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).
View original pathway at Reactome.</div>
Dierks T, Schmidt B, Borissenko LV, Peng J, Preusser A, Mariappan M, von Figura K.; ''Multiple sulfatase deficiency is caused by mutations in the gene encoding the human C(alpha)-formylglycine generating enzyme.''; PubMedEurope PMCScholia
Landgrebe J, Dierks T, Schmidt B, von Figura K.; ''The human SUMF1 gene, required for posttranslational sulfatase modification, defines a new gene family which is conserved from pro- to eukaryotes.''; PubMedEurope PMCScholia
Krut O, Wiegmann K, Kashkar H, Yazdanpanah B, Krönke M.; ''Novel tumor necrosis factor-responsive mammalian neutral sphingomyelinase-3 is a C-tail-anchored protein.''; PubMedEurope PMCScholia
Michel C, van Echten-Deckert G, Rother J, Sandhoff K, Wang E, Merrill AH.; ''Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide.''; PubMedEurope PMCScholia
Lahiri S, Futerman AH.; ''LASS5 is a bona fide dihydroceramide synthase that selectively utilizes palmitoyl-CoA as acyl donor.''; PubMedEurope PMCScholia
Tani M, Kuge O.; ''Sphingomyelin synthase 2 is palmitoylated at the COOH-terminal tail, which is involved in its localization in plasma membranes.''; PubMedEurope PMCScholia
Kitamura T, Naganuma T, Abe K, Nakahara K, Ohno Y, Kihara A.; ''Substrate specificity, plasma membrane localization, and lipid modification of the aldehyde dehydrogenase ALDH3B1.''; PubMedEurope PMCScholia
Yoshida K, Oshima A, Shimmoto M, Fukuhara Y, Sakuraba H, Yanagisawa N, Suzuki Y.; ''Human beta-galactosidase gene mutations in GM1-gangliosidosis: a common mutation among Japanese adult/chronic cases.''; PubMedEurope PMCScholia
Chruszcz M, Laidler P, Monkiewicz M, Ortlund E, Lebioda L, Lewinski K.; ''Crystal structure of a covalent intermediate of endogenous human arylsulfatase A.''; PubMedEurope PMCScholia
Preusser-Kunze A, Mariappan M, Schmidt B, Gande SL, Mutenda K, Wenzel D, von Figura K, Dierks T.; ''Molecular characterization of the human Calpha-formylglycine-generating enzyme.''; PubMedEurope PMCScholia
Kudo N, Kumagai K, Tomishige N, Yamaji T, Wakatsuki S, Nishijima M, Hanada K, Kato R.; ''Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide.''; PubMedEurope PMCScholia
Dawkins JL, Hulme DJ, Brahmbhatt SB, Auer-Grumbach M, Nicholson GA.; ''Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I.''; PubMedEurope PMCScholia
Németh K, Plumb GW, Berrin JG, Juge N, Jacob R, Naim HY, Williamson G, Swallow DM, Kroon PA.; ''Deglycosylation by small intestinal epithelial cell beta-glucosidases is a critical step in the absorption and metabolism of dietary flavonoid glycosides in humans.''; PubMedEurope PMCScholia
Kapitonov D, Yu RK.; ''Cloning, characterization, and expression of human ceramide galactosyltransferase cDNA.''; PubMedEurope PMCScholia
Bishop DF, Calhoun DH, Bernstein HS, Hantzopoulos P, Quinn M, Desnick RJ.; ''Human alpha-galactosidase A: nucleotide sequence of a cDNA clone encoding the mature enzyme.''; PubMedEurope PMCScholia
Rudenko G, Bonten E, d'Azzo A, Hol WG.; ''Three-dimensional structure of the human 'protective protein': structure of the precursor form suggests a complex activation mechanism.''; PubMedEurope PMCScholia
