4.1.2.27: sphinganine-1-phosphate aldolase
This is an abbreviated version!
For detailed information about sphinganine-1-phosphate aldolase, go to the full flat file.
Word Map on EC 4.1.2.27
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4.1.2.27
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sphingolipids
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ceramide
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sphingoid
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egress
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lymphopenia
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dihydrosphingosine-1-phosphate
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medicine
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fingolimod
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s1p-degrading
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sphks
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4-deoxypyridoxine
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steroid-resistant
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analysis
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lyase-deficient
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s1p-dependent
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spinster
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s1p-induced
- 4.1.2.27
- sphingolipids
- ceramide
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sphingoid
-
egress
- lymphopenia
- dihydrosphingosine-1-phosphate
- medicine
- fingolimod
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s1p-degrading
-
sphks
- 4-deoxypyridoxine
-
steroid-resistant
- analysis
-
lyase-deficient
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s1p-dependent
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spinster
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s1p-induced
Reaction
Synonyms
aldolase, dihydrosphingosine 1-phosphate, Dihydrosphingosine 1-phosphate aldolase, dihydrosphingosine phosphate lyase, Dpl1, Dpl1p, LegS2, S-1-P-lyase, S1P lyase, S1P-lyase, S1PL, S1PL2021, Sgpl1, sphinganine 1-phosphate lyase, sphinganine-1-phosphate aldolase, sphinganine-1-phosphate lyase, sphinganine-1-phosphate-alkanal-lyase, sphingosine 1-phosphate lyase, sphingosine phosphate lyase, sphingosine-1-phosphate lyase, sphingosine-phosphate lyase, SPL, SPL1
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General Information
General Information on EC 4.1.2.27 - sphinganine-1-phosphate aldolase
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malfunction
metabolism
physiological function
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downregulation/inhibition of SPL prevents premature cell cycle progression and mitotic death. Oral administration of an SPL inhibitor to mice prolonges their survival after exposure to a lethal dose (10Gy) of total body ionizing radiation
malfunction
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hearts of heterozygous SPL knockout mice exhibit reduced SPL activity, elevated sphingosine 1-phosphate levels, smaller infarct size, and increased functional recovery after ischemia-reperfusion injury compared with littermate controls
malfunction
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inhibition of S1PL with 4-deoxypyridoxine or knockdown of S1PL with siRNA increases intracellular sphingosine-1-phosphate 3fold, potentiates motility of HPAEC cells to extracellular sphingosine-1-phosphate or serum, and augments activated Rac1 as well as stimulates Rac1 and IQGAP1 translocation to the cell periphery
malfunction
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enzyme inhibition causes protein-losing glomerulopathy due to podocyte dysfunction, skin irritation, and platelet activation and may also be associated with pathological alterations in other tissues such as lung, liver, thymus, and the red blood cell system
malfunction
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enzyme inhibition causes protein-losing glomerulopathy due to podocyte dysfunction, skin irritation, and platelet activation and may also be associated with pathological alterations in other tissues such as lung, liver, thymus, and the red blood cell system
malfunction
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enzyme-deficient mutants display impaired intracellular replication in murine macrophages (associated with an inability to evade the maturing phagosome)
malfunction
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enzyme-deficient mutants display impaired intracellular replication in murine macrophages (associated with an inability to evade the maturing phagosome)
malfunction
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the absence of the enzyme is associated with reduced NF-kappaB activation and atypical morphology of mitochondria
malfunction
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the absence of the enzyme is associated with reduced NF-kappaB activation and atypical morphology of mitochondria
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malfunction
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enzyme-deficient mutants display impaired intracellular replication in murine macrophages (associated with an inability to evade the maturing phagosome)
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S1P lyase catalyzes the irreversible degradation of sphingosine 1-phosphate in the final step of sphingolipid metabolism
metabolism
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sphingosine-1-phosphate lyase is a key enzyme of sphingolipid metabolism
metabolism
sphingosine-1-phosphate lyase is a key enzyme of sphingolipid metabolism
metabolism
sphingosine-1-phosphate lyase is a key enzyme of sphingolipid metabolism
metabolism
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SPL functions as the exit gate of the sphingolipid metabolism
metabolism
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SPL functions as the exit gate of the sphingolipid metabolism
metabolism
