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evolution
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ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
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ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
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ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
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ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
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ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
-
ceramidases are classified into three distinct groups, acid (Asah1), neutral (Asah2), and alkaline (Asah3) CDases, based on their primary structure and optimum pH. Acid CDase catabolizes ceramide in lysosomes and is found only in vertebrates. In contrast, the distribution of neutral and alkaline CDases is broad, with both being found in species ranging from lower eukaryotes to mammals; however, only neutral CDase is found in prokaryotes, including some pathogenic bacteria. Neutral CDase is thought to have gained a specific domain (mucin box) in the N-terminal region after the vertebrate split, allowing the enzyme to be stably expressed at the plasmamembrane as a type II membrane protein. Molecular evolution of neutral ceramidase acquiring a mucin box, overview
evolution
phylogenetic analysis of alkaline ceramidases
evolution
the enzyme belongs to the CREST superfamily
evolution
ADIPORs display distant homology with alkaline ceramidases, comparison of structures of ADIPOR1 and ADIPOR2
evolution
distant homologues from nCDase are found in taxa all over evolution reinforcing a crucial role for ceramide
evolution
distant homologues from nCDase are found in taxa all over evolution reinforcing a crucial role for ceramide
evolution
distant homologues from nCDase are found in taxa all over evolution reinforcing a crucial role for ceramide
evolution
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distant homologues from nCDase are found in taxa all over evolution reinforcing a crucial role for ceramide
evolution
distant homologues from nCDase are found in taxa all over evolution reinforcing a crucial role for ceramide
evolution
the Arabidopsis thaliana ceramidase AtNCER1 is a homologue of human neutral ceramidase
evolution
the fold of ACER3 is similar to adiponectin receptors (ADIPORs), structure comparisons, overview
evolution
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the Arabidopsis thaliana ceramidase AtNCER1 is a homologue of human neutral ceramidase
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malfunction
abnormal overexpression of acid ceramidase is related to tumor progression and protection from cell death, while deficiency of acid ceramidase results in Farber disease
malfunction
acid ceramidase ASAH1 knockdown leads to a decrease in cell proliferation with a concomitant reduction in the protein levels of BETA-catenin, proliferating cell nuclear antigen, and cyclin B2. ASAH1 silencing increases basal and cAMP-dependent cortisol and dehydroepiandrosterone secretion
malfunction
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cells deficient in acid ceramidase exhibit defects in CCL5 transcriptional induction
malfunction
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inhibition of acid ceramidase activity stimulates apoptotic cell death. Point mutations in the acid ceramidase gene cause rare autosomal recessive Farber disease. Homozygous acid ceramidase-deficient mice are embryonic lethal
malfunction
a tetracycline-inducible ASAH1 short hairpin RNA H295R human adrenocortical stable cell line shows increased transcription of multiple steroidogenic genes, including Cytochrome P450 monooxygenase (CYP)17A1, CYP11B1/2, CYP21A2, steroidogenic acute regulatory protein, hormone-sensitive lipase, 18-kDa translocator protein, and the melanocortin-2 receptor. Induced gene expression positively correlates with enhanced histone H3 acetylation at target promoters. Repression of ASAH1 expression also induces the expression of members of the nuclear receptor nuclear receptor subfamily 4 family while concomitantly suppressing the expression of dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1. ASAH1 knockdown alters the expression of genes involved in sphingolipid metabolism and changes the cellular amounts of distinct sphingolipid species. Enzyme silencing increases basal and cAMP-dependent cortisol and dehydroepiandrosterone secretion, establishing ASAH1 as a pivotal regulator of steroidogenic capacity in the human adrenal cortex
malfunction
ASAH1-knockdown PC-3/Mc cells show impairment of ceramide catabolism with increased sphingosine levels, sphingolipid content, overview. ASAH1 knockdown by shRNA inhibits the growth of PC-3/Mc cells under low-density and low-serum conditions and abrogates their anchorage-independent colony-forming potential
malfunction
enzyme overexpression attenuates steroidogenic factor 1-stimulated CYP17A1 reporter gene activity. The enzyme not only abrogates Bt2cAMP-dependent CYP17A1 reporter gene activity but also inhibits SF-1-stimulated CYP17A1 reporter gene activity in both untreated and Bt2cAMP-stimulated cells
malfunction
enzyme-deficient tod1 mutant pollen tubes have higher turgor than wild-type and show growth retardation both in pistils and in agarose medium. In addition, tod1 mutant guard cells are insensitive to abscisic acid-induced stomatal closure, whereas sphingosine-1-phosphate, a putative downstream component of abscisic acid signalling and product of alkaline ceramidases, promotes closure in both wild-type and tod1, TOD1 is sufficient to rescue pollen tube growth defect. Pollen tube growth defects of tod1-2 are suppressed by the gaut13 mutation, a single-nucleotide substitution in the galacturonosyltransferase13 gene. Phenotypes, overview
