Sphingolipids are derivatives of long chain sphingoid bases such as sphingosine (trans-1,3-dihydroxy 2-amino-4-octadecene), an 18-carbon unsaturated amino alcohol which is the most abundant sphingoid base in mammals. Amide linkage of a fatty acid to sphingosine yields ceramides. Esterification of phosphocholine to ceramides yields sphingomyelin, and ceramide glycosylation yields glycosylceramides. Introduction of sialic acid residues yields gangliosides. These molecules appear to be essential components of cell membranes, and intermediates in the pathways of sphingolipid synthesis and breakdown modulate processes including apoptosis and T cell trafficking.
While sphingolipids are abundant in a wide variety of foodstuffs, these dietary molecules are mostly degraded by the intestinal flora and intestinal enzymes. The body primarily depends on de novo synthesis for its sphingolipid supply (Hannun and Obeid 2008; Merrill 2002). De novo synthesis proceeds in four steps: the condensation of palmitoyl-CoA and serine to form 3-ketosphinganine, the reduction of 3-ketosphinganine to sphinganine, the acylation of sphinganine with a long-chain fatty acyl CoA to form dihydroceramide, and the desaturation of dihydroceramide to form ceramide.<p>Other sphingolipids involved in signaling are derived from ceramide and its biosynthetic intermediates. These include sphinganine (dihydrosphingosine) 1-phosphate, phytoceramide, sphingosine, and sphingosine 1-phosphate.<p>Sphingomyelin is synthesized in a single step in the membrane of the Golgi apparatus from ceramides generated in the endoplasmic reticulum (ER) membrane and transferred to the Golgi by CERT (ceramide transfer protein), an isoform of COL4A3BP that is associated with the ER membrane as a complex with PPM1L (protein phosphatase 1-like) and VAPA or VAPB (VAMP-associated proteins A or B). Sphingomyelin synthesis appears to be regulated primarily at the level of this transport process through the reversible phosphorylation of CERT (Saito et al. 2008).
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Bernardo K, Hurwitz R, Zenk T, Desnick RJ, Ferlinz K, Schuchman EH, Sandhoff K.; ''Purification, characterization, and biosynthesis of human acid ceramidase.''; PubMedEurope PMCScholia
Mao C, Xu R, Szulc ZM, Bielawska A, Galadari SH, Obeid LM.; ''Cloning and characterization of a novel human alkaline ceramidase. A mammalian enzyme that hydrolyzes phytoceramide.''; PubMedEurope PMCScholia
Keller MA, Watschinger K, Golderer G, Maglione M, Sarg B, Lindner HH, Werner-Felmayer G, Terrinoni A, Wanders RJ, Werner ER.; ''Monitoring of fatty aldehyde dehydrogenase by formation of pyrenedecanoic acid from pyrenedecanal.''; PubMedEurope PMCScholia
Schmidt B, Selmer T, Ingendoh A, von Figura K.; ''A novel amino acid modification in sulfatases that is defective in multiple sulfatase deficiency.''; PubMedEurope PMCScholia
Stein C, Hille A, Seidel J, Rijnbout S, Waheed A, Schmidt B, Geuze H, von Figura K.; ''Cloning and expression of human steroid-sulfatase. Membrane topology, glycosylation, and subcellular distribution in BHK-21 cells.''; PubMedEurope PMCScholia
Marchesini N, Luberto C, Hannun YA.; ''Biochemical properties of mammalian neutral sphingomyelinase 2 and its role in sphingolipid metabolism.''; PubMedEurope PMCScholia
Liu H, Sugiura M, Nava VE, Edsall LC, Kono K, Poulton S, Milstien S, Kohama T, Spiegel S.; ''Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform.''; PubMedEurope PMCScholia
Jacoby E, Bouhelal R, Gerspacher M, Seuwen K.; ''The 7 TM G-protein-coupled receptor target family.''; PubMedEurope PMCScholia
Liu YY, Hill RA, Li YT.; ''Ceramide glycosylation catalyzed by glucosylceramide synthase and cancer drug resistance.''; PubMedEurope PMCScholia