Nagata Y, Yamashiro S, Yodoi J, Lloyd KO, Shiku H, Furukawa K.; ''Expression cloning of beta 1,4 N-acetylgalactosaminyltransferase cDNAs that determine the expression of GM2 and GD2 gangliosides.''; PubMedEurope PMCScholia
Suzuki T, Hirato K, Yanaihara T, Kadofuku T, Sato T, Hoshino M, Yanaihara N.; ''Purification and properties of steroid sulfatase from human placenta.''; PubMedEurope PMCScholia
Sillén A, Anton-Lamprecht I, Braun-Quentin C, Kraus CS, Sayli BS, Ayuso C, Jagell S, Küster W, Wadelius C.; ''Spectrum of mutations and sequence variants in the FALDH gene in patients with Sjögren-Larsson syndrome.''; PubMedEurope PMCScholia
Giordano F, Giordano F, Saheki Y, Idevall-Hagren O, Colombo SF, Pirruccello M, Milosevic I, Gracheva EO, Bagriantsev SN, Borgese N, De Camilli P.; ''PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins.''; PubMedEurope PMCScholia
Tuuf J, Mattjus P.; ''Human glycolipid transfer protein--intracellular localization and effects on the sphingolipid synthesis.''; PubMedEurope PMCScholia
Gieselmann V, Fluharty AL, Tønnesen T, Von Figura K.; ''Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy.''; PubMedEurope PMCScholia
Johnson KR, Johnson KY, Becker KP, Bielawski J, Mao C, Obeid LM.; ''Role of human sphingosine-1-phosphate phosphatase 1 in the regulation of intra- and extracellular sphingosine-1-phosphate levels and cell viability.''; PubMedEurope PMCScholia
Yamaoka S, Miyaji M, Kitano T, Umehara H, Okazaki T.; ''Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells.''; PubMedEurope PMCScholia
Garman SC, Garboczi DN.; ''The molecular defect leading to Fabry disease: structure of human alpha-galactosidase.''; PubMedEurope PMCScholia
Ding T, Li Z, Hailemariam T, Mukherjee S, Maxfield FR, Wu MP, Jiang XC.; ''SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis.''; PubMedEurope PMCScholia
Boot RG, Verhoek M, Donker-Koopman W, Strijland A, van Marle J, Overkleeft HS, Wennekes T, Aerts JM.; ''Identification of the non-lysosomal glucosylceramidase as beta-glucosidase 2.''; PubMedEurope PMCScholia
Hannun YA, Obeid LM.; ''Principles of bioactive lipid signalling: lessons from sphingolipids.''; PubMedEurope PMCScholia
Schuchman EH, Suchi M, Takahashi T, Sandhoff K, Desnick RJ.; ''Human acid sphingomyelinase. Isolation, nucleotide sequence and expression of the full-length and alternatively spliced cDNAs.''; PubMedEurope PMCScholia
Schröder M, Schnabel D, Suzuki K, Sandhoff K.; ''A mutation in the gene of a glycolipid-binding protein (GM2 activator) that causes GM2-gangliosidosis variant AB.''; PubMedEurope PMCScholia
Pitson SM, D'andrea RJ, Vandeleur L, Moretti PA, Xia P, Gamble JR, Vadas MA, Wattenberg BW.; ''Human sphingosine kinase: purification, molecular cloning and characterization of the native and recombinant enzymes.''; PubMedEurope PMCScholia
Ullman MD, Radin NS.; ''The enzymatic formation of sphingomyelin from ceramide and lecithin in mouse liver.''; PubMedEurope PMCScholia
Xu R, Jin J, Hu W, Sun W, Bielawski J, Szulc Z, Taha T, Obeid LM, Mao C.; ''Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P.''; PubMedEurope PMCScholia
Schuchman EH, Levran O, Pereira LV, Desnick RJ.; ''Structural organization and complete nucleotide sequence of the gene encoding human acid sphingomyelinase (SMPD1).''; PubMedEurope PMCScholia
Kawano M, Kumagai K, Nishijima M, Hanada K.; ''Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT.''; PubMedEurope PMCScholia
