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Information on EC 2.3.1.50 - serine C-palmitoyltransferase
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EC Tree
2.3.1.50 serine C-palmitoyltransferaseIUBMB Comments
A pyridoxal-phosphate protein.
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Word Map
- 2.3.1.50
- sphingolipids
- ceramide
- sphingomyelin
- myriocin
- sphingosine
- sphingomyelinase
-
sphingoid
- neuropathy
-
long-chain
- fumonisin
-
sptlc1
-
hereditary
- glucosylceramide
-
plp-dependent
- corneum
- dihydroceramide
- glycosphingolipids
- dihydrosphingosine
- l-cycloserine
- sphingosine-1-phosphate
- 3-ketodihydrosphingosine
- phytosphingosine
- paucimobilis
- asmase
- medicine
- sphingomonas
-
ormdl3
- molecular biology
- analysis
The enzyme appears in viruses and cellular organisms
Synonyms
3-oxosphinganine synthetase, acyl-CoA:serine C-2 acyltransferase decarboxylating, LCB1, More, palmitoyltransferase, serine, serine palmitoyl transferase, serine palmitoyltransferase, serine palmitoyltransferase 1, serine palmitoyltransferase a, serine-palmitoyl transferase, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
3-oxosphinganine synthetase
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acyl-CoA:serine C-2 acyltransferase decarboxylating
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palmitoyltransferase, serine
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serine palmitoyl transferase
serine palmitoyltransferase
serine-palmitoyl transferase
serine-palmitoyltransferase
SPT
additional information
serine palmitoyltransferase
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serine palmitoyltransferase
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serine palmitoyltransferase
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serine-palmitoyltransferase
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SPT
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SPT
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additional information
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the amount of enzyme activity in microsomes is inversely correlated with the amount of the major coat Gag protein of the L-A dsRNA virus particles
additional information
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SPT belongs to the fold type I family of the pyridoxal 5'-phosphate-dependent enzymes, and the alpha-oxamine synthase subfamily enzymes
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
mechanism
-
palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
ordered bi-bi mechanism
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
mechanism
-
palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
formation of the external aldimine intermediate
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
using 1HNMR the exchange of the alpha-proton of L-serine with the solvent in the presence and absence of S-(2- oxoheptadecyl)-CoA, the structural analogue of palmitoyl-CoA is investagated. Results demonstrate the presence of substrate synergism, in which the alpha-proton of L-serine is activated by the binding of the second substrate palmitoyl-CoA
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
via reaction intermediate pyridoxal 5'-phosphate-L-serine aldimine, His138 changes its hydrogen bond partner from the carboxyl group of L-serine to the carbonyl group of palmitoyl-CoA upon the binding of palmitoyl-CoA, making the L-serine Ca–H bond perpendicular to the pyridoxal 5'-phosphate-Schiff base plane, reaction mechanism with substrate synergism in the SPT reaction, overview. Modelling of reaction intermediates
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
the enzyme forms a pyridoxal 5'-phosphate-L-serine-aldimine intermediate during the reaction, His159 plays multiple roles in the reaction mechanism by exploiting the stereochemistry of Dunathan’s conjecture. His159 promotes both the Claisen-type condensation as an acid catalyst and the protonation at Calpha of the second quinonoid to form the pyridoxal 5'-phosphate-KDS aldimine, spectral analysis, overview
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
the enzyme forms an external aldimine intermediate, as well as dunathan and quinoid intermediates, followed by external beta-keto acid intermediate, and finally product quinoid and product external aldimine intermediates, reaction cycle, overview
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
the enzyme forms an external aldimine intermediate, as well as dunathan and quinoid intermediates, and followed by external beta-keto acid intermediate, and finally product quinoid and product external aldimine intermediates, reaction cycle, overview
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
the reaction proceeds via a key carbanion/quinonoid species and an internal aldimine/PLP-bound form of the enzyme
palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
the reaction proceeds via a key carbanion/quinonoid species and an internal aldimine/PLP-bound form of the enzyme
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
the reaction proceeds via several intermediate states, the pyridoxal 5'-phosphate cofactor binds to an active site lysine residue as an internal aldimine/Schiff’s base (I). The L-serine displaces the lysine residue (Lys265) to form the PLP-L-serine external aldimine (II). Deprotonation of II gives a carbanion/quinonoid species (III) which condenses in a Claisen-like manner with the acyl-CoA thioester substrate to form a PLP-beta-keto acid, which then decarboxylates to generate the PLP-KDS product quinonoid (IV). This then reprotonates to form PLP-KDS aldimine (V) which is finally displaced by Lys265. The step releasing CoA and CO2 and producing the quinonoid intermediate species is irreversible. Interaction between the hydroxyl group of the L-serine substrate and the 5'-phosphate group of pyridoxal 5'-phosphate occurs in the formation of the external aldimine II, overview
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
pyridoxal 5'-phosphate dependent reaction mechanism, key active site residues are His159, Asp231, His234, and Lys265
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
via reaction intermediate pyridoxal 5'-phosphate-L-serine aldimine, His138 changes its hydrogen bond partner from the carboxyl group of L-serine to the carbonyl group of palmitoyl-CoA upon the binding of palmitoyl-CoA, making the L-serine Ca–H bond perpendicular to the pyridoxal 5'-phosphate-Schiff base plane, reaction mechanism with substrate synergism in the SPT reaction, overview. Modelling of reaction intermediates
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
ordered bi-bi mechanism; the enzyme forms an external aldimine intermediate, as well as dunathan and quinoid intermediates, and followed by external beta-keto acid intermediate, and finally product quinoid and product external aldimine intermediates, reaction cycle, overview
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palmitoyl-CoA + L-serine = CoA + 3-dehydro-D-sphinganine + CO2
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Acyl group transfer
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condensation
decarboxylation
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
palmitoyl-CoA:L-serine C-palmitoyltransferase (decarboxylating)
A pyridoxal-phosphate protein.
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CAS REGISTRY NUMBER
COMMENTARY
62213-50-7
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
arachidoyl-CoA + L-serine
CoA + 2-amino-1-hydroxydocosan-3-one + CO2
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37% activity compared to that with palmitoyl-CoA
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?
elaidoyl-CoA + L-serine
CoA + 2-amino-1-hydroxy-trans-11-eicosen-3-one + CO2
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39% activity compared to that with palmitoyl-CoA
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?
L-serine + stearoyl-CoA
CoA + (2S)-2-amino-1-hydroxyicosan-3-one + CO2
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-
-
-
?
lauroyl-CoA + L-serine
CoA + 2-amino-1-hydroxytetradecan-3-one + CO2
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18% activity compared to that with palmitoyl-CoA
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?
myristoleoyl-CoA + L-serine
CoA + 2-amino-1-hydroxy-cis-11-hexadecen-3-one + CO2
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46% activity compared to that with palmitoyl-CoA
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?
oleoyl-CoA + L-serine
CoA + 2-amino-1-hydroxy-11-cis-eicosen-3-one + CO2
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57% activity compared to that with palmitoyl-CoA
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?
palmitoyl-CoA + L-serine
3-dehydrosphinganine + CoA + CO2
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?
stearoyl-CoA + L-serine
(2S)-2-amino-1-hydroxyicosan-3-one + CoA + CO2
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?
stearoyl-CoA + L-serine
CoA + (2S)-2-amino-1-hydroxyicosan-3-one + CO2
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?
stearoyl-CoA + L-serine
CoA + 2-amino-1-hydroxyeicosan-3-one + CO2
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51% activity compared to that with palmitoyl-CoA
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?
L-serine + palmitoyl-CoA
CoA + 3-dehydro-D-sphinganine + CO2
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?