Rizzo WB, Lin Z, Carney G.; ''Fatty aldehyde dehydrogenase: genomic structure, expression and mutation analysis in Sjögren-Larsson syndrome.''; PubMedEurope PMCScholia
Conzelmann E, Sandhoff K.; ''Purification and characterization of an activator protein for the degradation of glycolipids GM2 and GA2 by hexosaminidase A.''; PubMedEurope PMCScholia
Lukatela G, Krauss N, Theis K, Selmer T, Gieselmann V, von Figura K, Saenger W.; ''Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis.''; PubMedEurope PMCScholia
Vaccaro AM, Salvioli R, Muscillo M, Renola L.; ''Purification and properties of arylsulfatase C from human placenta.''; PubMedEurope PMCScholia
Fujii T, Kobayashi T, Honke K, Gasa S, Ishikawa M, Shimizu T, Makita A.; ''Proteolytic processing of human lysosomal arylsulfatase A.''; PubMedEurope PMCScholia
Arylsulfatase A (ARSA) (Stein et al. 1989) hydrolyses a sulfatide (a cerebroside 3-sulfate) to form a cerebroside and sulfate. ARSA is present in the lysosomal lumen and comprises two chains, component B and C linked by disulphide bonds (Fujii et al. 1992). The conversion to 3-oxoalanine (formylglycine, FGly) of a cysteine residue is critical for catalytic activity in all eukaryotes (Chruszcz et al. 2003, Lukatela et al. 1998). Defects in ARSA are a cause of leukodystrophy metachromatic (MLD) (MIM:250100), characterized by lysosomal storage of cerebroside-3-sulfate in neural and non-neural tissues (Gieselmann et al. 1991, Polten et al. 1991). Arylsulfatase A activity is reduced in multiple sulfatase deficiency (MSD) (MIM:272200), a disorder characterized by decreased activity of sulfatases. The defect is due to the lack of post-translational modification of the critical cysteine needed for activity (Schmidt et al. 1995).
Membrane-bound ectonucleotide pyrophosphatase/phosphodiesterase 7 (ENPP7) mediates the hydrolysis of sphingomyelin to ceramide and choline phosphate (Duan et al. 2003, Wu et al. 2005).
Galactosylceramide sulfotransferase (GAL3ST1) (Honke et al. 1997) catalyses the transfer of sulfate from the sulfate donor PAPS to glycosphingolipids. A good substrate for this enzyme is galactosylceramide (GalCer) (Honke et al. 1996).
Beta-galactosidase can hydrolyse a galactose moeity from globosides to form cerebrosides. Here, lactosylceramide is hydrolysed to glucosylceramide (Asp et al. 1969).
Ceramide glucosyltransferase (UGCG) catalyses the first glycosylation step in glycosphingolipid biosynthesis by the transfer of glucose to ceramide (Ichikawa et al. 1996).
Human glucosylceramidase (GBA) hydrolyses the glucosidic bond of glucocerebrosides to form ceramide (Dinur et al. 1986). GBA requires a low weight, non-enzymatic protein (one of the sphingolipids activator proteins) called Saposin-C (SAP-C) which acts with GBA to form an activated complex (Salvioli et al. 2000). Defects in GBA are the cause of Gaucher disease (GD) (MIM:230800), the most common glycolipid storage disorder, characterized by storage of glucocerebroside in the liver, spleen, and marrow (Beutler & Gelbart 1996).
Human glucosylceramidase 3 (GBA3) hydrolyses the glucosidic bond of glucocerebrosides to form ceramide in the cytosol. GBA3 may be involved in the intestinal absorption and metabolism of dietary flavonoid glycosides (Berrin et al. 2002, Nemeth et al. 2003).
The Ganglioside GM2 activator protein (GM2A) is a small lysosomal lipid transfer protein that extracts a single GM2 molecule from membranes and presents it in a soluble form to beta-hexosaminidase A for cleavage (Wright et al. 2003). Defects in GM2A are the cause of GM2-gangliosidosis type AB (GM2GAB) (MIM:272750), also known as Tay-Sachs disease AB variant (Schroeder et al. 1991).