malfunction
Farber disease, also known as Farber's lipogranulomatosis, is a clinically heterogeneous autosomal recessive disease caused by mutations in the ASAH1 gene, genotype-phenotype correlation, overview
malfunction
inhibition of acid ceramidase activity sensitizes tumor cells to the effects of antineoplastic agents and radiation
malfunction
inhibition of acid ceramidase activity sensitizes tumor cells to the effects of antineoplastic agents and radiation. Carmofur inhibits acid ceramidase and increases ceramide levels in human SW403 and LNCaP cells
malfunction
knockdown of the zebrafish neutral CDase with an antisense morpholino oligonucleotide led to an increase in the number of zebrafish embryos with severe morphological abnormalities, such as defects in blood circulation, which were possibly caused by abnormal heart formation
malfunction
KO mice are impaired in the intestinal degradation of sphingolipids
malfunction
leptomycin B prevents acid ceramidase and sphingosine 1-phosphate mediated loss of nuclear PTEN, suggesting an active exportin-mediated event
malfunction
overexpression of Ydc1p protein significantly increases the levels of free long-chain bases and long-chain base-phosphates and reduces the biosynthetic flow of long-chain bases towards mature sphingolipids
malfunction
overexpression of Ypc1p protein significantly increases the levels of free long-chain bases and long-chain base-phosphates and reduces the biosynthetic flow of long-chain bases towards mature sphingolipids, whereas deletion of gene YPC1 causes a significant increase in mature sphingolipids
malfunction
the acer-1 T-DNA insertion mutant has pleiotropic phenotypes, including reduction of leaf size, dwarfing and an irregular wax layer, compared with wild-type plants, higher level of phytoceramides in acer-1 and amiR-ACER-1 plants than in the wild-type, phenotype, overview. Acer-1 mutants and AtACER RNAi lines show increased sensitivity to salt stress, and lines overexpressing AtACER show increased tolerance to salt stress. Reduction of AtACER also increases plant susceptibility to Pseudomonas syringae
malfunction
a Dacer-deficient Drosophila melanogaster mutant has higher catalase (CAT) activity and CAT transcription level, leading to higher resistance to oxidative stress induced by paraquat. Altered antioxidative activity in Dacer mutant might be responsible for increased oxidative stress resistance. Quantitative proteomic analysis of wild-type and mutant cells. Three oxidoreductases, including two cytochrome P450 (CG3050, CG9438) and an oxoglutarate/iron-dependent dioxygenase (CG17807), are most significantly upregulated in the Dacer overexpressing mutant
malfunction
a significantly lower level of acid ceramidase expression was detected in gingival tissues from periodontal patients compared to those from healthy subjects
malfunction
abnormal function of the enzyme leads to Farber disease, spinal muscular atrophy with progressive myoclonic epilepsy, and is associated with Alzheimer's, diabetes, and cancer. Structural mapping of disease mutations reveals that most destabilize the protein fold
malfunction
acid ceramidase overexpression in HL-60 confers resistance to the acute myeloid leukemia chemotherapeutic drugs, cytarabine, mitoxantrone, and daunorubicin, and is linked to P-glycoprotein upregulation
malfunction
ASAH1 reduction stimulates cell migration to the same extent as MITF inhibition. ASAH1 silencing in different cell types results in a significant increase in FAK phosphorylation. Conversely, forced expression of ASAH1 inhibits FAK phosphorylation. ASAH1-depleted cells are positive for the senescence-associated beta-galactosidase staining, and also MITF-silenced melanoma cells display features of senescence
malfunction
genetic loss or inhibition of acid ceramidase prevents formation of glycosphingoid bases
malfunction
inhibition of nCDase decreases the development and progression of colorectal tumor growth. Cells overexpressing nCDase are protected from the cell death and Golgi fragmentation induced by C6-ceramide, and they show reduced levels of C6-ceramide and higher levels of sphingosine-1-phosphate (S1P) and sphingosine. nCDase-overexpressing cells show larger increases of sphingosine by 2.3fold compared to control
malfunction
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knocking down NlnCDase by RNA interference increases female survival under starvation and temperature stresses
malfunction
loss of function in E33G-ACER3 mutant found in leukodystrophic patients, ACER3 deficiency leads to progressive leukodystrophy in early childhood, mutation impaires the ACER3 ceramidases activity in patients' cells. This loss of function results in higher level of several ceramide species in the blood, in particular for the ACER3 preferred substrates, C18:1 and C20:1 ceramides. It is proposed that these aberrant levels of ceramides in the brain result in an incorrect central myelination leading to the clinical phenotype associated with the ACER3 mutant, i.e., neurological regression at 6-13 months of age, truncal hypotonia, appendicular spasticity, dystonia, optic disc pallor, peripheral neuropathy, and neurogenic bladder
malfunction
nCDase deficient mice are viable with no obvious deficiency under normal breeding conditions. Further investigation reveals that nCDase deficient mice are not able to degrade dietary sphingolipids. Gemcitabine treated cells show an increase of the levels of specific ceramides, attributed to a reduction of nCDase expression. The increased ceramide is also implicated in suppression of cell growth. nCDase deficient mice treated with DSS show a paradoxical elevation of sphingosine and an increase of sphingosine 1-phosphate. Knockout mice are partly protected from brain injury. MEFs from nCDase deficient mice present an increase of autophagic flux and more specifically mitophagy when subjected to the 2DG/AA model of necroptosis. They showed as well that inhibition of autophagy reverses this phenotype. Inhibition of nCDase may enhance cell survival by increasing the clearance of damaged mitochondria via mitophagy