L-serine + palmitoyl-CoA
CoA + 3-dehydro-D-sphinganine + CO2
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?
myristoyl-CoA + L-serine
CoA + 2-amino-1-hydroxy-cis-11-hexadecen-3-one + CO2
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SPT is the first and rate-limiting enzyme of sphingolipid biosynthesis
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-
?
myristoyl-CoA + L-serine
CoA + 2-amino-1-hydroxy-cis-11-hexadecen-3-one + CO2
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the viral enzyme exhibits preference for myristoyl-CoA rather than palmitoyl-CoA
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?
myristoyl-CoA + L-serine
CoA + 2-amino-1-hydroxyhexadecan-3-one + CO2
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75% activity compared to that with palmitoyl-CoA
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?
myristoyl-CoA + L-serine
CoA + 2-amino-1-hydroxyhexadecan-3-one + CO2
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75% activity compared to that with palmitoyl-CoA
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?
myristoyl-CoA + L-serine
CoA + ? + CO2
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recombinant SPTLC3 subunit in HEK-293 cells
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?
n-heptadecanoyl-CoA + L-serine
CoA + 2-amino-1-hydroxynonadecan-3-one + CO2
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75% activity compared to that with palmitoyl-CoA
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?
n-heptadecanoyl-CoA + L-serine
CoA + 2-amino-1-hydroxynonadecan-3-one + CO2
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75% activity compared to that with palmitoyl-CoA
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?
palmitoleoyl-CoA + L-serine
CoA + 2-amino-1-hydroxy-cis-11-octadecen-3-one + CO2
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80% activity compared to that with palmitoyl-CoA
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?
palmitoleoyl-CoA + L-serine
CoA + 2-amino-1-hydroxy-cis-11-octadecen-3-one + CO2
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80% activity compared to that with palmitoyl-CoA
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?
palmitoyl-CoA + L-alanine
CoA + (2S)-2-aminooctadecan-3-one + CO2
wild-type enzyme can metabolize L-alanine under certain conditions
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?
palmitoyl-CoA + L-alanine
CoA + (2S)-2-aminooctadecan-3-one + CO2
low activity with the wild-type enzyme, but increased activity with some mutants of the enzyme, overview
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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-
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
step in the sphingolipid biosynthetic pathway, overview
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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-
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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-
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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SPT is the first and rate-limiting enzyme of sphingolipid biosynthesis
-
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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the viral enzyme exhibits preference for myristoyl-CoA rather than palmitoyl-CoA
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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-
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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key enzyme of sphingolipid metabolism
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme catalyses the rate limiting step for the de novo synthesis of sphingolipids
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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palmitoyl-CoA is the preferred substrate
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ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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optimal palmitoyl-CoA concentration is 0.2 mM
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ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
palmitoyl-CoA is used in preference to other saturated or unsaturated acyl-CoA substrates
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ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
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-
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
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ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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palmitoyl-CoA is used in preference to other saturated or unsaturated acyl-CoA substrates
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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involved in cellular stress response
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
first step of biosynthesis of sphingolipid bases
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palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
rate-limiting enzyme in synthesis of sphingolipids
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palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
rate-limiting enzyme in synthesis of sphingolipids
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
rate-limiting enzyme in synthesis of sphingolipids
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
initial step of de novo ceramide biosynthesis
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palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
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the enzyme catalyzes the initial and rate-limiting step in de novo sphingolipid synthesis. Potential role for overexpression of SPT in processes of cell metastasis
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?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme catalyses the rate limiting step for the de novo synthesis of sphingolipids
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme catalyses the rate limiting step for the de novo synthesis of sphingolipids, the dynamic composition of the SPT complex could provide a cellular mechanism to adjust SPT activity to tissue specific requirements in sphingolipid synthesis
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first and rate-limiting step in the de novo synthesis of sphingolipids
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
key enzyme in ceramide synthesis, overview
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
-
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
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ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
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ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
i.e. 2-amino-1-hydroxyoctadecane-3-one, i.e. 3-oxo-dihydroxysphingosine
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
palmitoyl-CoA is the preferred substrate
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
palmitoyl-CoA is the preferred substrate
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
activities are greatest with palmitoyl-CoA and palmitelaidoyl-CoA, followed by fully saturated homologs, activity considerably diminishes as the alkyl-chain length increases or decreases, or with the presence of a cis-double bond
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
no other amino acids can substitute for serine
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
-
-
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme catalyses the first step in the ceramide biosynthesis pathway
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme is involved in the ceramide metabolism, overview
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
involved in cellular stress response
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
rate-limiting enzyme in synthesis of sphingolipids
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
palmitoyl-CoA is the preferred substrate
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
no other amino acids can substitute for serine
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
rate-limiting enzyme in synthesis of sphingolipids
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
His159 is the anchoring site for L-serine and regulates the alpha-deprotonation of L-serine by fixing the conformation of the pyridoxal 5'-phosphate-L-serine aldimine to prevent unwanted side reactions
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
interaction between the hydroxyl group of the L-serine substrate and the 5'-phosphate group of pyridoxal 5'-phosphate. This interaction is important for substrate specificity and optimal catalytic efficiency
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
palmitoyl-CoA is the preferred substrate
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
no other amino acids can substitute for serine
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
-
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
i.e. 2-amino-1-hydroxyoctadecane-3-one, i.e. 3-oxo-dihydroxysphingosine
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
ir
additional information
?
-
the LCB2 subunit of the sphingolipid biosynthesis enzyme SPT can function as an attenuator of the hypersensitive response and Bax-induced cell death, overview
-
-
-
additional information
?
-
-
the viral single-chain enzyme might form multiprotein complexes in vivo with functions different from the monomer
-
-
-
additional information
?
-
-
increasing the acyl-CoA chain length above C16 by 1 or 2 carbons is less detrimental to activity than similar decrements in chain length
-
-
-
additional information
?
-
-
44% reduction of SPT activity in patiens with hereditary sensory neuropathy type I with mutation T399G in the SPTLC1 gene. However the decrease in SPT activity has no effect on de novo sphingolipid biosynthesis, cellular sphingolipid content, cell proliferation and death. Despite the inhibition of mutant allele, the activity of nonmutant allele of SPT may be sufficient for adequate sphingolipid biosynthesis and cell viability. The neurodegeneration in HSN1 is likely to be caused by subtler and rather long-term effects of these mutations such as loss of a cell-type selective facet of sphingolipid metabolism and/or function, or perhaps accumulation of toxic species, including abnormal proteins
-
-
-
additional information
?
-
-
elevation of ceramide in serum lipoproteins during acute phase response to inflammation is accompanied by activation of serine-palmitoyl transferase in liver
-
-
-
additional information
?
-
-
mutations in the enzyme subunit SPTLC1 cause hereditary sensory and autonomic neuropathy type I, HSAN1, an adult onset, autosomal dominant neuropathy, HSAN1 patients have reduced SPT activity, link between mutant SPT and neuronal dysfunction
-
-
-
additional information
?
-
-
the expression of two SPT isoforms could be a cellular mechanism to adjust SPT activity to tissue-specific requirements of sphingolipid synthesis
-
-
-
additional information
?
-
-
ability of the ssSPT subunits to modulate the chain lengths of LCBs in mammalian cells
-
-
-
additional information
?
-
-
assay optimization measuring radio-labeled L-serine incorporation into 3-oxodihydrosphingosine in microsomes or crude cell lysate, usage of an nonradioactive HPLC-based detection protocol, overview
-
-
-
additional information
?
-
1-deoxysphingolipids are atypical sphingolipids that are formed by the enzyme serine palmitoyltransferase due to a promiscuous use of L-alanine over its canonical substrate L-serine. Wild-type SPT forms 1-deoxysphingolipids under certain conditions, and elevated levels are found in individuals with the metabolic syndrome and diabetes
-
-
-
additional information
?
-
the small subunit of serine palmitoyltransferase a (ssSPTa) as an lysophosphatidylinositol acyltransferase 1 (LPIAT1)-interacting protein
-
-
-
additional information
?
-
-
elevation of ceramide in serum lipoproteins during acute phase response to inflammation is accompanied by activation of serine-palmitoyl transferase in liver
-
-
-
additional information
?
-
-
stearoyl-CoA desaturase-1 deficiency, SCD1 deficiency, reduces ceramide synthesis by downregulating SPT and increasing beta-oxidation in skeletal muscle
-
-
-
additional information
?
-
-
the enzyme activity and expression in the heart is not affected by high-fat feeding
-
-
-
additional information
?