Steryl sulfatase (formerly arylsulfatase C, ARSC) hydrolyses sulfate from steroid sulfates (Noel et al. 1983, Vaccaro et al. 1987, Suzuki et al. 1992). It is located on the ER membrane (Stein et al. 1989) and functions as a homodimer, using calcium as a cofactor. Defects in STS are the cause of ichthyosis X-linked (IXL) (MIM:308100), a keratinisation disorder (Basler et al. 1992, Alperin & Shapiro 1997).
Sialidase-3 (NEU3) cleaves Neu5Ac from GM3 in the plasma membrane. NEU3 is thought to play a role in modulating the ganglioside content of the lipid bilayer (Monti et al. 2000).
Human glucosylceramidase 2 (GBA2) hydrolyses the glucosidic bond of glucocerebrosides to form ceramide at the plasma membrane (Matern et al. 2001, Boot et al. 2007).
Galactocerebrosidase (GALC) hydrolyses the galactosyl moiety from galactocerebroside (also called galactosylceramide, GalCer) to form ceramide (Sakai et al. 1994). Defects in GALC are the cause of leukodystrophy globoid cell (GLD) (MIM:245200), also called Krabbe disease (Wenger et al. 1997).
Alpha-galactosidase A (GLA) (Bishop et al. 1986) removes the terminal galactose residue from glycolipids or glycoproteins resulting in galactose and an alcohol. An example is the Fabry disease substrate globotriaosylceramide (Gb3Cer) which is hydrolysed to form galactose and lactosylceramide. GLA functions as a homodimer (Garman & Garboczi 2004) and defects in this enzyme lead to Fabry disease (FD) (MIM:301500), a rare X-linked sphingolipidosis disease where glycolipids such as GB3 accumulate in many tissues (Garman & Garboczi 2004, Eng et al. 1993). Multiple mutations in GLA can cause the disease symptoms of Fabry disease (Shabeer et al. 2006).
There are two major forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988, Mahuran et al. 1988). Both are able to cleave GalNAc from globoside (a glycosphingolipid with more than one sugar attached as the side chain). Here, globoside is cleaved to form Gb3Cer (a globotriaosylceramide) (Mark et al. 2003).
The mammalian brain-specific, Mg2+-dependent, neutral sphingomyelin phosphodiesterases 2 (Tomiuk et al. 1998, Hofmann et al. 2000) and 3 (Marchesini et al. 2003) (SMPD2 and 3) hydrolyse sphingomyelin (SPHM) to ceramide (CERA) at the plasma membrane.
Neutral ceramidase (ASAH2) is an enzyme localised to the plasma membrane that catalyses the hydrolysis of ceramide to sphingosine and free fatty acid (Hwang et al. 2005, Galadari et al. 2006).
Acid ceramidase (ASAH1) is a lysosomal enzyme that catalyses the hydrolysis of ceramide to sphingosine and free fatty acid. It functions as a heterodimer of one alpha and one beta subunit (Bernardo et al. 1995). Defects in ASAH1 are the cause of Farber lipogranulomatosis (FL) (MIM:228000), also called Farber disease (FD) (Zhang et al. 2000, Koch et al. 1996).
Gangliosides are glycosphingolipids in which oligosaccharide chains containing N-acetylneuraminic acid (NeuNAc) are attached to a ceramide. The prototypical ganglioside GM1 can be hydrolysed to the GM2 ganglioside by beta-galactosidase (GLB1), cleaving off the terminal galactose (Asp et al. 1969). Defects in GLB1 causes the lysosomal storage diseases GM1-gangliosidosis (Yoshida et al. 1991) and Morquio syndrome B (Oshima et al. 1991).