malfunction
nCDase downregulation induces a decrease of cell growth and neuronal differentiation. Gemcitabine treated cells show an increase of the levels of specific ceramides, attributed to a reduction of nCDase expression. The increased ceramide is also implicated in suppression of cell growth. UVB irradiation decreases nCDase activity in keratinocytes, and ceramidase inhibition or siRNA-mediated suppression sensitizes keratinocytes to low-dose-UVB-induced apoptosis. ATRA downregulated nCDase expression at the message level results in less protein and activity in SH-SY5Y neuroblastoma cells. Inhibition of nCDase in colorectal cancer (CRC) cells induces a decrease of phosphorylation of GSK3beta, which activates the kinase. In turn, activated GSK3beta phosphorylated beta-catenin, resulting in a significant decrease in its levels. Inhibition of nCDase results in dephosphorylation and inactivation of Akt, which is responsible for the loss of phosphorylation of GSK3beta and the loss of beta-catenin. Cells overexpressing nCDase are protected from cell death induced by the short chain C6-ceramide
malfunction
NS-1 cell nCDase-containing exosomes block apoptosis induced by palmitate
malfunction
the enzyme is overexpressed in several types of cancer and Alzheimer's disease, and its genetic defect causes different incurable disorders
malfunction
the genetic loss or inhibition of acid ceramidase prevents formation of glycosphingoid bases
malfunction
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the knockdown of this enzyme enhances survival of the female planthopper at high (32°C) or low (22°C) temperature
malfunction
upregulation of ASAH1 confers resistance to radiation by altering the sphingolipid metabolism pathway. ASAH1 plays a similar role in recurrent or irradiated glioblastoma multiforme. ASAH1 inhibition by camofur results in cell death and elevated levels of ceramides in U87, SJGBM2, U87-10gy and SJGBM2-10gy cells
malfunction
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enzyme-deficient tod1 mutant pollen tubes have higher turgor than wild-type and show growth retardation both in pistils and in agarose medium. In addition, tod1 mutant guard cells are insensitive to abscisic acid-induced stomatal closure, whereas sphingosine-1-phosphate, a putative downstream component of abscisic acid signalling and product of alkaline ceramidases, promotes closure in both wild-type and tod1, TOD1 is sufficient to rescue pollen tube growth defect. Pollen tube growth defects of tod1-2 are suppressed by the gaut13 mutation, a single-nucleotide substitution in the galacturonosyltransferase13 gene. Phenotypes, overview
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metabolism
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ceramide metabolism, sphingolipid signaling, and aberrant ceramide signaling and cancer development, overview. Pathways of sphingolipid metabolism, overview
metabolism
Dacer plays a role in fly development and longevity by controlling the metabolism of ceramides
metabolism
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inverse regulation of ACER2 and dihydrosphingosine desaturase is an important mechanism by which N-(4-hydroxyphenyl)retinamide exerts its cytotoxic and apoptotic effects in tumor cells
metabolism
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the enzyme is one of the key players, which determine the dynamic balance between the intracellular levels of ceramide and its breakdown products, in ceramide metabolism and sphingolipid biosynthesis, metabolism and interconversions, overview
metabolism
acid ceramidase catalyzes the hydrolysis of ceramide into sphingosine, in turn a substrate of sphingosine kinases that catalyze its conversion into the mitogenic sphingosine 1-phosphate
metabolism
ACTH/cAMP signaling promotes nuclear sphingolipid metabolism in an enzyme-dependent manner. ACTH/cAMP signaling promotes the recruitment of the enzyme to multiple steroidogenic gene promoters
metabolism
key biological functions of ceramidases in biotic and abiotic stresses in plants
metabolism
acid ceramidase overexpression increased NF-kappaB activation whereas NF-kappaB inhibitors reduce P-glycoprotein levels, indicating that the NF-kappaB pathway contributes to acid ceramidase-mediated modulation of P-glycoprotein expression
metabolism
adiponectin receptors (ADIPORs) are integral membrane proteins that control glucose and lipid metabolism by mediating, at least in part, a cellular ceramidase activity that catalyses the hydrolysis of ceramide to produce sphingosine and a free fatty acid. ADIPOR2 possesses intrinsic basal ceramidase activity that is enhanced by adiponectin
metabolism
sphingolipid metabolism and interconnected bioactive metabolites derived from ceramide, overview. Ceramide, the essential synthetic building block for sphingomyelin, glycosphingolipids, and ceramide-1-phosphate is hydrolyzed by ceramidase to fatty acid and sphingosine, which then is phosphorylated to sphingosine-1-phosphate (S1P) by sphingosine kinases
metabolism
the enzyme activity is vital to tumor cell biology
metabolism
the enzyme is a target of the microphthalmia-associated transcription factor (MITF). ASAH1 controls the switch between the proliferative and invasive phenotype in melanoma cells, and MITF also is a critical regulator of switch between proliferative and invasive phenotypes promoted by melanoma plasticity. MITF is also involved in the regulation of sphingolipid metabolism