-
-
no activity with L-phosphoserine
-
-
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
myristoyl-CoA + L-serine
CoA + 2-amino-1-hydroxy-cis-11-hexadecen-3-one + CO2
-
SPT is the first and rate-limiting enzyme of sphingolipid biosynthesis
-
-
?
myristoyl-CoA + L-serine
CoA + ? + CO2
-
recombinant SPTLC3 subunit in HEK-293 cells
-
-
?
palmitoyl-CoA + L-alanine
CoA + (2S)-2-aminooctadecan-3-one + CO2
O15270
wild-type enzyme can metabolize L-alanine under certain conditions
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
Q9LSZ9
step in the sphingolipid biosynthetic pathway, overview
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
E2RKV3
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
SPT is the first and rate-limiting enzyme of sphingolipid biosynthesis
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
key enzyme of sphingolipid metabolism
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme catalyses the rate limiting step for the de novo synthesis of sphingolipids
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
O15269, O15270
-
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
O15269 and O15270
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
involved in cellular stress response
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
O15269, O15270
first step of biosynthesis of sphingolipid bases
-
-
-
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
O15269, O15270
rate-limiting enzyme in synthesis of sphingolipids
-
-
-
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
rate-limiting enzyme in synthesis of sphingolipids
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
rate-limiting enzyme in synthesis of sphingolipids
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
O15269, O15270
initial step of de novo ceramide biosynthesis
-
-
-
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme catalyzes the initial and rate-limiting step in de novo sphingolipid synthesis. Potential role for overexpression of SPT in processes of cell metastasis
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme catalyses the rate limiting step for the de novo synthesis of sphingolipids
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme catalyses the rate limiting step for the de novo synthesis of sphingolipids, the dynamic composition of the SPT complex could provide a cellular mechanism to adjust SPT activity to tissue specific requirements in sphingolipid synthesis
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first and rate-limiting step in the de novo synthesis of sphingolipids
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
key enzyme in ceramide synthesis, overview
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
-
-
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme catalyses the first step in the ceramide biosynthesis pathway
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
the enzyme is involved in the ceramide metabolism, overview
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
involved in cellular stress response
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
rate-limiting enzyme in synthesis of sphingolipids
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
initial step of de novo ceramide biosynthesis
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
A7BFV6
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
Q93UV0
rate-limiting enzyme in synthesis of sphingolipids
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
Q93UV0
-
-
-
?
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
-
-
ir
palmitoyl-CoA + L-serine
CoA + 3-dehydro-D-sphinganine + CO2
-
first step of biosynthesis of sphingolipid bases
-
ir
additional information
?
-
B5LED9
the LCB2 subunit of the sphingolipid biosynthesis enzyme SPT can function as an attenuator of the hypersensitive response and Bax-induced cell death, overview
-
-
-
additional information
?
-
-
the viral single-chain enzyme might form multiprotein complexes in vivo with functions different from the monomer
-
-
-
additional information
?
-
-
44% reduction of SPT activity in patiens with hereditary sensory neuropathy type I with mutation T399G in the SPTLC1 gene. However the decrease in SPT activity has no effect on de novo sphingolipid biosynthesis, cellular sphingolipid content, cell proliferation and death. Despite the inhibition of mutant allele, the activity of nonmutant allele of SPT may be sufficient for adequate sphingolipid biosynthesis and cell viability. The neurodegeneration in HSN1 is likely to be caused by subtler and rather long-term effects of these mutations such as loss of a cell-type selective facet of sphingolipid metabolism and/or function, or perhaps accumulation of toxic species, including abnormal proteins
-
-
-
additional information
?
-
-
elevation of ceramide in serum lipoproteins during acute phase response to inflammation is accompanied by activation of serine-palmitoyl transferase in liver
-
-
-
additional information
?
-
-
mutations in the enzyme subunit SPTLC1 cause hereditary sensory and autonomic neuropathy type I, HSAN1, an adult onset, autosomal dominant neuropathy, HSAN1 patients have reduced SPT activity, link between mutant SPT and neuronal dysfunction
-
-
-
additional information
?
-
-
the expression of two SPT isoforms could be a cellular mechanism to adjust SPT activity to tissue-specific requirements of sphingolipid synthesis
-
-
-
additional information
?
-
O15270
1-deoxysphingolipids are atypical sphingolipids that are formed by the enzyme serine palmitoyltransferase due to a promiscuous use of L-alanine over its canonical substrate L-serine. Wild-type SPT forms 1-deoxysphingolipids under certain conditions, and elevated levels are found in individuals with the metabolic syndrome and diabetes
-
-
-
additional information
?
-
Q969W0
the small subunit of serine palmitoyltransferase a (ssSPTa) as an lysophosphatidylinositol acyltransferase 1 (LPIAT1)-interacting protein
-
-
-
additional information
?
-
-
elevation of ceramide in serum lipoproteins during acute phase response to inflammation is accompanied by activation of serine-palmitoyl transferase in liver
-
-
-
additional information
?
-
-
stearoyl-CoA desaturase-1 deficiency, SCD1 deficiency, reduces ceramide synthesis by downregulating SPT and increasing beta-oxidation in skeletal muscle
-
-
-
additional information
?
-
-
the enzyme activity and expression in the heart is not affected by high-fat feeding
-
-
-
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pyridoxal 5'-phosphate
-
pyridoxal 5'-phosphate can be resolved from the enzyme by dialysis
pyridoxal 5'-phosphate
-
bound to epsilon-amino group of a lysine residue in the active site
pyridoxal 5'-phosphate
-
dependent on, the re face of SPT of the pyridoxal 5'-phosphate-Lys aldimine is occupied by a His159 residue instead of an aromatic amino acid residue as in the other type I enzymes
pyridoxal 5'-phosphate
-
dependent on, bound at the active site at the dimer interface
pyridoxal 5'-phosphate
-
all subunits contain a pyridoxal 5'-phosphate consensus motif sequence
pyridoxal 5'-phosphate
the pyridoxal 5'-phosphate binding site is required for the LCB2 gene cell death inducing function; the pyridoxal 5'-phosphate binding site is required for the LCB2 gene cell death inducing function
pyridoxal 5'-phosphate
subunit LCB2 possesses a binding site
pyridoxal 5'-phosphate
dependent on, bound by lysine 265 residue on subunit LCB2a
pyridoxal 5'-phosphate
-
dependent on, bound by lysine 265 residue, interaction between the hydroxyl group of the L-serine substrate and the 5'-phosphate group of pyridoxal 5'-phosphate. This interaction is important for substrate specificity and optimal catalytic efficiency
pyridoxal 5'-phosphate
-
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mn2+
additional information
-
NaCl, LiCl, MgCl2, MnCl2 have no effect on activity
Please wait a moment until the data is sorted. This message will disappear when the data is sorted.