Beta-hexosaminidase A (bHEXA) cleaves the terminal N-acetyl galactosamine from GM2 ganglioside to form GM3 ganglioside (Lemieux et al. 2006). There are two major forms of bHEX: hexosaminidase A and B. The A form is a trimer of the subunits alpha, beta A and beta B. The B form is a tetramer of 2 beta A and 2 beta B subunits (O'Dowd et al. 1988). Only form A is active towards GM2 ganglioside (Conzelmann & Sandhoff 1979). Defects in the two subunits cause lysosomal storage diseases marked by the accumulation of GM2 ganglioside in neuronal cells. Defects in the alpha subunits are the cause of GM2-gangliosidosis type 1 (GM2G1) (MIM:272800), also known as Tay-Sachs disease (Nakano et al. 1988). Defects in the beta subunits are the cause of GM2-gangliosidosis type 2 (GM2G2) (MIM:268800), also known as Sandhoff disease (Banerjee et al. 1991).
Ceramide kinase (CERK) mediates the phosphorylation of ceramide (CERA) to the lipid second messenger, ceramide 1-phosphate (C1P) (Sugiura et al. 2002).
Sialidases (NEU, neuraminidases) hydrolyze sialic acids (N-acetylneuramic acid, Neu5Ac, NANA) to produce asialo compounds, a step in the degradation process of glycoproteins and gangliosides. NEU1 and NEU4 hydrolyse NANA in the lysosomal lumen. NEU1 is active in a multienzyme complex comprising cathepsin A protective protein (CTSA) and beta-galactosidase (Bonten et al. 1996, Rudenko et al. 1995). Defects in NEU1 are the cause of Sialidosis (MIM:256550) (Bonten et al. 1996). CTSA is thought to exert a protective function necessary for stability and activity of these enzymes (Galjart et al. 1988). Defects in CTSA are the cause of galactosialidosis (GSL, MIM:256540) (Zhou et al. 1991). NEU4 is also a lysosmal sialidase which, unlike NEU1, doesn't require association with other proteins for enzymatic activity. Isoform 2 is thought to be the lysosomal sialidase (Seyrantepe et al. 2004).
Sphingomyelin phosphodiesterase (SMPD1), also called acid sphingomyelinase (ASM), is a lysosomal phosphodiesterase that hydrolyses sphingomyelin to ceramide and phosphocholine (Schuchman et al. 1991, Schuchman et al. 1992). Defects in SMPD1 are the cause of two types of Niemann-Pick disease. Type A (NPDA, Niemann-Pick disease classical infantile form) (MIM:257200) (Ferlinz et al. 1991) and type B (NPDB, Niemann-Pick disease visceral form) (MIM:607616) (Rodriguez-Pascau et al. 2009).
The sulfatase-modifying factor 1 (SUMF1, also called C-alpha-formylglycine-generating enzyme, FGE) (Preusser-Kunze et al. 2005, Cosma et al. 2003, Landgrebe et al. 2003) oxidises the critical cysteine residue in arylsulfatases to an active site 3-oxoalanine residue thus confering sulfatase activity (Roeser et al. 2006). Defects in SUMF1 cause multiple sulfatase deficiency (MSD) (MIM:272200), an impairment of arylsulfatase activity due to defective post-translational modification of the cysteine residue (Cosma et al. 2003, Dierks et al, 2003). This post-translational modification is thought to be highly conserved in eukaryotes (Selmer et al. 1996, von Figura et al. 1998). SUMF1 is active as either a monomer or a homodimer. A monomer is described in this reaction.
ACER3 (alkaline ceramidase 3) catalyzes the hydrolysis of phytoceramide to yield a free fatty acid (annotated here as stearate) and phytosphingosine. ACER3 mRNA is widely expressed in the body, although most abundant in placenta. Immunofluoresence studies of cultured cells over-expressing GFP-tagged protein suggest its localization to membranes of the endoplasmic reticulum (annotated here) and also the Golgi apparatus (Mao et al. 2001).
Cytosolic PRKD1 (protein kinase D1) catalyzes the phosphorylation of serine residue 132 of “CERT� (ceramide transfer protein) (Fugmann et al. 2007).
Cytosolic CSNK1G2 (casein kinase 1, gamma 2) catalyzes the phosphorylation of multiple serine and threonine residues of “CERT� (ceramide transfer protein) already phosphorylated on serine-132 (Tomishige et al. 2009). This reaction has the effect of inhibiting ceramide transport from the endoplasmic reticulum to the Golgi apparatus as multiphospho-CERT is unable to bind ceramides or associate with the Golgi membrane.