metabolism
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Dacer plays a role in fly development and longevity by controlling the metabolism of ceramides
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physiological function
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ACER2 catalyzes the hydrolysis of dihydroceramides to generate dihydrosphingosine. ACER2 upregulation plays a key role in mediating the N-(4-hydroxyphenyl)retinamide-induced generation of dihydrosphingosine as well as the cytotoxicity of 4-HPR in tumor cells, while ACER3 has a limited role, overview
physiological function
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ACER2 plays an important role in cellular responses by regulating the hydrolysis of ceramides in cells, activity regulation, overview
physiological function
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ACER3 specifically controls the hydrolysis of ceramides carrying unsaturated long acyl chains, unsaturated long-chain ceramides
physiological function
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acid ceramidase improves the quality of oocytes and embryos and the outcome of in vitro fertilization, the level of the enzyme is positively correlated with the quality of human embryos formed in vitro. Addition of recombinant acid ceramidase to human oocyte culture medium maintains the healthy cell morphology in vitro
physiological function
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alkaline ceramidases have a compensatory role in controlling sphingosine and sphingosine 1-phosphate generation in erythroid cells
physiological function
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alkaline ceramidases have a compensatory role in controlling sphingosine and sphingosine 1-phosphate generation in erythroid cells
physiological function
Dacer plays a role in fly development and longevity by controlling the metabolism of ceramides. Dacer inactivation delays Drosophila pre-adult development, while Dacer inactivation increases Drosophila lifespan
physiological function
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synthesis of sphingosine is essential for oxidative stress-induced apoptosis of photoreceptors, pathway regulation, overview
physiological function
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the enzyme is involved in ceramide metabolism and is a critical regulator of cancer cell growth and/or survival, acid ceramidase upregulation in prostate cancer plays a role in tumor development. A dysfunctional ceramide pathway is responsible for tumor progression and resistance to chemotherapy and radiation
physiological function
acid ceramidase activity enhances acid sphingomyelinase secretion
physiological function
acid ceramidase ASAH1 is a global regulator of steroidogenic capacity and adrenocortical gene expression
physiological function
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acid ceramidase, through generation of sphingosine-1-phosphate, promotes an invasive phenotype in prostate cancer and promotes Ets1 nuclear expression and binding to the promoter region of matrix-degrading protease cathepsin B. Acid ceramidase overexpression promotes pericellular localization of cathepsin B and its translocation to the outer leaflet of the cell membrane
physiological function
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co-expression of acid sphingomyelinase and acid ceramidase is sufficient to strongly induce CCL5 transcription
physiological function
intestinal secreted neutral ceramidase is involved in digestion of dietary sphingolipids
physiological function
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neutral ceramidase is a key participant of ceramide formation in liver mitochondria. The reverse activity of neutral ceramidase contributes to sphingolipid homeostasis in this organelle in vivo. The enzyme contributes to the overall ceramide profile of liver mitochondria at basal conditions in vivo
physiological function
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neutral ceramidase is a key participant of ceramide formation in liver mitochondria. The reverse activity of neutral ceramidase contributes to sphingolipid homeostasis in this organelle in vivo. The enzyme contributes to the overall ceramide profile of liver mitochondria at basal conditions in vivo
physiological function
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the enzyme determines cell fate, namely, death or survival, by controlling the balance between the intracellular levels of ceramide and sphingosine 1-phosphate. Acid ceramidase plays an important role in tumorigenesis and in prolonging the survival of cells
physiological function
acid ceramidase directly regulates the intracellular balance of ceramide, sphingosine, and sphingosine-1-phosphate by catalyzing the hydrolysis of ceramide into sphingosine. The enzyme plays a role in glucocorticoid production and regulating steroidogenic capacity
physiological function
acid ceramidase is a cysteine amidase that hydrolyses the proapoptotic lipid ceramide, and is abnormally high in several human tumors, which is suggestive of a role in chemoresistance. The enzyme is involved in the regulation of ceramide levels in cells and modulates the ability of this lipid messenger to influence the survival, growth and death of tumor cells
physiological function
acid ceramidase is a cysteine amidase that hydrolyses the proapoptotic lipid ceramide, and is abnormally high in several human tumors, which is suggestive of a role in chemoresistance. The enzyme is involved in the regulation of ceramide levels in cells and modulates the ability of this lipid messenger to influence the survival, growth and death of tumor cells