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SPL functions as the exit gate of the sphingolipid metabolism
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all S1PL-deficient genetic models used display lymphopenia, with sequestration of mature T-cells in the thymus and lymph nodes. In addition to the lymphoid phenotypes, S1PL KO mice also develop myeloid cell hyperplasia and significant lesions in the lung, heart, urinary tract, and bone, and have a markedly reduced life span. Complete absence of S1PL affects both maturation/development and egress of mature T cells from the thymus, whereas low level S1PL activity affects T-cell egress more than differentiation
physiological function
all S1PL-deficient genetic models used display lymphopenia, with sequestration of mature T-cells in the thymus and lymph nodes. In addition to the lymphoid phenotypes, S1PL KO mice also develop myeloid cell hyperplasia and significant lesions in the lung, heart, urinary tract, and bone, and have a markedly reduced life span. Complete absence of S1PL affects both maturation/development and egress of mature T cells from the thymus, whereas low level S1PL activity affects T-cell egress more than differentiation
physiological function
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complete loss of SPL activity leads to upregulation of the antiapoptotic proteins Bcl-2 and Bcl-xL and consequently protects against apoptosis induced by chemotherapy and nutrient starvation but not against autophagy. Disruption of the gene encoding SPL is accompanied by concomitant accumulation of sphingosine and ceramide. SPL deficiency blocks the apoptotic cascade upstream of mitochondrial damage and leads to upregulation of the antiapoptotic proteins Bcl-2 and Bcl-xL without affecting the levels of the proapoptotic members Bax and Bid. Whereas starvation-induced apoptosis is reduced in Sgpl1-/- compared to Sgpl1+/+ cells, autophagy is similar in both cell types
physiological function
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in mice with an inactive S1P lyase gene, in addition to the expected increase of sphingoid base phosphates, other sphingolipids including sphingosine, ceramide, and sphingomyelin are substantially elevated in the serum and/or liver. The S1P lyase deficiency results in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Lipids in serum and lipid storage are elevated in liver, but adiposity is reduced in the S1P lyase-deficient mice. The S1P lyase deficiency causes widespread changes in the expression pattern of lipid metabolism genes, with a significant increase in the expression of PPAR, a master transcriptional regulator of lipid metabolism. The mRNA expression of the genes encoding the sphingosine kinases and S1P phosphatases, which directly control the levels of S1P, are not significantly changed in liver of the S1P lyase-deficient mice
physiological function
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in mouse embryonic fibroblasts deficient in S1P lyase, sphingosine 1-phosphate and sphingosine concentrations are elevated about 6fold and 2fold, respectively. Resting intracellular Ca2+ is elevated and agonist-induced intracellular Ca2+ increases are augmented in S1P lyase-deficient cells both in the presence and absence of extracellular Ca2+. Intracellular Ca2+ increases and Ca2+ mobilization induced by the SERCA inhibitor, thapsigargin, are augmented. At least two cell types can be distinguished, one with a rapid and transient intracellular Ca2+-increase and the other with a slower and prolonged intracellular Ca2+ elevation upon stimulation with thapsigargin. Intracellular Ca2+ increases upon thapsigargin stimulation, reflecting overall Ca2+ release, by more than 50% in both rapidly and slowly responding S1P lyase-deficient cells
physiological function
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incubation of lyase-deficient neurons with either sphingosine or S1P results in a similar elevation in cellular S1P, but only S1P addition to the culture medium induces apoptosis. This is not due to S1P acting on the S1P receptor but to hydrolysis of S1P to sphingosine that is phosphorylated by the cells. Although the cells produce S1P from both exogenously added sphingosine as well as sphingosine derived from exogenous S1P, the S1P from these two sources are not equivalent, because the former is primarily produced by SK1, whereas the latter is mainly formed by sphingosine kinase-2
physiological function
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thymocyte development in SGPL1-deficient mice which exhibit postnatal discontinuation of early thymocytopoies is starting at 2 weeks after birth. SGPL-/- thymi show a loss of developing thymocytes in the thymic cortex between 2 and 4 weeks of age, whereas mature thymocytes accumulate in the medulla. Increased ceramide levels in the thymus of SGPL1-/- mice abrogates thymic development postnatally by enhanced thymocyte apoptosis and depletion of thymic ETP. Potentially therapeutic immunosuppression by SGPL1 inhibition should benefit from monitoring ceramides to prevent their increase to apoptosis-inducing levels
physiological function
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in renal mesangial cells, endothelial cells, breast (MCF-7) and colon (HCT 116) carcinoma cells, wild type SPL from Symbiobacterium thermophilum disrupts MAPK phosphorylation stimulated by exogenous sphingosine 1-phosphate. Under in vivo conditions SPL from Symbiobacterium thermophilum inhibits tumor cell-induced angiogenesis as an sphingosine 1-phosphate-dependent process
physiological function
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SPL contributes to oxidative stress by depleting sphingosine 1-phosphate pools available for cardioprotective signaling
physiological function
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SPL is the final enzyme in the sphingolipid degradative pathway and an important regulator of sphingosine 1-phosphate as well as the levels of other sphingolipid intermediates which influence various aspects of cell growth, proliferation and death. SPL is necessary for maintaining lipid homeostasis and appropriate cell fate responses. SPL serves as a therapeutic target for immune modulation