KDSR (3-ketodihydrosphingosine reductase) enzyme associated with the cytosolic face of the endoplasmic reticulum membrane catalyzes the reduction of 3-ketosphinganine by NADPH to form sphinganine (dihydrosphingosine) (Kihara and Igarashi 2004).
ACER1 (alkaline ceramidase 1), associated with the endoplasmic reticulum membrane, catalyzes the reversible hydrolysis of ceramide to yield a free fatty acid (annotated here as stearate) and sphingosine (Sun et al. 2008).
PPAP2A, B, and C (phosphatidate phosphohydrolase type 2A, B, and C) enzymes associated with the plasma membrane catalyze the hydrolysis of cytosolic sphingosine 1-phosphate to form sphingosine and orthophosphate (Roberts et al 1998).
“CERT� (ceramide transfer protein), associated with the cytosolic face of the endoplasmic reticulum (ER) in a complex with VAPA or VAPB (VAMP-associated proteins A or B) (Kawano et al. 2006) and PPM1L (protein phosphatase 1-like) (Saito et al. 2008), can bridge the gap between the ER and the Golgi apparatus via its PH domain and transfer a molecule of ceramide extracted from the ER membrane to the Golgi (Hanada et al. 2003; Saito et al. 2008). “CERT�-mediated ceramide transfer is positively regulated by OSBP (oxysterol binding protein), by an unknown mechanism (Perry and Ridgway 2006).
“CERT� (ceramide transfer protein), an isoform of COL4A3BP, mediates the translocation of ceramides from the endoplasmic reticulum (ER) membrane to the membrane of the Golgi apparatus. Immunoprecipitation experiments suggest that “CERT� is associated with the ER membrane as part of a complex with PPM1L (protein phosphatase 1-like) (Saito et al. 2008) and VAPA or VAPB (VAMP-associated proteins A or B) (Kawano et al. 2006). The carboxyterminal “START� domain of “CERT� protein specifically binds ceramides (Hanada et al. 2003; Kudo et al. 2008).
LASS (“longevity assurance homolog�, also known as ceramide synthase, CerS) enzymes associated with the endoplasmic reticulum membrane catalyze the reaction of sphinganine (dihydrosphingosine) and a long-chain fatty acyl CoA such as stearyl-CoA to form a dihydroceramide and CoASH (Pewzner-Jung et al. 2006). Six human LASS genes have been identified; they differ in the identities of the fatty acyl CoAs that they use most efficiently as substrates (Lahiri and Futerman 2005; Laviad et al. 2008).
Multiphospho-CERT retains its affinity for VAPA or VAPB (VAMP-associated proteins A or B) and PPM1L (protein phosphatase 1-like) in the endoplasmic reticulum membrane, and can associate with them to form a membrane-associated complex (Saito et al. 2008).
DEGS2 (sphingolipid C4-hydroxylase 2 / “degenerative spermatocyte homolog 2�) enzyme associated with the cytosolic face of the endoplasmic reticulum catalyzes the hydroxylation of dihydroceramide to form phytoceramide (Mizutani et al. 2004). Sequence similarity to the bifunctional mouse DEGS2 enzyme suggests that human DEGS2 protein might also catalyze the C4-dehydrogenation of dihydroceramide, but this hypothesis has not been tested experimentally.
DEGS1 (sphingolipid delta(4)-desaturase 1 / “degenerative spermatocyte homolog 1�) enzyme associated with the cytosolic face of the endoplasmic reticulum catalyzes the desaturation of dihydroceramide to form ceramide (Cadena et al. 1997; Ternes et al. 2002). The stoichiometry and cofactor requirements of the reaction are inferred from those observed in studies of ceramide synthesis in vitro catalyzed by rat liver microsomes (Michel et al. 1997). DEGS1 may also catalyze the 4-hydroxylation of dihydroceramide to form 4-hydroxysphinganine, but with low efficiency.