physiological function
alkaline ceramidase TOD1 is preferentially expressed in pollen tubes and in silique guard cells, where it is required for turgor pressure regulation, it is a key turgor pressure regulator in plant cells, molecular mechanism. Turgor pressure plays pivotal roles in the growth and movement of walled cells
physiological function
ceramide hydrolysis by acid ceramidase stops the biological activity of ceramides and influences survival and function of normal and neoplastic cells
physiological function
ceramide hydrolysis by acid ceramidase stops the biological activity of ceramides and influences survival and function of normal and neoplastic cells
physiological function
LsnCer is a bona fide neutral ceramidase that may have a role in adaption of Laodelphax striatellus to environmental stresses
physiological function
neutral CDase is expressed in the intestines of humans and plays a major role in ceramide metabolism in the gut
physiological function
neutral CDase may be involved in a pathway for the digestion of dietary sphingolipids in mice
physiological function
nuclear receptor steroidogenic factor 1 is essential for steroidogenic gene transcription. Acid ceramidase represses nuclear receptor steroidogenic factor 1-dependent gene transcription in H295R human adrenocortical cells by binding to the receptor, molecular mechanism, overview. The enzyme is a coregulatory protein that represses steroidogenic factor 1 function by directly binding to the receptor on steroidogenic factor 1 target gene promoters and plays a key role for nuclear lipid metabolism in regulating gene transcription
physiological function
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the bacterial enzyme alone does not affect TNF-alpha gene expression in three-dimensionally cultured human primary keratinocytes. In the presence of the detergent Triton X-100, which damages stratum corneum structure, the active enzyme, but not heat-inactivated enzyme or inactive mutant enzyme, induces the production of TNF-alpha, endothelin-1, and interleukin-8, indicating that this production is dependent on ceramidase activity, it is also inhibited by a sphingosine kinase inhibitor and by an sphingosine 1-phosphate receptor antagonist VPC 23019. Among various ceramide metabolites, sphingosine and sphingosine 1-phosphate enhance the gene expression of TNF-alpha, endothelin-1, and interleukin-8, overview
physiological function
the enzyme catalyzes the lysosomal degradation of ceramide to sphingosine and fatty acid
physiological function
the enzyme is involved in salt tolerance and in disease resistance
physiological function
the influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. A protective feedback mechanism mitigates the apoptotic effect of ionizing radiation-induced ceramide generation. c-Jun-regulated acid veramidase mediates PCa cell radioresistance and relapse in vitro and in vivo
physiological function
tumor promotion of acid ceramidase in prostate cancer. Impact of acid ceramidase on the nuclear-cytoplasmic trafficking of tumor suppressor PTEN, immunohistochemical analysis, overview. Acid ceramidase, through sphingosine 1-phosphate, promotes nuclear export of PTEN as a means of promoting tumor formation, cell proliferation, and resistance to therapy. Acid ceramidase promotes a reduction in nuclear PTEN that is dependent upon sphingosine 1-phosphate-mediated activation of Akt
physiological function
acid ceramidase (aCDase, ASAH1) hydrolyzes lysosomal membrane ceramide into sphingosine, the backbone of all sphingolipids, to regulate many cellular processes
physiological function
acid ceramidase (ASAH1), a lysosomal cysteine amidase, helps metabolize ceramides into sphingosine and free fatty acids. Ceramides promote senescence and apoptosis, while sphingososine-1-phospate (Sph-1P), the immediate metabolite of sphingosine, promotes cell survival, proliferation, inflammation, and angiogenesis. As such, overexpression of ASAH1 confers resistance to apoptosis
physiological function
acid ceramidase actively forms glycosphingoid bases in Gaucher and Fabry disease. Molecular basis of the formation of glucosylsphingosine and globotriaosylsphingosine during deficiency of glucocerebrosidase (Gaucher disease) and alpha-galactosidase A (Fabry disease), active role of acid ceramidase in both processes through deacylation of lysosomal glycosphingolipids, overview. Analysis of the potential pathophysiological relevance of elevated glycosphingoid bases generated through this alternative metabolism in patients suffering from lysosomal glycosidase defects. Possibility of broadened substrate specificity of acid ceramidase during lysosomal lipid accumulation
physiological function
acid ceramidase actively forms glycosphingoid bases in Gaucher and Fabry disease. Molecular basis of the formation of glucosylsphingosine and globotriaosylsphingosine during deficiency of glucocerebrosidase (Gaucher disease) and alpha-galactosidase A (Fabry disease), active role of acid ceramidase in both processes through deacylation of lysosomal glycosphingolipids, overview. Possibility of broadened substrate specificity of acid ceramidase during lysosomal lipid accumulation
physiological function
acid ceramidase ASAH1 is a key enzyme of sphingolipid metabolism. ASAH1 controls melanoma cell proliferation and motile features. ASAH1 acts as a rheostat of the phenotypic switch in melanoma cells. Low ASAH1 expression is associated with an invasive behavior mediated by activation of the integrin alphavbeta5-FAK signaling cascade. ASAH1 controls the switch between the proliferative and invasive phenotype in melanoma cells
physiological function