physiological function
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SPL is the final enzyme in the sphingolipid degradative pathway and an important regulator of sphingosine 1-phosphate as well as the levels of other sphingolipid intermediates which influence various aspects of cell growth, proliferation and death. SPL is necessary for maintaining lipid homeostasis and appropriate cell fate responses. SPL serves as a therapeutic target for immune modulation
physiological function
SPL is the final enzyme in the sphingolipid degradative pathway and an important regulator of sphingosine 1-phosphate as well as the levels of other sphingolipid intermediates which influence various aspects of cell growth, proliferation and death. SPL is necessary for maintaining lipid homeostasis and appropriate cell fate responses. SPL serves as a therapeutic target for immune modulation
physiological function
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SPL modulates the kinetics of DNA repair, speed of recovery from G2 cell cycle arrest and the extent of apoptosis after ionizing radiation. SPL expression affects the Cdk1-cyclin B complex
physiological function
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SPL plays a crucial role in the migration of T-cells from lymphoid tissues by maintaining the sphingosine 1-phosphate gradient necessary for T-cells to egress from the lymph nodes into the blood stream. SPL plays a central role in neutrophil egress from blood to tissues. SPL is a central and crucial regulator of lipid homeostasis. SPL activity is linked to an increase in CER levels in response to stress factors and is involved in apoptosis
physiological function
a myoblast sphingosine-1-phosphate lyase-knockdown cell accumulates intracellular and extracellular sphingosine-1-phosphate and fails to form myotubes under conditions that normally stimulate myogenic differentiation. Under differentiation conditions, knockdown cells also demonstrate delayed induction of myogenic microRNAs, miR-1, miR-206, and miR-486. Knockdown cells successfully differentiate when treated with an S1P1 agonist, S1P2 antagonist, and combination treatments, which also increase myogenic miRNA levels. Knockdown cells transfected with mimics for miR-1 or miR-206 also overcome the differentiation block
physiological function
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in C4-2B and PC-3 cells, silencing of sphingosine 1-phosphate lyase enhances survival after irradiation or chemotherapy by decreasing expression of proteins involved in sensing and repairing DNA damage or apoptosis, respectively. Enforced expression of sphingosine 1-phosphate lyase sensitizes cancer cells to irradiation or docetaxel by tilting the ceramide/sphingosine 1-phosphate balance toward cell death
physiological function
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inducible sphingosine-1-phosphate lyase knockout mice featuring partial reduction of sphingosine-1-phosphate lyase activity are viable but feature profound reduction of peripheral T cells, similar to the constitutive knockout mice. While thymic T cell development in these mice appears normal, mature T cells are retained in thymus and lymph nodes, leading to reduced T cell numbers in spleen and blood, with a skewing towards increased proportions of memory T cells and T regulatory cells. The inducible knockout mice are protected in experimental autoimmune encephalomyelitis. T cell immigration into the CNS is profoundly reduced
physiological function
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silencing or inhibition of sphingosine-1-phosphate lyase with short interfering RNA or active site-directed inhibitors in cultured mammalian cells does not cause a relevant increase of sphingosine-1-phosphate in the cells. The addition of sphingosine to cultures of cell lines or primary cells provides a source of intracellular sphingosine-1-phosphate that is susceptible to degradation by the lyase and, hence, increases on inhibition or silencing of the enzyme
physiological function
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sphingosine phosphate lyase knockdown via short hairpin RNA in embryonic stem cells shows a 5fold increase in cellular sphingosine 1-phosphate levels, increased proliferation rates and high expression of cell surface pluripotency markers SSEA1 and OCT4 compared to vector control cells. Knockdown cells show robust activation of STAT3 and a 10fold increase in S1P2 expression. Inhibition of S1P2 or STAT3 reverses the proliferation and pluripotency phenotypes of knockdown cells. Inhibition of S1P2 attenuates, in a dose-dependent fashion, the high levels of OCT4 and STAT3 activation. Knockdown cells are capable of generating embryoid bodies from which muscle stem cells, called satellite cells, can be isolated
physiological function
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enzyme expression in mature T cells contributes to efficient thymic egress
physiological function
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enzyme overexpression reduces cytokine-induced endoplasmic reticulum stress, regulates Ca2+ homeostasis and Bcl2-associated death promotor phosphorylation in INS1E cells, and protects against cytokine-mediated inhibition of cell proliferation and caspase-3 activation in insulin-secreting INS1E cells
physiological function
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the enzyme plays a critical role in virulence and is required for intracellular survival
physiological function
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the enzyme plays a critical role in virulence and is required for intracellular survival
physiological function
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the enzyme plays a critical role in virulence and is required for intracellular survival
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