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2S,3R)-2-amino-12-hydroxy-2-hydroxymethyl-3-sulfooxy-octadecanoic acid
-
IC50: 5.4 nM
(2S,3R)-2-amino-12-[(Z)-hydroxyimino]-2-hydroxymethyl-3-sulfooxy-octadecanoic acid
-
IC50: 30 nM
(2S,3R)-2-amino-3,12-dihydroxy-2-hydroxymethyl-octadecanoic acid
-
IC50: 3.2 nM
(2S,3R)-2-amino-3-hydroxy-2-hydroxymethyl-12-oxo-octadecanoic acid
-
IC50: 3.5 nM
(2S,3R)-2-amino-3-hydroxy-2-hydroxymethyl-12-oxo-octadecanoic acid methyl ester
-
IC50: 17 nM
4-amino-3-isoxazolidone
-
D-cycloserine and L-cycloserine are inhibitors, L-cycloserine is 14-fold more effective than D-cycloserine
ceramide 1-phosphate
-
from bovine brain, inhibits the enzyme and blocks apoptosis in alveolar macrophages, overview
cis-4-methylsphingosine
-
time- and concentration-dependent, causes drastic morphological changes of the cells in vivo
mycotoxin fumonisin B1
-
enzyme sensitivity to the inhibitor is increased by small subunit ssSPTa overexpression
palmitoyl CoA
enzyme shows remarkable substrate inhibition at palmitoyl-CoA concentrations higher than 0.1 nM
thermozymocidin
-
i.e. ISP-1; strong inhibition, reversible by sphingosine
beta-chloro-L-alanine
-
rapid, irreversible and time dependent inhibition at the active site; stereospecific, no inhibition by beta-chloro-D-alanine; suicide substrate
myriocin
a potent inhibitor of SPT, that has no effect on Bax-induced programmed cell death
myriocin
-
i.e. sphingofungin B; strong inhibition, reversible by sphingosine
myriocin
-
in vivo intraperitoneal application to apolipoprotein E knockout mice leads to inhibition of atherosclerosis while feeding a high fat diet to the mice, and is associated with reduced plasma glycosphingolipid concentration and reduction of lesions in aorta regions, overview
myriocin
-
; the inhibition of SPT in hyperlipidemic apolipoprotein E knockout mice lowers plasma sphingolipids and atherogenic plasma lipids leading to the regression of pre-existing atherosclerotic lesions and to the formation of a stable plaque phenotype
myriocin
inhibits the enzyme and inhibits defense response against a nonhost pathogen; inhibits the enzyme and inhibits defense response against a nonhost pathogen
myriocin
-
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
myriocin
-
i.e. (2S,3R,4R,6E)-2-amino-3,4-dihydroxy-2-(hydroxymethyl)-14-oxo-6-eicosenoic acid, or thermozymocidin and ISP-1, is a fungal natural product, kinetics and molecular mechanism of enzyme inhibition, overview. Myriocin is a potent SPT enzyme inhibitor. It initially forms an external aldimine with pyridoxal 5'-phosphate at the active site, the structure of the resulting co-complex explains its nanomolar affinity for the enzyme. The cofactor-inhibitor co-complex, PLP-myriocin aldimine, catalytically degrades via an unexpected retro-aldol-like cleavage mechanism to a C18 aldehyde which in turn acts as a suicide inhibitor of the enzyme by covalent modification of the essential catalytic lysine. This dual mechanism of inhibition rationalizes the extraordinary potency and longevity of myriocin inhibition. Incubations of enzyme SPT with myriocin is consistent with the formation of an initial enzyme-inhibitor complex which is noncovalent in nature and reversible, albeit with a very slow off rate (koff), the PLP-myriocin aldimine as the initial competitive inhibitory species. In contrast, for the enzyme preincubated with myriocin for 16 h, no detectable regain in activity is observed after dialysis either at 3 or 24 h, the second formed covalent adduct acts as an irreversible inhibitor of enzyme SPT
additional information
-
recombinant expression of C133W mutant SPTLC1 in cell cultures dominantly inhibits the endogenous SPT activity
-
additional information
time-dependent degradation of enzyme mRNA by etoposide, activation of enzyme activity on protein level, time-dependent; time-dependent degradation of enzyme mRNA by etoposide, activation of enzyme activity on protein level, time-dependent
-
additional information
time-dependent degradation of enzyme mRNA by etoposide, activation of enzyme activity on protein level, time-dependent; time-dependent degradation of enzyme mRNA by etoposide, activation of enzyme activity on protein level, time-dependent
-
additional information
-
the enzyme activity and expression in the heart is not affected by high-fat feeding
-
additional information
-
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
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pioglitazone
-
increases the enzyme activity in vitro and in vivo independent of standard or high-fat diet
retinoic acid
-
up-regulates enzyme activity in embryonic carcinoma cell ine PCC7-Mz1
S-(2-oxoheptadecyl)-CoA
-
binds to the smSPT-external aldimine complex and enhances the exchange rate of the alpha-proton of L-serine by smSPT
small activating subunit of serine palmitoyltransferase
-
ssSPT, the small subunits of human serine palmitoyltransferase (hssSPTs) are glycoproteins and activate the catalytic hLCB1/hLCB2 heterodimer. Two isoforms exist, ssSPTa and ssSPTb, a single amino acid, residue 25, difference between ssSPTa and ssSPTb is responsible for the acyl-CoA preference of heterotrimers containing each isoform. the role of the small activating subunits of serine palmitoyltransferase, ssSPTs, is to increase SPT activity without compromising substrate specificity. Activity and acyl-CoA selectivity of the ssSPTs reside in the conserved core. Deletion of the N-terminal 10 amino acids of small activating subunit of serine palmitoyltransferase isoforms ssSPTa or ssSPTb has no effect on the ability of the proteins to activate hLCB1/hLCB2a heterodimers sufficiently to complement growth of yeast lacking endogenous serine palmitoyltransferase. The region responsible for the acyl-CoA selectivity of ssSPTa lays between residues Ser11 and Glu27, the acyl-CoA selectivity does not lie in the C-terminal region of ssSPTb, overview
-
etoposide
; activates enzyme activity, but decreases mRNA level, time-dependent; activates enzyme activity, but decreases mRNA level, time-dependent
etoposide
-
enhanced activity due to chemotherapy with epotoside as therapeutic agent in Molt-4 leukemic cells
small subunits of serine palmitoyltransferase
-
isoforms ssSPTa and ssSPTb, UniProt A8MSB8 and F4IPU5, strongly stimulate SPT activity. Small subunit ssSPTa transcripts are more enriched in all organs and over 400fold more abundant in pollen than small subunit ssSPTb transcripts. Homozygous ssSPTa T-DNA mutants are not recoverable, and 50% nonviable pollen is detected in heterozygous ssspta mutants. The small subunits are essential for male gametophytes, are important for mycotoxin fumonisin B1 sensitivity, and limit sphingolipid synthesis in planta
-
small subunits of serine palmitoyltransferase
small subunits of SPT, ssSPTa and ssSPTb, increase human SPT activity by 50-100fold when coexpressed with enzyme subunits hLCB1 and hLCBa
-
additional information
-
enzyme activity is enhanced under stress and in apoptosis, e.g. in pancreatic cells in a model for diabetes, in case of angiotensin II type receptor occupancy
-
additional information
-
enzyme activity is enhanced under stress and in apoptosis, e.g. in pancreatic cells in a model for diabetes, in case of angiotensin II type receptor occupancy
-
additional information
-
increased SPT enzyme activity in reactive astrocytes of the hippocampus at 2 weeks post-kainate injection
-
additional information
-
the enzyme activity and expression in the heart is not affected by high-fat feeding
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
alpha-galactosidase deficiency
Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice.
Alzheimer Disease
Inhibition of serine palmitoyltransferase reduces A? and tau hyperphosphorylation in a murine model: a safe therapeutic strategy for Alzheimer's disease.
Alzheimer Disease
MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid ?, novel targets in sporadic Alzheimer's disease.
Atherosclerosis
Cell polarity factor Par3 binds SPTLC1 and modulates monocyte serine palmitoyltransferase activity and chemotaxis.
Atherosclerosis
Enzymology of long-chain base synthesis by aorta: induction of serine palmitoyltransferase activity in rabbit aorta during atherogenesis.
Atherosclerosis
Inhibition of atherosclerosis by the serine palmitoyl transferase inhibitor myriocin is associated with reduced plasma glycosphingolipid concentration.
Atherosclerosis
Inhibition of serine palmitoyltransferase activity in rabbit aorta by L-cycloserine.
Atherosclerosis
Myeloid cell-specific serine palmitoyltransferase subunit 2 haploinsufficiency reduces murine atherosclerosis.
Atherosclerosis
Myriocin slows the progression of established atherosclerotic lesions in apolipoprotein E gene knockout mice.
Atherosclerosis
Myriocin-mediated up-regulation of hepatocyte apoA-I synthesis is associated with ERK inhibition.
Atherosclerosis
Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice.
Brain Neoplasms
Novel Functional Association of Serine Palmitoyltransferase Subunit 1-A Peptide in Sphingolipid Metabolism with Cytochrome P4501A1 Transactivation and Proliferative Capacity of the Human Glioma LN18 Brain Tumor Cell Line.
