2.3.1.50: serine C-palmitoyltransferase
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For detailed information about serine C-palmitoyltransferase, go to the full flat file.
Word Map on EC 2.3.1.50
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2.3.1.50
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sphingolipids
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ceramide
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myriocin
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sphingomyelin
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sphingosine
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sphingomyelinase
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neuropathy
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sphingoid
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cholesterol
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fumonisin
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glucosylceramide
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sphingosine-1-phosphate
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3-ketodihydrosphingosine
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corneum
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glycosphingolipids
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dihydroceramide
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dihydrosphingosine
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plp-dependent
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l-cycloserine
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ormdl3
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molecular biology
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sphingomonas
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paucimobilis
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transepidermal
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charcot-marie-tooth
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analysis
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ceramide-induced
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phytosphingosine
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medicine
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asmase
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aldimine
- 2.3.1.50
- sphingolipids
- ceramide
- myriocin
- sphingomyelin
- sphingosine
- sphingomyelinase
- neuropathy
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sphingoid
- cholesterol
- fumonisin
- glucosylceramide
- sphingosine-1-phosphate
- 3-ketodihydrosphingosine
- corneum
- glycosphingolipids
- dihydroceramide
- dihydrosphingosine
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plp-dependent
- l-cycloserine
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ormdl3
- molecular biology
- sphingomonas
- paucimobilis
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transepidermal
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charcot-marie-tooth
- analysis
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ceramide-induced
- phytosphingosine
- medicine
- asmase
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aldimine
Reaction
Synonyms
3-oxosphinganine synthetase, acyl-CoA:serine C-2 acyltransferase decarboxylating, LCB1, LCB2, LCB2a, LCB2b, More, palmitoyltransferase, serine, serine palmitoyl transferase, serine palmitoyltransferase, serine palmitoyltransferase 1, serine palmitoyltransferase a, serine-palmitoyl transferase, serine-palmitoyltransferase, SPT, SPT1, SPT2, SPT3, SPTase, SPTLC1, SPTLC2, ssSPT, ssSPTa, Tsc3
ECTree
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General Information
General Information on EC 2.3.1.50 - serine C-palmitoyltransferase
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evolution
the enzyme belongs to the PLP-superfamily and a member of the alpha-oxoamine synthase family (AOS, fold type I)
malfunction
metabolism
physiological function
additional information
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IRS1 serine phosphorylation and PKCtheta recruitment to the plasma membrane are increased in cells with reduced SPT expression and activity. Short-term inhibition of SPT ameliorates palmitate/ceramide-induced insulin resistance, sustained loss/reduction in SPT expression/activity promotes greater partitioning of palmitate towards diacylglycerol synthesis, which impacts negatively upon IRS1-directed insulin signalling
malfunction
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mutations in human SPT cause hereditary sensory autonomic neuropathy type 1, HSAN1, a disease characterized by loss of feeling in extremities and severe pain
malfunction
mutations in the SPTLC1 subunit associated with hereditary sensory and autonomic neuropathy type I
malfunction
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both short and prolonged time of inhibition of the enzyme by myriocin is sufficient to prevent ceramide accumulation and simultaneously reverse palmitate induced inhibition of insulin-stimulated glucose transport
malfunction
hereditary sensory and autonomic neuropathy type 1 (HSAN1) is a rare autosomal dominant inherited peripheral neuropathy caused by mutations in the SPTLC1 and SPTLC2 subunits of serine palmitoyltransferase. The mutations induce a permanent shift in the substrate preference from L-serine to L-alanine, which results in the pathological formation of atypical and neurotoxic 1-deoxy-sphingolipids. Overview of clinical features of HSAN1 patients with SPTLC1 mutations, genotype-phenotype association in HSAN1
malfunction