Nakano T, Muscillo M, Ohno K, Hoffman AJ, Suzuki K.; ''A point mutation in the coding sequence of the beta-hexosaminidase alpha gene results in defective processing of the enzyme protein in an unusual GM2-gangliosidosis variant.''; PubMedEurope PMCScholia
Berrin JG, McLauchlan WR, Needs P, Williamson G, Puigserver A, Kroon PA, Juge N.; ''Functional expression of human liver cytosolic beta-glucosidase in Pichia pastoris. Insights into its role in the metabolism of dietary glucosides.''; PubMedEurope PMCScholia
Dinur T, Osiecki KM, Legler G, Gatt S, Desnick RJ, Grabowski GA.; ''Human acid beta-glucosidase: isolation and amino acid sequence of a peptide containing the catalytic site.''; PubMedEurope PMCScholia
Malinina L, Malakhova ML, Teplov A, Brown RE, Patel DJ.; ''Structural basis for glycosphingolipid transfer specificity.''; PubMedEurope PMCScholia
Malinina L, Malakhova ML, Kanack AT, Lu M, Abagyan R, Brown RE, Patel DJ.; ''The liganding of glycolipid transfer protein is controlled by glycolipid acyl structure.''; PubMedEurope PMCScholia
Banerjee P, Siciliano L, Oliveri D, McCabe NR, Boyers MJ, Horwitz AL, Li SC, Dawson G.; ''Molecular basis of an adult form of beta-hexosaminidase B deficiency with motor neuron disease.''; PubMedEurope PMCScholia
Nagahashi M, Kim EY, Yamada A, Ramachandran S, Allegood JC, Hait NC, Maceyka M, Milstien S, Takabe K, Spiegel S.; ''Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network.''; PubMedEurope PMCScholia
Koch J, Gärtner S, Li CM, Quintern LE, Bernardo K, Levran O, Schnabel D, Desnick RJ, Schuchman EH, Sandhoff K.; ''Molecular cloning and characterization of a full-length complementary DNA encoding human acid ceramidase. Identification Of the first molecular lesion causing Farber disease.''; PubMedEurope PMCScholia
Okajima T, Nakamura Y, Uchikawa M, Haslam DB, Numata SI, Furukawa K, Urano T, Furukawa K.; ''Expression cloning of human globoside synthase cDNAs. Identification of beta 3Gal-T3 as UDP-N-acetylgalactosamine:globotriaosylceramide beta 1,3-N-acetylgalactosaminyltransferase.''; PubMedEurope PMCScholia
Van Veldhoven PP, Gijsbers S, Mannaerts GP, Vermeesch JR, Brys V.; ''Human sphingosine-1-phosphate lyase: cDNA cloning, functional expression studies and mapping to chromosome 10q22(1).''; PubMedEurope PMCScholia
Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN.; ''Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis.''; PubMedEurope PMCScholia
Shabbeer J, Yasuda M, Benson SD, Desnick RJ.; ''Fabry disease: identification of 50 novel alpha-galactosidase A mutations causing the classic phenotype and three-dimensional structural analysis of 29 missense mutations.''; PubMedEurope PMCScholia
Hornemann T, Richard S, Rütti MF, Wei Y, von Eckardstein A.; ''Cloning and initial characterization of a new subunit for mammalian serine-palmitoyltransferase.''; PubMedEurope PMCScholia
Monti E, Bassi MT, Papini N, Riboni M, Manzoni M, Venerando B, Croci G, Preti A, Ballabio A, Tettamanti G, Borsani G.; ''Identification and expression of NEU3, a novel human sialidase associated to the plasma membrane.''; PubMedEurope PMCScholia
Duan RD, Bergman T, Xu N, Wu J, Cheng Y, Duan J, Nelander S, Palmberg C, Nilsson A.; ''Identification of human intestinal alkaline sphingomyelinase as a novel ecto-enzyme related to the nucleotide phosphodiesterase family.''; PubMedEurope PMCScholia