Breast Neoplasms
Enhanced de novo ceramide generation through activation of serine palmitoyltransferase by the P-glycoprotein antagonist SDZ PSC 833 in breast cancer cells.
Carcinogenesis
Liver Serine Palmitoyltransferase (SPT) Activity Deficiency in Early Life Impairs Adherens Junctions and Promotes Tumorigenesis.
Carcinoma
Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation.
Carcinoma, Hepatocellular
Comparison of serine palmitoyltransferase in Morris hepatoma 7777 and rat liver.
Carcinoma, Hepatocellular
Hepatic expression of the Sptlc3 subunit of serine palmitoyltransferase is associated with the development of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis.
Carcinoma, Merkel Cell
Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation.
Demyelinating Diseases
Aberrant Upregulation of Astroglial Ceramide Potentiates Oligodendrocyte Injury.
Diabetes Mellitus, Type 2
Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase.
Diphtheria
Diphtheria toxin translocation across cellular membranes is regulated by sphingolipids.
Dyslipidemias
Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase.
Encephalitis
Insights into abnormal sphingolipid metabolism in multiple sclerosis: targeting ceramide biosynthesis as a unique therapeutic strategy.
Glioma
Novel Functional Association of Serine Palmitoyltransferase Subunit 1-A Peptide in Sphingolipid Metabolism with Cytochrome P4501A1 Transactivation and Proliferative Capacity of the Human Glioma LN18 Brain Tumor Cell Line.
Hepatitis C
A serine palmitoyltransferase inhibitor blocks hepatitis C virus replication in human hepatocytes.
Hepatitis C
The suppressive effect that myriocin has on hepatitis C virus RNA replication is independent of inhibition of serine palmitoyl transferase.
Hepatitis C
[Suppression of hepatitis C virus (HCV) replication with serine palmitoyltransferase inhibitor]
Hereditary Sensory and Autonomic Neuropathies
A global in vivo Drosophila RNAi screen identifies a key role of ceramide phosphoethanolamine for glial ensheathment of axons.
Hereditary Sensory and Autonomic Neuropathies
A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.
Hereditary Sensory and Autonomic Neuropathies
Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24.
Hereditary Sensory and Autonomic Neuropathies
Clinical, pathological and genetic characterization of hereditary sensory and autonomic neuropathy type 1 (HSAN I).
Hereditary Sensory and Autonomic Neuropathies
Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation.
Hereditary Sensory and Autonomic Neuropathies
Exclusion of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) as a common cause for hereditary sensory neuropathy.
Hereditary Sensory and Autonomic Neuropathies
Hereditary sensory and autonomic neuropathy type I in a Chinese family: British C133W mutation exists in the Chinese.
Hereditary Sensory and Autonomic Neuropathies
Hereditary sensory neuropathy type 1 mutations confer dominant negative effects on serine palmitoyltransferase, critical for sphingolipid synthesis.
Hereditary Sensory and Autonomic Neuropathies
Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause neurotoxicity, acute calcium handling abnormalities and mitochondrial dysfunction in vitro.
Hereditary Sensory and Autonomic Neuropathies
Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype.
Hereditary Sensory and Autonomic Neuropathies
Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.
Hereditary Sensory and Autonomic Neuropathies
Mutations in the SPTLC1 Protein Cause Mitochondrial Structural Abnormalities and Endoplasmic Reticulum Stress in Lymphoblasts.
Hereditary Sensory and Autonomic Neuropathies
Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase.
Hereditary Sensory and Autonomic Neuropathies
Substrate Availability of Mutant SPT Alters Neuronal Branching and Growth Cone Dynamics in Dorsal Root Ganglia.
Hypertension
Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure.
Infections
Drosophila melanogaster as a complementary system for studying HIV-1-related genes and proteins.
Infections
Effects of Mycoplasma pneumoniae infection on sphingolipid metabolism in human lung carcinoma A549 cells.
Infections
Leishmania (Viannia) braziliensis Inositol Phosphorylceramide: Distinctive Sphingoid Base Composition.
Infections
Viral serine palmitoyltransferase induces metabolic switch in sphingolipid biosynthesis and is required for infection of a marine alga.
Influenza, Human
Intact sphingomyelin biosynthetic pathway is essential for intracellular transport of influenza virus glycoproteins.
Insulin Resistance
Dietary supplement of conjugated linoleic acids or polyunsaturated fatty acids suppressed the mobilization of body fat reserves in dairy cows at early lactation through different pathways.
Insulin Resistance
Effects of inhibition of serine palmitoyltransferase (SPT) and sphingosine kinase 1 (SphK1) on palmitate induced insulin resistance in L6 myotubes.
Insulin Resistance
Inhibition of serine palmitoyl transferase I reduces cardiac ceramide levels and increases glycolysis rates following diet-induced insulin resistance.
Insulin Resistance
Modulating serine palmitoyl transferase (SPT) expression and activity unveils a crucial role in lipid-induced insulin resistance in rat skeletal muscle cells.
Insulin Resistance
Overexpression of the Adiponectin Receptor AdipoR1 in Rat Skeletal Muscle Amplifies Local Insulin Sensitivity.
Insulin Resistance
Sulforaphane Prevents Hepatic Insulin Resistance by Blocking Serine Palmitoyltransferase 3-Mediated Ceramide Biosynthesis.
Liver Neoplasms, Experimental
Comparison of serine palmitoyltransferase in Morris hepatoma 7777 and rat liver.
Lung Neoplasms
Using a biologically annotated library to analyze the anticancer mechanism of serine palmitoyl transferase (SPT) inhibitors.
Lymphoma
De novo ceramide accumulation due to inhibition of its conversion to complex sphingolipids in apoptotic photosensitized cells.
Magnesium Deficiency
Magnesium deficiency upregulates serine palmitoyl transferase (SPT 1 and SPT 2) in cardiovascular tissues: relationship to serum ionized Mg and cytochrome c.
Malnutrition
Undernutrition decreases serine palmitoyltransferase activity in developing rat hypothalamus.
Melanoma
Myriocin, a serine palmitoyltransferase inhibitor, suppresses tumor growth in a murine melanoma model by inhibiting de novo sphingolipid synthesis.
Melanoma
Serine palmitoyltransferase inhibitor myriocin induces growth inhibition of B16F10 melanoma cells through G(2) /M phase arrest.
Myocardial Infarction
Increased de novo ceramide synthesis and accumulation in failing myocardium.
Neoplasms
Antitumor activity of a novel and orally available inhibitor of serine palmitoyltransferase.
Neoplasms
Aster glehni Extract Containing Caffeoylquinic Compounds Protects Human Keratinocytes through the TRPV4-PPAR?-AMPK Pathway.
Neoplasms
Cycloserine and threo-dihydrosphingosine inhibit TNF-alpha-induced cytotoxicity: evidence for the importance of de novo ceramide synthesis in TNF-alpha signaling.
Neoplasms
Dietary Soy Protein Reduces Cardiac Lipid Accumulation and the Ceramide Concentration in High-Fat Diet-Fed Rats and ob/ob Mice.
Neoplasms
Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents.
Neoplasms
Enhanced serine palmitoyltransferase expression in proliferating fibroblasts, transformed cell lines, and human tumors.
Neoplasms
Myriocin, a serine palmitoyltransferase inhibitor, suppresses tumor growth in a murine melanoma model by inhibiting de novo sphingolipid synthesis.
Neoplasms
Spinal ceramide modulates the development of morphine antinociceptive tolerance via peroxynitrite-mediated nitroxidative stress and neuroimmune activation.
Neuroblastoma
N-(4-hydroxyphenyl)retinamide elevates ceramide in neuroblastoma cell lines by coordinate activation of serine palmitoyltransferase and ceramide synthase.
Neurodegenerative Diseases
A systematic comparison of all mutations in hereditary sensory neuropathy type I (HSAN I) reveals that the G387A mutation is not disease associated.
Non-alcoholic Fatty Liver Disease
Hepatic expression of the Sptlc3 subunit of serine palmitoyltransferase is associated with the development of hepatocellular carcinoma in a mouse model of nonalcoholic steatohepatitis.