acid ceramidase hydrolyzes ceramides into sphingoid bases and fatty acids
physiological function
acid ceramidase promotes drug resistance in acute myeloid leukemia through NF-kappaB-dependent P-glycoprotein upregulation. Elevated acid ceramidase levels in acute myeloid leukemia contribute to blast survival. Important role for the enzyme in drug resistance as well as cell survival
physiological function
alkaline ceramidases (ACERs) are a class of poorly understood transmembrane enzymes controlling the homeostasis of ceramides. They are implicated in human pathophysiology, including progressive leukodystrophy, colon cancer as well as acute myeloid leukemia. ACER3 has a catalytic Zn2+ binding site in its core and a Ca2+ binding site physically and functionally connected to the Zn2+ providing a structural explanation for the known regulatory role of Ca2+ on ACER3 enzymatic activity
physiological function
ceramidases hydrolyze ceramides into sphingosine and fatty acids, with sphingosine being further metabolized into sphingosine-1-phosphate (S1P). Ceramidases control the levels of these bioactive sphingolipids in cells and tissues. Neutral ceramidase (nCDase) activity is involved in Wnt/beta-catenin signaling. nCDase is involved in the metabolism of C6-ceramide to sphingosine and subsequently to S1P and possibly ceramide. nCDase is found to be located in both the plasma membrane and in the Golgi apparatus, but it has minimal effects on basal levels of ceramide, sphingosine, or S1P
physiological function
endogenous acid ceramidase protects epithelial cells from Porphyromonas gingivalis (ATCC 33277)-induced inflammation in vitro. Anti-inflammatory and anti-apoptotic effects of acid ceramidase in host cells exposed to periodontal bacteria, and the attenuation of the expression of host-protective acid ceramidase in periodontal lesions
physiological function
enzyme Dacer regulates expression of oxidative stress proteins
physiological function
nCDase regulates the levels of bioactive sphingolipid metabolites in the intestinal tract. CDase may protect against inflammation using a dextran sodium sulfate (DSS) mouse model. Role of nCDase in traumatic brain injury
physiological function
nCDase regulates the levels of bioactive sphingolipid metabolites in the intestinal tract. Exosomes expressing nCDase can protect INS-1 cells or rat primary Langerhans islets against apoptosis induced by high dose cytokines
physiological function
nCDase regulates the levels of bioactive sphingolipid metabolites in the intestinal tract. Role of nCDase in traumatic brain injury. The enzyme is involved in intracellular signaling
physiological function
neutral ceramidase (nCDase) catalyzes conversion of the apoptosis-associated lipid ceramide to sphingosine, the precursor for the proliferative factor sphingosine-1-phosphate. Enzyme nCDase regulates the balance of ceramide and sphingosine-1-phosphate
physiological function
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neutral ceramidase, NlnCDase, is involved in the stress responses of brown planthopper, Nilaparvata lugens. The NlnCDase level might be elevated in adult reproductive organs to mediate developmental process. NlnCDase might be involved in the stress response
physiological function
neutral ceramidases are key enzymes of sphingolipid metabolism that hydrolyze the fatty acyl/sphingosine amide linkage of ceramide at neutral pH
physiological function
signalling effects induced by acid ceramidase in human epithelial or leukemic cell lines
physiological function
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Dacer plays a role in fly development and longevity by controlling the metabolism of ceramides. Dacer inactivation delays Drosophila pre-adult development, while Dacer inactivation increases Drosophila lifespan
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physiological function
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alkaline ceramidase TOD1 is preferentially expressed in pollen tubes and in silique guard cells, where it is required for turgor pressure regulation, it is a key turgor pressure regulator in plant cells, molecular mechanism. Turgor pressure plays pivotal roles in the growth and movement of walled cells
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additional information
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alkaline ceramidase overexpression along with sphingosine 1-phosphate lyase knockdown results in sphingosine 1-phosphate accumulation in cells
additional information
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ceramidase inhibition abolishes contractile effects in cardiomyocytes
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human acid ceramidase deficiency is associated with Farber disease. It plays a role in androgen depletion therapy and in resistance to chemotherapy and to radiation therapy, overview
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in cells, ACER3 overexpression decreases C18:1- and C20:1-ceramides and dihydroceramides, whereas ACER3 knockdown by RNA interference in HeLa cells has the opposite effect. ACER3 knockdown inhibits cell proliferation and up-regulates the cyclin-dependent kinase inhibitor p21CIP1/WAF1. Blocking p21CIP1/WAF1 up-regulation attenuates the inhibitory effect of ACER3 knockdown on cell proliferation, suggesting that ACER3 knockdown inhibits cell proliferation because of p21CIP1/WAF1 up-regulation. ACER3 knockdown inhibits cell apoptosis in response to serum deprivation. ACER3 knockdown up-regulates the expression of ACER2, and the ACER2 up-regulation decreases non-ULC ceramide species while increasing both sphingosine and its phosphate
additional information
enzyme structure-function relationship, homology modeling of the enzymes using Pseudomonas CDase as the template, overview. The enzyme contains a signal/anchor sequence and a mucin box