Mizutani Y, Kihara A, Igarashi Y.; ''Identification of the human sphingolipid C4-hydroxylase, hDES2, and its up-regulation during keratinocyte differentiation.''; PubMedEurope PMCScholia
Selmer T, Hallmann A, Schmidt B, Sumper M, von Figura K.; ''The evolutionary conservation of a novel protein modification, the conversion of cysteine to serinesemialdehyde in arylsulfatase from Volvox carteri.''; PubMedEurope PMCScholia
Ogawa C, Kihara A, Gokoh M, Igarashi Y.; ''Identification and characterization of a novel human sphingosine-1-phosphate phosphohydrolase, hSPP2.''; PubMedEurope PMCScholia
Galjart NJ, Gillemans N, Harris A, van der Horst GT, Verheijen FW, Galjaard H, d'Azzo A.; ''Expression of cDNA encoding the human "protective protein" associated with lysosomal beta-galactosidase and neuraminidase: homology to yeast proteases.''; PubMedEurope PMCScholia
Alperin ES, Shapiro LJ.; ''Characterization of point mutations in patients with X-linked ichthyosis. Effects on the structure and function of the steroid sulfatase protein.''; PubMedEurope PMCScholia
Sakai N, Inui K, Midorikawa M, Okuno Y, Ueda S, Iwamatsu A, Okada S.; ''Purification and characterization of galactocerebrosidase from human lymphocytes.''; PubMedEurope PMCScholia
Tafesse FG, Huitema K, Hermansson M, van der Poel S, van den Dikkenberg J, Uphoff A, Somerharju P, Holthuis JC.; ''Both sphingomyelin synthases SMS1 and SMS2 are required for sphingomyelin homeostasis and growth in human HeLa cells.''; PubMedEurope PMCScholia
Polten A, Fluharty AL, Fluharty CB, Kappler J, von Figura K, Gieselmann V.; ''Molecular basis of different forms of metachromatic leukodystrophy.''; PubMedEurope PMCScholia
Amado M, Almeida R, Carneiro F, Levery SB, Holmes EH, Nomoto M, Hollingsworth MA, Hassan H, Schwientek T, Nielsen PA, Bennett EP, Clausen H.; ''A family of human beta3-galactosyltransferases. Characterization of four members of a UDP-galactose:beta-N-acetyl-glucosamine/beta-nacetyl-galactosamine beta-1,3-galactosyltransferase family.''; PubMedEurope PMCScholia
Mark BL, Mahuran DJ, Cherney MM, Zhao D, Knapp S, James MN.; ''Crystal structure of human beta-hexosaminidase B: understanding the molecular basis of Sandhoff and Tay-Sachs disease.''; PubMedEurope PMCScholia
von Figura K, Schmidt B, Selmer T, Dierks T.; ''A novel protein modification generating an aldehyde group in sulfatases: its role in catalysis and disease.''; PubMedEurope PMCScholia
Ashibe B, Hirai T, Higashi K, Sekimizu K, Motojima K.; ''Dual subcellular localization in the endoplasmic reticulum and peroxisomes and a vital role in protecting against oxidative stress of fatty aldehyde dehydrogenase are achieved by alternative splicing.''; PubMedEurope PMCScholia
Hwang YH, Tani M, Nakagawa T, Okino N, Ito M.; ''Subcellular localization of human neutral ceramidase expressed in HEK293 cells.''; PubMedEurope PMCScholia
Pewzner-Jung Y, Ben-Dor S, Futerman AH.; ''When do Lasses (longevity assurance genes) become CerS (ceramide synthases)?: Insights into the regulation of ceramide synthesis.''; PubMedEurope PMCScholia
Stein C, Gieselmann V, Kreysing J, Schmidt B, Pohlmann R, Waheed A, Meyer HE, O'Brien JS, von Figura K.; ''Cloning and expression of human arylsulfatase A.''; PubMedEurope PMCScholia