Pancreatic Neoplasms
?-Tocotrienol induces apoptosis in pancreatic cancer cells by upregulation of ceramide synthesis and modulation of sphingolipid transport.
Peripheral Nervous System Diseases
Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause neurotoxicity, acute calcium handling abnormalities and mitochondrial dysfunction in vitro.
Peripheral Nervous System Diseases
HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship.
Pneumonia
Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression.
Pulmonary Fibrosis
Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression.
stearoyl-coa 9-desaturase deficiency
Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing beta-oxidation in skeletal muscle.
Thrombosis
Ceramidase critically affects GPVI-dependent platelet activation and thrombus formation.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
9.6
L-alanine
-
C133W mutant protein, pH not specified in the publication, temperature not specified in the publication
0.0129
stearoyl-CoA
-
pH not specified in the publication, temperature not specified in the publication
0.75
L-serine
-
wild type protein, pH not specified in the publication, temperature not specified in the publication
0.78
L-serine
-
pH not specified in the publication, temperature not specified in the publication
1.4
L-serine
-
C133W mutant protein, pH not specified in the publication, temperature not specified in the publication
0.0234
palmitoyl-CoA
-
pH not specified in the publication, temperature not specified in the publication
0.031
palmitoyl-CoA
-
pH 7.5, 37°C, recombinant mutant N100Y; pH 7.5, 37°C, recombinant mutant R378N
0.0356
palmitoyl-CoA
-
recombinant wild-type enzyme, pH 7.5, 25°C
additional information
L-alanine
-
wild-type enzyme does not utilize alanine efficiently
additional information
additional information
-
kinetics analysis, detailed overview
-
additional information
additional information
-
kinetics of the recombinant SPTLC3 subunit in HEK-293 cells, overview
-
additional information
additional information
Michaelis-Menten kinetics of wild-type and mutant enzymes
-
additional information
additional information
-
Michaelis-Menten kinetics of wild-type and mutant enzymes
-
additional information
additional information
-
Michaelis-Menten kinetics.The regenerated enzyme displays similar Km and kcat values to the purified enzyme, with only a small increase in the Km for L-serine
-
additional information
additional information
-
Michaelis-Menten kinetics of wild-type and mutant enzyme
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.083
stearoyl-CoA
-
pH not specified in the publication, temperature not specified in the publication
0.0687
palmitoyl-CoA
-
pH not specified in the publication, temperature not specified in the publication
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
6.416
stearoyl-CoA
-
pH not specified in the publication, temperature not specified in the publication
0.0881
L-serine
-
pH not specified in the publication, temperature not specified in the publication
2.936
palmitoyl-CoA
-
pH not specified in the publication, temperature not specified in the publication
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2
L-alanine
-
wild type protein, substrate serine, pH and temperature not specified in the publication
5
L-alanine
-
C133W mutant protein, substrate serine, pH and temperature not specified in the publication
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000054
(2S,3R)-2-amino-12-hydroxy-2-hydroxymethyl-3-sulfooxy-octadecanoic acid
Cricetulus griseus
-
IC50: 5.4 nM
0.00003
(2S,3R)-2-amino-12-[(Z)-hydroxyimino]-2-hydroxymethyl-3-sulfooxy-octadecanoic acid
Cricetulus griseus
-
IC50: 30 nM
0.0000032
(2S,3R)-2-amino-3,12-dihydroxy-2-hydroxymethyl-octadecanoic acid
Cricetulus griseus
-
IC50: 3.2 nM
0.0000035
(2S,3R)-2-amino-3-hydroxy-2-hydroxymethyl-12-oxo-octadecanoic acid
Cricetulus griseus
-
IC50: 3.5 nM
0.000017
(2S,3R)-2-amino-3-hydroxy-2-hydroxymethyl-12-oxo-octadecanoic acid methyl ester
Cricetulus griseus
-
IC50: 17 nM
0.000003
sulfamisterin
Cricetulus griseus
-
antibiotic derived from Pycnidiella sp., IC50: 3 nM
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.000044
0.00011
-
substrate alanine, C133W mutant protein, pH not specified in the publication, temperature not specified in the publication
0.000275
-
substrate serine, C133W mutant protein, pH not specified in the publication, temperature not specified in the publication
0.00135
-
substrate serine, wild type protein, pH not specified in the publication, temperature not specified in the publication
additional information
additional information
-
intramuscular fatty acid composition and ceramide content of wild-type and SCD1-deficiency mice, overview
additional information
-
increased enzymatic activity of SPT in reactive astrocytes of the hippocampus after kainate injections is shown; quantitation of ceramide or sphingomyelin
additional information
-
enzyme activty and ceramide synthesis in macrophages, overview
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.4
7.5 - 8
8.3
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7 - 8
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
37
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
infects the globally important marine calcifying microalga Emiliania huxleyi, gene ehv050
-
-
brenda
genetically corrected revertant strain LY-B/cLCB1 of deficient mutant LY-B; mutant defective strain LY-B
-
-
brenda
two subunits of SPT, Sptlc1 and Sptlc2, i.e. LCB1 and LCB2 or SPT1 and SPT2
-
-
brenda
-
487159, 487173, 487174, 657659, 659621, 671900, 673939, 674711, 688211, 704496, 704998, 719871, 736411
-
-
brenda
subunits SPTLC1 (O15269) and SPTLC2(O15270); subunits SPTLC1 and SPTLC2
UniProt
brenda
subunit LCB1 fragment; two genes encoding the LCB2 and LCB1 subunits of the enzyme
UniProt
brenda
subunit LCB2; two genes encoding the LCB2 and LCB1 subunits of the enzyme
UniProt
brenda
-
-
-
brenda
-
SwissProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
the cell shows very low enzyme activity due to deficiency of subunit LCB1
brenda
-
protein expression of SPT in both psoriatic epidermis and non-lesional epidermis is investigated. Expression of SPT in psoriatic epidermis is significantly less than that of the non-lesional epidermis, which is inversely correlated with PASI score
brenda
except for ovarian epithelium; except for ovarian epithelium
brenda
-
increased expression of SPT in reactive astrocytes of the hippocampus after kainate injections is shown; increased SPT enzyme activity in reactive astrocytes of the hippocampus at 2 weeks post-kainate injection
brenda
-
small subunit ssSPTa transcripts are more enriched in all organs and over 400fold more abundant in pollen than small subunit ssSPTb transcripts
brenda
additional information
-
increased SPT enzyme activity in reactive astrocytes of the hippocampus at 2 weeks post-kainate injection
brenda
leukemia Molt-4 cells; leukemia Molt-4 cells; leukemia Molt-4 cells
brenda
young, expression of LCB1; young, expression of LCB2
brenda
-
elevation of ceramide in serum lipoproteins during acute phase response to inflammation is accompanied by activation of serine-palmitoyl transferase in liver
brenda
-
elevation of ceramide in serum lipoproteins during acute phase response to inflammation is accompanied by activation of serine-palmitoyl transferase in liver
brenda
mucosal from colon, lung, prostate, stomach, thyroid, uterus, vascular tissue; mucosal from colon, lung, prostate, stomach, thyroid, uterus, vascular tissue
brenda
additional information
ubiquitous expression of subunits LCB1 and LCB2 in the plant
brenda
additional information
AtLCB1 is expressed ubiquitously in all organs of Arabidopsis thaliana examined, but the transcript level is higher in flowers and stems than in leaves and roots; AtLCB2 is expressed ubiquitously in all organs of Arabidopsis thaliana examined, but the transcript level is higher in flowers and stems than in leaves and roots
brenda
additional information
AtLCB1 is expressed ubiquitously in all organs of Arabidopsis thaliana examined, but the transcript level is higher in flowers and stems than in leaves and roots; AtLCB2 is expressed ubiquitously in all organs of Arabidopsis thaliana examined, but the transcript level is higher in flowers and stems than in leaves and roots
brenda
additional information
BcLCB2 expression is detected by RT-PCR in all nonheading Chinese cabbage organs
brenda
additional information
not in neuronal cells like astrocytes, microglia, and oligodendritic cells, not in skin and heart; not in neuronal cells like astrocytes, microglia, and oligodendritic cells, not in skin and heart
brenda
additional information
not in neuronal cells like astrocytes, microglia, and oligodendritic cells, not in skin and heart; not in neuronal cells like astrocytes, microglia, and oligodendritic cells, not in skin and heart
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
-
the Lcb1p and Lcb2p subunits of the SPT heterodimer may interact in the cytosol, as well as within the membrane and/or the lumen of the endoplasmic reticulum
brenda
-
the N-terminal is orientated to the lumenal side, the C-terminal is orienated to the cytosolic side
brenda
SPT subunit 1 is present in the endoplasmic reticulum
brenda
-
lumen, the Lcb1p and Lcb2p subunits of the SPT heterodimer may interact in the cytosol, as well as within the membrane and/or the lumen of the endoplasmic reticulum