additional information
enzyme structure-function relationship, homology modeling of the enzymes using Pseudomonas CDase as the template, overview. The enzyme contains a signal/anchor sequence and a mucin box
additional information
enzyme structure-function relationship, homology modeling of the enzymes using Pseudomonas CDase as the template, overview. The enzyme contains a signal/anchor sequence and a mucin box
additional information
enzyme structure-function relationship, homology modeling of the enzymes using Pseudomonas CDase as the template, overview. The enzyme contains a signal/anchor sequence but no mucin box
additional information
enzyme structure-function relationship, overview. The enzyme contains a signal/anchor sequence and a mucin box
additional information
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enzyme structure-function relationship, overview. The enzyme contains a signal/anchor sequence but no mucin box
additional information
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enzyme structure-function relationship, overview. The enzyme contains a signal/anchor sequence but no mucin box
additional information
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enzyme structure-function relationship, overview. The enzyme contains a signal/anchor sequence but no mucin box
additional information
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enzyme structure-function relationship, overview. The enzyme contains a signal/anchor sequence but no mucin box
additional information
enzyme structure-function relationship, overview. The enzyme contains a signal/anchor sequence but no mucin box
additional information
enzyme structure-function relationship, overview. The enzyme contains a signal/anchor sequence but no mucin box
additional information
enzyme structure-function relationship, overview. The enzyme contains a signal/anchor sequence but no mucin box
additional information
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enzyme structure-function relationship, overview. The enzyme contains a signal/anchor sequence but no mucin box
additional information
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enzyme structure-function relationship, overview. The enzyme contains no signal/anchor sequence and no mucin box
additional information
two of the five natural cysteines, Cys27 and Cys219, are essential for enzymatic activity and form a disulfide bridge. Enzyme Ypc1p possesses the Pfam PF05875 ceramidase motif containing seven predicted transmembranes
additional information
two of the five natural cysteines, Cys27 and Cys219, are essential for enzymatic activity and form a disulfide bridge. Enzyme Ypc1p possesses the Pfam PF05875 ceramidase motif containing seven predicted transmembranes
additional information
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two of the five natural cysteines, Cys27 and Cys219, are essential for enzymatic activity and form a disulfide bridge. Enzyme Ypc1p possesses the Pfam PF05875 ceramidase motif containing seven predicted transmembranes
additional information
a hydrophobic surface surrounding the substrate binding channel appears to be a site of membrane attachment where the enzyme accepts substrates facilitated by the accessory protein, saposin-D. The shape of the substrate binding channel appears to be specific for ceramide, as other membrane-resident lipids with bulky head groups, such as sphingomyelin, phospholipids, and cerebrosides, result in steric clashes binding in a manner similar to the modelled ceramide. Catalytic mechanism of substrate hydrolysis, molecular docking and simulation, overview. Uncovering the substrate-binding site upon autocleavage, the concomitant conformational change to the alpha-beta junction causes strand-beta3 containing Cys 143 to shift. This moves Cys143 away from Arg159 breaking their putative hydrogen bond, suggesting that for substrate cleavage Arg159 may not act as the general base. Instead, the general base in the activated state is mostly likely to be the newly formed N-terminus of the beta-subunit. Active site residue N320 stabilizes the N-terminus of Cys143 through hydrogen bonding with its side chain oxygen, whereas its side chain nitrogen provides the oxyanion hole for substrate hydrolysis and stabilizes the position of Glu225, also important for oxyanion hole formation. R333 hydrogen bonds to N320 and based on the substrate modeling above, is predicted to be important for engaging ceramide
additional information
analysis of the catalytic mechanism of eukaryotic neutral ceramidase, structurally based explanation for ceramide specificity, comparison to the bacterial neutral ceramidase, overview. A general acid-base catalysis mechanism is proposed for amide bond hydrolysis by nCDase. In this mechanism, the Zn2+ ion functions to activate a water molecule for nucleophilic attack of the amide carbon. His196 serves as a general base for proton extraction from water and subsequently, a general acid to shuttle this proton to the nitrogen of ceramide during amide bond cleavage. The catalytic domain of the human enzyme contains an extra 30-residue subdomain inserted within the loop between beta14 and alpha7. In human nCDase, the 30-residue subdomain insert replacing the 6-residue span of bacterial CDase displays specific mobility. Stabilization of the subdomain conformation is aided by two internal disulfide bridges, formed by four cysteines that are conserved in eukaryotes
additional information