SGMS2 (sphingomyelin synthase 2) catalyzes the reversible reaction of phosphatidylcholine and ceramide to form sphingomyelin and diacylglycerol. Most SGMS2 actitiy is associated with the plasma membrane, although active enzyme is also present in the Golgi apparatus (Tafesse et al. 2007; Villani et al. 2008; Ding et al. 2008). Phosphatidylcholine was identified as the source of the phosphocholine moiety donated to ceramide in this reaction, in studies of the mouse enzyme in the 1970s (Diringer et al. 1972; Ullman and Radin 1974). Palmitoylation of at least two cysteine residues near the carboxy terminus of SGMS2 appears to be required for association of the protein with the plasma membrane (Tani and Kuge 2009). SGMS2 is widely expressed in the body and while studies of cultured cells indicate that this is a minor source of cellular sphingomyelin, blockage of SGMS2 activity inhibits cell growth (Huitema et al. 2004; Tafesse et al. 2007).
PPM1L (protein phosphatase 1-like) catalyzes the dephosphorylation of multiphospho-“CERT� (ceramide transfer protein) that is complexed with it in the endoplasmic reticulum membrane (Saito et al. 2008).
“CERT� (ceramide transfer protein) can dissociate from its complex in the endoplasmic reticulum membrane with VAPA or VAPB (VAMP-associated proteins A or B) and PPM1L (protein phosphatase 1-like) and is released into the cytosol (Kawano et al. 2006).
PPAP2A (phosphatidate phosphohydrolase type 2A) enzyme associated with the plasma membrane catalyzes the hydrolysis of extracellular sphingosine 1-phosphate to form sphingosine and orthophosphate (Roberts et al 1998).
SGPL1 (sphingosine-1-phosphate lyase 1), associated with the endoplasmic reticulum membrane, catalyzes the cleavage of cytosolic sphinganine (dihydrosphingosine) 1-phosphate to form phosphoethanolamine and hexadecanal (Van Veldhoven et al. 2000; Fyrst and Saba 2008).
SPHK1 and 2 (sphingosine kinases 1 and 2) catalyze the reaction of sphingosine and ATP to form sphingosine 1-phosphate and ADP. Both enzymes are found in the cytosol (although they are also present in membrane-associated forms). Both enzymes also catalyze the phosphorylation of sphinganine (dihydrosphingosine) (Liu et al. 2000; Nava et al. 2000; Pitson et al. 2000).
SGPP1 and 2 (sphingosine-1-phosphate phosphatase 1 and 2) enzymes associated with the endoplasmic reticulum membrane catalyze the hydrolysis of cytosolic sphinganine 1-phosphate to form sphinganine (dihydrosphingosine) and orthophosphate (Johnson et al. 2003; Ogawa et al. 2003).
SGPL1 (sphingosine-1-phosphate lyase 1), associated with the endoplasmic reticulum membrane, catalyzes the cleavage of cytosolic sphingosine 1-phosphate to form phosphoethanolamine and hexadec-2-enal (Van Veldhoven et al. 2000; Fyrst and Saba 2008).
SGPP1 and 2 (sphingosine-1-phosphate phosphatase 1 and 2) enzymes associated with the endoplasmic reticulum membrane catalyze the hydrolysis of cytosolic sphingosine 1-phosphate to form sphingosine and orthophosphate (Johnson et al. 2003; Ogawa et al. 2003).
SPTLC (serine palmitoyltransferase) enzyme complexes associated with the endoplasmic reticulum membrane catalyze the reaction of palmitoyl-CoA and serine to form 3-ketosphinganine. SPTLC2 and SPTLC3 polypeptides exhibit enzyme activity when either is complexed with SPTLC1. SPTLC1 and 2 are abundant and widely expressed in human tissues, while SPTLC3 is expressed only in a smaller group of tissues and at variable levels. Results of studies in which siRNA was used to reduce levels of the three endogenous mRNAs differentially suggest that SPTLC2 and 3 both encode active serine palmitoyltransferases (Hornemann et al. 2006). Neither human nor mouse SPTLC1 has detectable enzyme activity, but the protein has an essential function, as mutations that disrupt it are associated with hereditary neuropathy (Dawkins et al. 2001). Studies of mouse and hamster proteins support the hypothesis that heterodimerization with SPTLC1 stabilizes SPTLC2 (or 3) and mediates its localization to the endoplasmic reticulum membrane (Hanada et al. 2000; Weiss and Stoffel 1997). Analyses of complexes extracted from human placenta, and of cultured human cells over-expressing various SPTLC constructs, suggest that these heterodimers may associate into larger complexes (Hanada et al. 2000; Weiss and Stoffel 1997; Hornemann et al. 2006, 2007).