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homozygous ssSPTa T-DNA mutants are not recoverable, and 50% nonviable pollen is detected in heterozygous ssSpta mutants. Pollen viability is recovered by expression of wild-type ssSPTa or ssSPTb under control of the ssSPTa promoter, indicating ssSPTa and ssSPTb functional redundancy. SPT activity and sensitivity to the PCD-inducing mycotoxin fumonisin B1 are increased by ssSPTa overexpression. Conversely, SPT activity and mycotoxin fumonisin B1 sensitivity are reduced in ssSPTa RNA interference lines
malfunction
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inhibiting the enzyme in the astrocytes decreases the levels of both TNFalpha and interleukin-1beta in the conditioned media, which in turn reduced the neural and acidic sphingomyelinase activities and BACE1 level in primary neurons, overview
malfunction
knockdown of small subunit of serine palmitoyltransferase a decreases the an lysophosphatidylinositol acyltransferase 1-dependent incorporation of exogenous aracidonic acid into phosphatidylinositol but does not affect the in vitro enzyme activity of an lysophosphatidylinositol acyltransferase 1 in the microsomal fraction. ssSPTa knockdown decreases the protein level of LPIAT1 in the crude mitochondrial fraction but not in total homogenate or the microsomal fraction
malfunction
mutations in both subunits hLCB1 (e.g., C133W and C133Y) and hLCB2a (e.g., V359M, G382V, and I504F) are identified in patients with hereditary sensory and autonomic neuropathy type I (HSAN1), an inherited disorder that affects sensory and autonomic neurons. These mutations result in substrate promiscuity, leading to formation of neurotoxic deoxysphingolipids found in affected individuals. Structure homology modeling to understand the impact of the hLCB2a mutations on the mechanism of the enzyme using the structure data from the Sphingomonas paucimobilis enzyme
malfunction
myeloid cell-specific serine palmitoyltransferase subunit 2 haploinsufficiency reduces murine atherosclerosis. SPT subunit 2-haploinsufficient (Sptlc2+/-) macrophages have significantly lower SM levels in plasma membrane and lipid rafts. This reduction not only impairs inflammatory responses triggered by TLR4 and its downstream NF-kappaB and MAPK pathways, but also enhances reverse cholesterol transport mediated by ABC transporters. LDL receptor-deficient (Ldlr-/-) mice transplanted with Sptlc2+/- bone marrow cells exhibit significantly fewer atherosclerotic lesions after high-fat and high-cholesterol diet feeding. Additionally, Ldlr-/- mice with myeloid cell-specific Sptlc2 haploinsufficiency exhibit significantly less atherosclerosis than controls. Sptlc2 haploinsufficiency in macrophages leads to significant reductions of SM, glucosylceramide, and GM3 in macrophage plasma membranes and lipid rafts, resulting in altered raft distribution. Detailed phenotype overview
malfunction
the S384D but not the S384E mutation is associated with increased 1-deoxysphingolipids formation
malfunction
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inhibiting the enzyme in the astrocytes decreases the levels of both TNFalpha and interleukin-1beta in the conditioned media, which in turn reduced the neural and acidic sphingomyelinase activities and BACE1 level in primary neurons, overview
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SPT catalyzes the first and rate-limiting step in the de novo synthesis of sphingolipids
metabolism
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SPT catalyzes the first and rate-limiting step of the sphingolipid biosynthetic pathway
metabolism
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SPT catalyzes the first and rate-limiting step of the sphingolipid biosynthetic pathway
metabolism
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SPT catalyzes the first committed step in sphingolipid biosynthesis
metabolism
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SPT catalyzes the rate-limiting step in the de novo synthesis of sphingolipids, subunit SPTLC3 generates C16-sphingoid bases, and sphingolipids with a C16 backbone constitute a significant proportion of human plasma sphingolipids
metabolism
SPT is a key enzyme of sphingolipid biosynthesis and catalyses the pyridoxal 5'-phosphate-dependent decarboxylative condensation reaction of L-serine with palmitoyl-CoA to generate 3-ketodihydrosphingosine
metabolism
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SPT is the key regulator enzyme in the ceramide de novo biosynthesis pathway
metabolism
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eukaryotic serine palmitoyltransferase is an integral endoplasmic reticulum membrane protein that contains a head-to-tail heterodimer of two related but distinct subunits, LCB1 and LCB2, with a single catalytic site. There are additional subunits necessary for maximal activity as well as associated negative regulatory components
metabolism
serine palmitoyltransferase is the first and rate-limiting enzyme of the de novo biosynthetic pathway of sphingomyelin. Both serine palmitoyltransferase and sphingomyelin are implicated in the pathogenesis of atherosclerosis, the development of which is driven by macrophages
metabolism
serine palmitoyltransferase long chain-1 (SPTLC1) is the first enzyme of sphingolipid biosynthesis
metabolism
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serine palmitoyltransferase, composed of LCB1 and LCB2 subunits, catalyzes the primary regulatory point for sphingolipid synthesis
metabolism
