annotated by BRENDA team
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cells resistant to TRAIL, i.e. tumor necrosis factor-related apoptosis-inducing ligand, expression of lower levels of ceranmide synthase 6 than SW-480 cells. Moderate elevation in ceramide synthase 6 expression is suffcient to reverse tumor necrosis factor-related apoptosis-inducing ligand resistance in SW-620 cells
Manually annotated by BRENDA team
LASS3 mRNA expression is limited almost solely to testis, LASS3 plays an important role in this gland
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
the N-terminal region faces the luminal side and the C-terminal region the cytosolic side of the endoplasmic reticulum membrane; the N-terminal region faces the luminal side and the C-terminal region the cytosolic side of the endoplasmic reticulum membrane; the N-terminal region faces the luminal side and the C-terminal region the cytosolic side of the endoplasmic reticulum membrane; the N-terminal region faces the luminal side and the C-terminal region the cytosolic side of the endoplasmic reticulum membrane; the N-terminal region faces the luminal side and the C-terminal region the cytosolic side of the endoplasmic reticulum membrane
Manually annotated by BRENDA team
eight putative membrane-spanning domains are identified in Lac1p; eight putative membrane-spanning domains are identified in Lag1p. The conserved Lag motif, potentially containing the active site, is most likely embedded in the membrane
Manually annotated by BRENDA team
additional information
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primarily localized to perinuclear region
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Manually annotated by BRENDA team
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37000
x * 42000, glycosylated enzyme, SDS-PAGE, x * 37000, deglycosylated enzyme, SDS-PAGE
42000
x * 42000, glycosylated enzyme, SDS-PAGE, x * 37000, deglycosylated enzyme, SDS-PAGE
62000
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x * 62000 + x * 72000, SDS-PAGE
72000
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x * 62000 + x * 72000, SDS-PAGE
240000 - 260000
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gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
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CerS activity can be modulated by dimer formation. CerS2 activity is enhanced by co-expression with a catalytically active form of CerS5 or CerS6; CerS activity can be modulated by dimer formation. CerS5 activity is inhibited in a dominant-negative fashion by co-expression with catalytically inactive CerS5; CerS dimers are formed rapidly upon stimulation of ceramide synthesis; CerS dimers are formed rapidly upon stimulation of ceramide synthesis
heterodimer
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in a constitutive heterodimer comprising CerS5 and CerS2, the activity of CerS2 depends on the catalytic activity of CerS5
additional information
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co-immunoprecipitation studies suggest that CerS2, 5, and 6 exist as heterocomplexes in HeLa cells; co-immunoprecipitation studies suggest that CerS2, 5, and 6 exist as heterocomplexes in HeLa cells; co-immunoprecipitation studies suggest that CerS2, 5, and 6 exist as heterocomplexes in HeLa cells
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
glycoprotein
phosphoprotein
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CerS1 is phosphorylated in vivo and activation of protein kinase C increases the phosphorylation of the protein
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
high concentrations of glycerol are essential in preventing deactivation of the enzyme
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information about stability of solubilized enzyme
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20C, several months
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4C, 48 h, liver enzyme loses 70% of activity, brain enzyme looes 41% of activity
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Lag1p, Lac1p and Lip1p
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liver and brain enzyme, NaSCN, Sepharose-CL-4B
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n-octyl beta-D-thioglucoside, DE-32, sphingosine-celite, Sepharose CL-6B
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solubilization with 2% Triton X-100, ammonium sulfate
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression in HEK-293 cell
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expression in HEK-293T cell and HeLa cell
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expression in HeLa cells
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expression of wild-type and mutant enzymes in Escherichia coli strain BJ5183, and transient expression in HEK293A cells, HT29 cells, and SW620 cells from an adenovirus vector
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gene cers2, expression analysis
MLE cells transiently transfected with His-tagged LASS5 plasmid
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recombinant expression of CERS1 in HEK-293 cells; recombinant expression of CERS2 in HEK-293 cells
recombinant heterologous expression of the LOH genes in Saccharomyces cerevisiae microsomal membranes
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
CerS6 knockdown is shown to up-regulate CerS5; expression of CerS1 is slightly up-regulated in MF-7 cells treated with UV-C
expression decreased to 50% following UV-C treatment in MF-7 cells
ionizing radiation induces de novo synthesis of ceramide to influence HeLa cell apoptosis by specifically activating CerS isoforms 2, 5, and 6 that generate opposing anti- and pro-apoptotic ceramides in mitochondrial membranes; ionizing radiation induces de novo synthesis of ceramide to influence HeLa cell apoptosis by specifically activating CerS isoforms 2, 5, and 6 that generate opposing anti- and pro-apoptotic ceramides in mitochondrial membranes; ionizing radiation induces de novo synthesis of ceramide to influence HeLa cell apoptosis by specifically activating CerS isoforms 2, 5, and 6 that generate opposing anti- and pro-apoptotic ceramides in mitochondrial membranes
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palmitate with high glucose induces CerS4 expression in pancreatic beta-cells
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
DELTA 332-392
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inactive mutant lacking the last putative transmembrane domain
DELTA332-392
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inactive mutant lacking the last putative transmembrane domain
H220A/H221A
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mutation of two residues (H220A/H221A) involved in catalytic activity completely abrogates CerS5 activity in a constitutive dimer; mutation of two residues (H220A/H221A) involved in catalytic activity completely abrogates CerS5 activity in a constitutive dimer
D210N
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mutation results in loss of activity in cells and in vitro
D213N
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mutation results in loss of activity in cells and in vitro
H182D
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mutation results in loss of activity in cells and in vitro
H183D
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mutation results in loss of activity in cells and in vitro
H212A
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site-directed mutagenesis
K220L
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mutant enzyme is able to increase cellular C18 and C18:1 ceramide levels to a similar or slightly lesser extent than wild-type LASS1
L189E
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mutation results in loss of activity in cells and in vitro
L216E
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mutation results in loss of activity in cells and in vitro
S193A
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mutant enzyme is able to increase cellular C18 and C18:1 ceramide levels to a similar or slightly lesser extent than wild-type LASS1
additional information
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enzyme knockout by shRNA
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
reconstitution of solubilized enzyme in membrane lipid liposomes
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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CerS2 and CerS6 mRNA is significantly elevated in breast cancer tissue compared to paired normal tissue, with approximately half of the individuals showing elevated CerS2 and CerS6 mRNA. A significant correlation is found between CerS2 and CerS6 expression, and between CerS4 and CerS2/CerS6 expression. Patients that express higher CerS2 or 4 mRNA levels tend to show no changes in sphingosine kinase 1 levels, and likewise patients that express no change in CerS2 or CerS4 mRNA levels tend to express higher levels of sphingosine kinase 1