SPHK1 and 2 (sphingosine kinases 1 and 2) each catalyze the reaction of sphinganine (dihydrosphingosine) and ATP to form dihydrosphingosine 1-phosphate and ADP. Both enzymes are found in the cytosol (although they are also present in membrane-associated forms). Both enzymes also catalyze the phosphorylation of sphingosine (Liu et al. 2000; Nava et al. 2000; Pitson et al. 2000).
ACER2 (alkaline ceramidase 2), associated with the membrane of the Golgi apparatus, catalyzes the hydrolysis of ceramide to yield a free fatty acid (annotated here as stearate) and sphingosine. ACER2 mRNA is widely expressed in the body, although only at low levels except in placenta (Xu et al. 2006).
SGMS1 (sphingomyelin synthase 1) associated with the membrane of the Golgi apparatus catalyzes the reversible reaction of phosphatidylcholine and ceramide to form sphingomyelin and diacylglycerol. Phosphatidylcholine was identified as the source of the phosphocholine moiety donated to ceramide in this reaction, in studies of the mouse enzyme in the 1970s (Diringer et al. 1972; Ullman and Radin 1974). SGMS1 is widely expressed in the body and studies of cultured cells indicate that this reaction provides the major source of cellular sphingomyelin (Yamaoka et al. 2004; Huitema et al. 2004; Tafesse et al. 2007).
While sphingolipids are abundant in a wide variety of foodstuffs, these dietary molecules are mostly degraded by the intestinal flora and intestinal enzymes. The body primarily depends on de novo synthesis for its sphingolipid supply (Hannun and Obeid 2008; Merrill 2002). De novo synthesis proceeds in four steps: the condensation of palmitoyl-CoA and serine to form 3-ketosphinganine, the reduction of 3-ketosphinganine to sphinganine, the acylation of sphinganine with a long-chain fatty acyl CoA to form dihydroceramide, and the desaturation of dihydroceramide to form ceramide.<p>Other sphingolipids involved in signaling are derived from ceramide and its biosynthetic intermediates. These include sphinganine (dihydrosphingosine) 1-phosphate, phytoceramide, sphingosine, and sphingosine 1-phosphate.<p>Sphingomyelin is synthesized in a single step in the membrane of the Golgi apparatus from ceramides generated in the endoplasmic reticulum (ER) membrane and transferred to the Golgi by CERT (ceramide transfer protein), an isoform of COL4A3BP that is associated with the ER membrane as a complex with PPM1L (protein phosphatase 1-like) and VAPA or VAPB (VAMP-associated proteins A or B). Sphingomyelin synthesis appears to be regulated primarily at the level of this transport process through the reversible phosphorylation of CERT (Saito et al. 2008).
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PPM1L
VAPA/B trimerCERT PPM1L
VAPA/B trimerPPM1L
VAPA/B trimerAnnotated Interactions
PPM1L
VAPA/B trimerPPM1L
VAPA/B trimerPPM1L
VAPA/B trimerDefects in ARSA are a cause of leukodystrophy metachromatic (MLD) (MIM:250100), characterized by lysosomal storage of cerebroside-3-sulfate in neural and non-neural tissues (Gieselmann et al. 1991, Polten et al. 1991). Arylsulfatase A activity is reduced in multiple sulfatase deficiency (MSD) (MIM:272200), a disorder characterized by decreased activity of sulfatases. The defect is due to the lack of post-translational modification of the critical cysteine needed for activity (Schmidt et al. 1995).
PPM1L
VAPA/B trimerPPM1L
VAPA/B trimer