brenda
-
the enzyme is a transmembrane protein
brenda
-
the N-termini of the small activating subunit of serine palmitoyltransferase isoforms are locatedin the cytosol, their C-termini in the lumen, and they contain a single transmembrane domain
brenda
-
the Lcb1p and Lcb2p subunits of the SPT heterodimer may interact in the cytosol, as well as within the membrane and/or the lumen of the endoplasmic reticulum
brenda
recombinant from HEK 293 cells; recombinant from HEK 293 cells
-
brenda
-
-
-
brenda
by immunoelectron microscopy it is shown that the protein is bound to the inner membrane of cells as peripheral membrane protein
-
brenda
-
by immunoelectron microscopy it is shown that the protein is bound to the inner membrane of cells as peripheral membrane protein
-
brenda
by immunoelectron microscopy it is shown that the protein is bound to the inner membrane of cells as peripheral membrane protein
-
brenda
additional information
-
ABL-mediated phosphorylation of enzyme SPTLC1 affects its endoplasmic reticulum localization
-
brenda
additional information
ABL-mediated phosphorylation of enzyme SPTLC1 affects its endoplasmic reticulum localization
-
brenda
additional information
in addition to its localization in the endoplasmic reticulum for de novo sphingolipid biosynthesis, subunit SPT1 is present in other cellular compartments, including focal adhesions where it is associated with cell morphology, immunofluorescent subcellular localization study, overview; SPT subunit 1, it binds to the focal adhesion protein vinculin
-
brenda
additional information
ABL-mediated phosphorylation of enzyme SPTLC1 affects its endoplasmic reticulum localization
-
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
malfunction
-
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
-
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
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
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
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
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
-
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
the S384D but not the S384E mutation is associated with increased 1-deoxysphingolipids formation
malfunction
-
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
-
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
-
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
-
metabolism
-
SPT is the key regulator enzyme in the ceramide de novo biosynthesis pathway
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
-
SPT catalyzes the first and rate-limiting step of the sphingolipid biosynthetic pathway
metabolism
-
SPT catalyzes the first and rate-limiting step of the sphingolipid biosynthetic pathway
metabolism
-
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 catalyzes the first and rate-limiting step in the de novo synthesis of sphingolipids
metabolism
-
SPT catalyzes the first committed step in sphingolipid biosynthesis
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
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
-
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
-
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 long chain-1 (SPTLC1) is the first enzyme of sphingolipid biosynthesis
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
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
-
serine palmitoyltransferase, composed of LCB1 and LCB2 subunits, catalyzes the primary regulatory point for sphingolipid synthesis
metabolism
-
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
-
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
-
physiological function
-
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
-
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
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
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; 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
-
the enzyme is required for de novo sphingolipid biosynthesis
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
-
the role of the small activating subunits of serine palmitoyltransferase, ssSPTs, is to increase SPT activity without compromising substrate specificity
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
-
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
-
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
-
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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additional information
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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
-
key active site residues are His159, Asp231, His234, and Lys265
Show AA Sequence and Transmembrane Helices (254 entries)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
Sphingomonas wittichii (strain RW1 / DSM 6014 / JCM 10273)
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
45000
50000
90000
480000
-
holoenzyme, gel filtration; molecular mass of SPT complex determined by gel filtration
90000
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about, recombinant wild-type enzyme and mutants V246M and G385F, gel filtration
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
heterodimer
heterotrimer
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SPT is a heterodimer of 2 highly-related subunits, LCB1 and LCB2, existing in two isozyme forms LCB2a and LCB2b, associated with a third small activating subunit, either protein ssSPTa and protein ssSPTb, the proteins have a conserved hydrophobic central domain, reside in the membrane and interact with both hLCB1 and hLCB2 subunits, overview,protein ssSPTa and protein ssSPTb are required for maximal enzyme activity. SPT subunit interaction analysis, overview
homodimer
octamer
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results show that functional SPT is not a dimer, but a higher organized complex, composed of three distinct subunits (SPTLC1, SPTLC2 and SPTLC3) with a molecular mass of 480 kDa (gel filtration). The stoichiometry of SPTLC2 and SPTLC3 in this complex is not to be fixed and is changed dynamically in dependence of the tissue specific SPTLC2 and SPTLC3 expression levels. A model of an octameric SPT structure is proposed. By Blue-native-PAGE experiments it is shown that all three SPT subunits (SPTLC1-3) are co-localized within a single SPT complex
oligomer
additional information
dimer
SPT is a heterodimer that consists of LCB1 and LCB2 subunits, which together form the active site of this enzyme
dimer
the enzyme is formed by two subunits, LCB1 and LCB2, i.e. long-chain base 1 and 2; the enzyme is formed by two subunits, LCB1 and LCB2, i.e. long-chain base 1 and 2
dimer
the enzyme is formed by two subunits, LCB1 and LCB2, i.e. long-chain base 1 and 2
dimer
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2 * 44916, electrospray mass spectrometry; 2 * 50000, SDS-PAGE
dimer
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2 * 44916, electrospray mass spectrometry; 2 * 50000, SDS-PAGE
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heterodimer
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serine palmitoyltransferase is composed of LCB1 and LCB2 subunits
heterodimer
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structure comparison with the SPT from Sphingomonas paucimobilis, overview
heterodimer
the membrane-bound heterodimer composed of two subunits hLCB1 and hLCB2a/b. The hLCB1 and hLCB2 subunits display relatively high sequence homology to each other, but only the hLCB2a subunit contains key catalytic residues including the lysine that binds pyridoxal 5'-phosphate. Subunit hLCB1 lacks these residues but contains other residues involved in catalysis,the hLCB1/hLCB2a heterodimer has a single active site
heterodimer
the membrane-bound heterodimer composed of two subunits SPTLC1 and SPTLC2
heterodimer
-
the membrane-bound heterodimer composed of two subunits hLCB1 and hLCB2a/b
oligomer
-
the enzyme is composed of three different types of subunits, the stoichiometry of SPTLC2 and SPTLC3 in this complex seems not to be fixed and is probably changed dynamically in dependence of the tissue specific SPTLC2 and SPTLC3 expression levels, overview
oligomer
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the enzyme is composed of three different types of subunits SPTLC1, SPTLC2, and SPTLC3
additional information
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reconstitution of the holoenzyme from subunits SPTLC1 and SPLC2, isolated from placenta extract, and recombinant subunit SPTLC3 forming a single multisubunit SPT complex, overview
additional information
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the small activating subunits of serine palmitoyltransferase, ssSPTs, are glycoproteins and are part of the enzyme complex
additional information
-
Lcbp1 and Lcp2 are 2 subunits of the enzyme, tightly associated and not stable independently, tsc3 protein is loosely associated to them
additional information
-
lcb1 and lcb2 are 2 subunits, both necessary for enzyme activity, complexed in ratio 1:1
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
-
the small activating subunits of serine palmitoyltransferase, ssSPTs, are glycoproteins and are part of the enzyme complex
phosphoprotein
additional information
-
carrier lipid during extraction required for activity
phosphoprotein
phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on tyrosine 164 by the fusion kinase ABL inhibits the SPTLC1 enzyme activity. ABL-mediated phosphorylation of SPTLC1 affects its endoplasmic reticulum localization
phosphoprotein
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. ABL-mediated phosphorylation of SPTLC1 affects its endoplasmic reticulum localization
phosphoprotein
the enzyme is phosphorylated at S284 regulating its substrate specificity
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CRYSTALLIZATION/commentary
ORGANISM
UNIPROT
LITERATURE
purified recombinant enzyme complexed with L-serine, sitting drop vapor diffusion method, 0.002 ml of protein solution containing 20 mg/ml SPT, 20 mM potasium phosphate, pH 7.7, and 10 mM pyridoxal 5'-phosphate, is mixed with 0.004 ml of reservoir solution containing 100 mM Tris-HCl; pH 8.5, 200 mM sodium acetate, 21.6% w/v PEG 4000, equilibration against 0.5 ml reservoir solution at 20°C, 2 weeks, Schiff base formation between L-serine and pyridoxal 5'-phosphate in the crystal, X-ray diffraction structure determination and analysis at 2.3 A resolution, structural modelling
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crystal structure of the holo-form of SPT is determined to 1.3 A resolution. Enzyme is a symmetrical homodimer with two active sites and a monomeric tertiary structure consisting of three domains. PLP cofactor is bound covalently to Lys265 as an internal aldimine/Schiff base and the active site is composed of residues from both subunits, located at the bottom of a deep cleft
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determination of the crystal structure of enzyme mutant K265A that diffract to 1.6 A resolution and contain a canonical dimer in the asymmetric unit. Crystallization of the wild-type SPT:PLP-myriocin aldimine complex is not possible, most likely due to aldimine degradation
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purified His-tagged recombinant wild-type and mutant enzymes in complex with cofactor and substrates, wild-type enzyme from 10 mM Tris, pH 7.5, 150 mM NaCl, and 0.025 mM or 0.250 mM pyridoxal 5'-phosphate, different conditions for the mutants, overview. Mass spectroscopic structure analysis, overview
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K311E
construction of mutant BcLCB2DELTAK311E that shows reduced activity compared to the wild-type enzyme
C133W
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site-directed mutagenesis, mutation of subunit SPTLC1, construction of transgenic mouse lines that ubiquitously overexpress either wild-type SPTLC1WT or mutant SPTLC1C133W in brain and liver microsomes, SPTLC1C133W mice develop age-dependent weight loss and mild sensory and motor impairments, fed SPTLC1C133W mice lose large myelinated axons in the ventral root of the spinal cord and demonstrate myelin thinning, there is also a loss of large myelinated axons in the dorsal roots, although the unmyelinated fibers are preserved, in the dorsal root ganglia, IB4 staining is diminished, whereas expression of the injury-induced transcription factor ATF3 is increased, phenotype, detailed overview
R246G
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naturally occuring mutation, comparison of de novo sphingolipid biosynthesis in wild-type LY-B cells and in LY-B cells expressing long-chain base subunit 1, LCB1, LC-ESI-MS/MS mass spectrometric analysis, overview
A182P
naturally occuring mutation in subunit LCB1 involved in hereditary sensory and autonomic neuropathy type I disease, and associated with increased synthesis of neurotoxic 1-deoxy-sphingolipids
A352V
subunit 1, naturally occuring mutation, reduced activity in cells expressing mutant protein
C133W
C133Y
G246R
expression of mutant G246R in in LYB cells, which is the same mutation that is present in LYB endogenously, neither restores canonical activity nor results in the formation of 1-deoxy-sphingolipids
G382V
I504F
I505Y
naturally occuring mutation in subunit LCB2 involved in hereditary sensory and autonomic neuropathy type I disease, and associated with increased synthesis of neurotoxic 1-deoxy-sphingolipids. The mutant shows an increased canonical activity and increased formation of C20 sphingoid base, associated with an exceptionally severe HSAN1 phenotype, where C20 sphingosine levels are also confirmed in plasma of patients
S331F
S331Y
naturally occuring mutation in subunit LCB1 involved in hereditary sensory and autonomic neuropathy type I disease, and associated with increased synthesis of neurotoxic 1-deoxy-sphingolipids.The mutant shows an increased canonical activity and increased formation of C20 sphingoid base, associated with an exceptionally severe HSAN1 phenotype, where C20 sphingosine levels are also confirmed in plasma of patients
S384A
a subunit SPTLC2 phosphorylation site mutant, the mutation has no effect n enzyme activity
S384D
a subunit SPTLC2 phosphorylation site mutant, the mutation is associated with increased 1-deoxysphingolipids formation
S384E
a subunit SPTLC2 phosphorylation site mutant, the mutation is not associated with increased 1-deoxysphingolipids formation
S384F
V359M
Y164F
site-directed mutagenesis, the mutant shows increased serine palmitoyltransferase activity compared to the wild-type enzyme. The Y164F mutation also promotes the remodeling of cellular sphingolipid content, thereby sensitizing K562 cells to apoptosis. the Y164F mutation affects SPTLC1 subcellular localization, induction of apoptosis, and sell sensitivity to imatinib
Y387F
a subunit SPTLC2 phosphorylation site mutant, the mutation has no effect n enzyme activity
Y387F/S384A
a subunit SPTLC2 phosphorylation sites mutant, the mutation has no effect n enzyme activity
DELTA2-9SPT
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mutant bearing deleted residues from Ala2 to Pro9: Km values are not significantly changed compared to wild-type
G268V
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site-directed mutagenesis, the mutation perturbs the pyridoxal 5'-phosphate cofactor binding and reduces the affinity for both substrates, inactive mutant, the protein is expressed in a completely insoluble form, structure homology modeling of the mutant enzyme using the Sp SPT PLP-L-serine external aldimine structure, PDB ID 2W8J
G385F
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site-directed mutagenesis, the mutation perturbs the pyridoxal 5'-phosphate cofactor binding, reduces the affinity for both substrates, decreases the enzyme activity, soluble protein
H159A
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site-directed mutagenesis, the mutant shows reduced activity and still forms the pyridoxal 5'-phosphate-L-serine-aldimine reaction intermediate
H159F
K265A
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site-directed mutagenesis, the mutant is unable to bind pyridoxal 5'-phosphate, structure of a SPT K265A:PLP-myriocin external aldimine complex, molecular replacement study
N100C
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site-directed mutagenesis, the mutation mimics the wild-type human enzyme and is fully active, crystal structure analysis
N100W
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site-directed mutagenesis, the mutation mimics the mutation in the human enzyme causing hereditary sensory autonomic neuropathy type 1, the mutant shows reduced activity compared to the wild-type enzyme. The mutation affects the chemistry of the pyridoxal 5'-phosphate, crystal structure analysis
N100Y
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site-directed mutagenesis, N100Y is less able to stabilize a quinonoid intermediate, the mutation mimics the mutation in the human enzyme causing hereditary sensory autonomic neuropathy type 1, the mutant shows reduced activity compared to the wild-type enzyme. The mutation affects the chemistry of the pyridoxal 5'-phosphate. The L-Ser external aldimine structure N100Y reveals significant differences that hinder the movement of a catalytically important Arg378 residue into the active site, crystal structure analysis
R378A
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site-directed mutagenesis, crystal structure analysis, the mutant is less able to stabilize a quinonoid intermediate
R378N
V246M
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site-directed mutagenesis, the mutation perturbs the pyridoxal 5'-phosphate cofactor binding, reduces the affinity for both substrates, decreases the enzyme activity, soluble protein
N100C
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site-directed mutagenesis, the mutation mimics the wild-type human enzyme and is fully active, crystal structure analysis
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N100W
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site-directed mutagenesis, the mutation mimics the mutation in the human enzyme causing hereditary sensory autonomic neuropathy type 1, the mutant shows reduced activity compared to the wild-type enzyme. The mutation affects the chemistry of the pyridoxal 5'-phosphate, crystal structure analysis
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N100Y
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site-directed mutagenesis, N100Y is less able to stabilize a quinonoid intermediate, the mutation mimics the mutation in the human enzyme causing hereditary senso