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analysis of the catalytic mechanism of eukaryotic neutral ceramidase, structurally based explanation for ceramide specificity, comparison to the bacterial neutral ceramidase, overview. A general acid-base catalysis mechanism is proposed for amide bond hydrolysis by nCDase. In this mechanism, the Zn2+ ion functions to activate a water molecule for nucleophilic attack of the amide carbon. His196 serves as a general base for proton extraction from water and subsequently, a general acid to shuttle this proton to the nitrogen of ceramide during amide bond cleavage. The catalytic domain of the human enzyme contains an extra 30-residue subdomain inserted within the loop between beta14 and alpha7. In human nCDase, the 30-residue subdomain insert replacing the 6-residue span of bacterial CDase displays specific mobility. Stabilization of the subdomain conformation is aided by two internal disulfide bridges, formed by four cysteines that are conserved in eukaryotes
additional information
development of a method for the specific visualization of catalytically active acid ceramidase in intracellular compartments. Development of activity-based probes for the detection of acid ceramidase, fluorescent SABRAC enzyme inhibitor analogues are used for enzyme detection. An azide-substituted analogue allows the unprecedented labeling of active acid ceramidase in living cells. Cys143 is the catalytic residue in the active site
additional information
possible mechanism for the catabolism of ceramide by the enzyme. The active site of human neutral ceramidase is a narrow, 20 A deep, hydrophobic pocket with a Zn2+ ion at the base. Hydrophobic residues line the pocket from outside to inside with one side of the active site cavity formed by the ny2-alpha8 helices. His196, Arg257, Tyr579, and Tyr591 were identified as playing critical roles in catalysis and stabilizing the transition state of ceramide hydrolysis, proposed model of ceramide hydrolysis by nCDase in membranes, overview. The membrane-tethered human nCDase involves extracting ceramide from membranes (left) or bile-acid micelles (right) into the deep hydrophobic pocket. The flexible tether allows human nCDase to hydrolyze ceramide in two different physiological forms
additional information
possible mechanism for the hydrolytic activity of ADIPOR2 using computational approaches. In molecular dynamics simulations, the side chains of residues coordinating the zinc rearrange quickly to promote the nucleophilic attack of a zinc-bound hydroxide ion onto the ceramide amide carbonyl. Enzyme structure analysis, overbiew. An uninterrupted cavity goes through the entire receptor from the domain exposed to the upper lipid bilayer to the domain exposed to the cytoplasm. A tunnel enters the top half of the receptor between TM5 and TM6 and links the upper lipid bilayer to the FFA binding pocket. Some electron density is present in this domain indicating that this large opening might play a key role in modulating the entrance or exit of molecules to or from the receptor. On the intracellular side of ADIPOR2, the cavity splits into two tunnels immediately below the zinc binding domain, one of which is largely exposed to the cytoplasm
additional information
substrate docking and hydrolysis mechanism, molecular dynamics simulation and docking study, overview. Computational docking of N-oleoyl-D-sphingosine
additional information
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substrate docking and hydrolysis mechanism, molecular dynamics simulation and docking study, overview. Computational docking of N-oleoyl-D-sphingosine
additional information
the human enzyme contains a 20 A deep, hydrophobic active site pocket stabilized by a eukaryotic-specific subdomain not present in bacterial ceramidases. Flexible ligand docking and prediction of a binding mode for ceramide. The nCDase uses a distinct catalytic strategy for Zn2+-dependent amidases, and generates ceramide specificity by sterically excluding sphingolipids with bulky headgroups and specifically recognizing the small hydroxyl headgroup of ceramide. Docking study with ligand C16-ceramide
additional information
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the human enzyme contains a 20 A deep, hydrophobic active site pocket stabilized by a eukaryotic-specific subdomain not present in bacterial ceramidases. Flexible ligand docking and prediction of a binding mode for ceramide. The nCDase uses a distinct catalytic strategy for Zn2+-dependent amidases, and generates ceramide specificity by sterically excluding sphingolipids with bulky headgroups and specifically recognizing the small hydroxyl headgroup of ceramide. Docking study with ligand C16-ceramide
additional information
treatment of cultured epithelial Chang cells or leukemic T-lymphocytes (Jurkat cells) with purified acid ceramidase results in a dose dependent activation of AKT, p38-kinase and p70S6-kinase, while tyrosine phosphorylation of intracellular proteins remains largely unchanged, determination of intracellular signalling events, proliferation and cell survival, overview. Acid ceramidase treatment does not change expression of tight junction proteins such as ZO-1, ZO-2 and occludin. Cellular viability and proliferation are not affected by acid ceramidase treatment
additional information
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treatment of cultured epithelial Chang cells or leukemic T-lymphocytes (Jurkat cells) with purified acid ceramidase results in a dose dependent activation of AKT, p38-kinase and p70S6-kinase, while tyrosine phosphorylation of intracellular proteins remains largely unchanged, determination of intracellular signalling events, proliferation and cell survival, overview. Acid ceramidase treatment does not change expression of tight junction proteins such as ZO-1, ZO-2 and occludin. Cellular viability and proliferation are not affected by acid ceramidase treatment