several mutations in SPT are associated with the hereditary sensory and autonomic neuropathy type I, HSAN1. Wild-type SPT forms 1-deoxysphingolipids under certain conditions, and elevated levels are found in individuals with the metabolic syndrome and diabetes
metabolism
sphingolipids are essential components of cellular membranes formed from the condensation of L-serine and a long-chain acyl thioester. This first step is catalyzed by the pyridoxal 5'-phosphate-dependent enzyme serine palmitoyltransferase
metabolism
the enzyme catalyses the first step of de novo sphingolipid biosynthesis
metabolism
the enzyme catalyses the first step of de novo sphingolipid biosynthesis
metabolism
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the first and rate-limiting step of de novo synthesis is the condensation of a fatty acyl-CoA, usually palmitoyl-CoA, with serine, which is catalyzed by the enzyme serine palmitoyltransferase to form 3-dehydrosphinganin
metabolism
the small subunit of serine palmitoyltransferase a (ssSPTa) as an lysophosphatidylinositol acyltransferase 1 (LPIAT1)-interacting protein and colocalizes with LPIAT1 in cultured mammalian cells
metabolism
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SPT is a key enzyme of sphingolipid biosynthesis and catalyses the pyridoxal 5'-phosphate-dependent decarboxylative condensation reaction of L-serine with palmitoyl-CoA to generate 3-ketodihydrosphingosine
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in the endoplasmic reticulum subunit SPT1 is responsible for de novo sphingolipid biosynthesis, it is also present in other cellular compartments, including focal adhesions where it is associated with cell morphology
physiological function
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SPT plays a crucial role in lipid-induced insulin resistance in skeletal muscle cells by desensitizing muscle cells to insulin in response to incubation with palmitate, overview. The effect is antagonized by inhibition of protein kinase C
physiological function
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the enzyme is required for ceramide synthesis as key regulatory enzyme of this pathway, major mechanism for ceramide generation in NR8383 macrophages is stimulation of their de novo synthesis
physiological function
the enzyme is required for resistance against pathogen Pseudomonas cichorii. The gene for the LCB2 subunit of SPT is a potent inducer of hypersensitive response-like cell death involving pyridoxal 5'-phosphate
physiological function
the LCB2 subunit of the sphingolipid biosynthesis enzyme SPT can function as an attenuator of the hypersensitive response and Bax-induced cell death, not involved in the dominant-negative effect that results from BcLCB2 overexpression, overview
physiological function
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enzyme activators, the small subunits are essential for male gametophytes, are important for mycotoxin fumonisin B1 sensitivity, and limit sphingolipid synthesis in planta
physiological function
phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on tyrosine 164 by the fusion kinase BCR-ABL inhibits the SPTLC1 enzyme activity. Inhibition of BCR-ABL kinase using either imatinib or shRNA-mediated silencing leads to the activation of SPTLC1 and to increased apoptosis in both K562 and LAMA-84 cells, a mechanistic explanation for imatinib-mediated cell death
physiological function
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serine palmitoyltransferase in the astrocytes increases ceramide levels, which enhances the release of cytokines that mediate the activation of neural and acidic sphingomyelinase (N-SMase and A-SMase) in the neurons, to propagate the deleterious effects of palmitate, i.e. BACE1 upregulation and amyloidogenesis in primary rat neurons, overview
physiological function
specificity of wild-type SPT might by dynamically regulated by a phosphorylation at position S384
physiological function
the enzyme is required for de novo sphingolipid biosynthesis
physiological function
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the role of the small activating subunits of serine palmitoyltransferase, ssSPTs, is to increase SPT activity without compromising substrate specificity
physiological function
the small subunit of serine palmitoyltransferase a (ssSPTa) plays a role in fatty acid remodeling of phosphatidyl inositol, probably by facilitating the MAM localization oflysophosphatidylinositol acyltransferase 1, LPIAT1
physiological function
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serine palmitoyltransferase in the astrocytes increases ceramide levels, which enhances the release of cytokines that mediate the activation of neural and acidic sphingomyelinase (N-SMase and A-SMase) in the neurons, to propagate the deleterious effects of palmitate, i.e. BACE1 upregulation and amyloidogenesis in primary rat neurons, overview
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key active site residues are His159, Asp231, His234, and Lys265
additional information
the interaction between the hydroxyl group of the L-serine substrate and the 5'-phosphate group of pyridoxal 5'-phosphate is important for substrate specificity and optimal catalytic efficiency. Structure of the PLP-L-serine external aldimine intermediate of the enzyme, PDB ID 2W8J, overview
additional information
wild-type and mutant enzyme structure homology modeling and structure-function analyses, overview
additional information
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wild-type and mutant enzyme structure homology modeling and structure-function analyses, overview