Hofmann K, Tomiuk S, Wolff G, Stoffel W.; ''Cloning and characterization of the mammalian brain-specific, Mg2+-dependent neutral sphingomyelinase.''; PubMedEurope PMCScholia
Boukhris A, Schule R, Loureiro JL, Lourenço CM, Mundwiller E, Gonzalez MA, Charles P, Gauthier J, Rekik I, Acosta Lebrigio RF, Gaussen M, Speziani F, Ferbert A, Feki I, Caballero-Oteyza A, Dionne-Laporte A, Amri M, Noreau A, Forlani S, Cruz VT, Mochel F, Coutinho P, Dion P, Mhiri C, Schols L, Pouget J, Darios F, Rouleau GA, Marques W, Brice A, Durr A, Zuchner S, Stevanin G.; ''Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia.''; PubMedEurope PMCScholia
Mariappan M, Preusser-Kunze A, Balleininger M, Eiselt N, Schmidt B, Gande SL, Wenzel D, Dierks T, von Figura K.; ''Expression, localization, structural, and functional characterization of pFGE, the paralog of the Calpha-formylglycine-generating enzyme.''; PubMedEurope PMCScholia
Hornemann T, Wei Y, von Eckardstein A.; ''Is the mammalian serine palmitoyltransferase a high-molecular-mass complex?''; PubMedEurope PMCScholia
Cadena DL, Kurten RC, Gill GN.; ''The product of the MLD gene is a member of the membrane fatty acid desaturase family: overexpression of MLD inhibits EGF receptor biosynthesis.''; PubMedEurope PMCScholia
Huitema K, van den Dikkenberg J, Brouwers JF, Holthuis JC.; ''Identification of a family of animal sphingomyelin synthases.''; PubMedEurope PMCScholia
Wright CS, Zhao Q, Rastinejad F.; ''Structural analysis of lipid complexes of GM2-activator protein.''; PubMedEurope PMCScholia
Galadari S, Wu BX, Mao C, Roddy P, El Bawab S, Hannun YA.; ''Identification of a novel amidase motif in neutral ceramidase.''; PubMedEurope PMCScholia
Kihara A, Igarashi Y.; ''FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane.''; PubMedEurope PMCScholia
Perry RJ, Ridgway ND.; ''Oxysterol-binding protein and vesicle-associated membrane protein-associated protein are required for sterol-dependent activation of the ceramide transport protein.''; PubMedEurope PMCScholia
Nava VE, Lacana E, Poulton S, Liu H, Sugiura M, Kono K, Milstien S, Kohama T, Spiegel S.; ''Functional characterization of human sphingosine kinase-1.''; PubMedEurope PMCScholia
O'Dowd BF, Cumming DA, Gravel RA, Mahuran D.; ''Oligosaccharide structure and amino acid sequence of the major glycopeptides of mature human beta-hexosaminidase.''; PubMedEurope PMCScholia
Marchitti SA, Brocker C, Orlicky DJ, Vasiliou V.; ''Molecular characterization, expression analysis, and role of ALDH3B1 in the cellular protection against oxidative stress.''; PubMedEurope PMCScholia
Mahuran DJ, Neote K, Klavins MH, Leung A, Gravel RA.; ''Proteolytic processing of pro-alpha and pro-beta precursors from human beta-hexosaminidase. Generation of the mature alpha and beta a beta b subunits.''; PubMedEurope PMCScholia
Ternes P, Franke S, Zähringer U, Sperling P, Heinz E.; ''Identification and characterization of a sphingolipid delta 4-desaturase family.''; PubMedEurope PMCScholia
Rodríguez-Pascau L, Gort L, Schuchman EH, Vilageliu L, Grinberg D, Chabás A.; ''Identification and characterization of SMPD1 mutations causing Niemann-Pick types A and B in Spanish patients.''; PubMedEurope PMCScholia
Hanada K, Hara T, Nishijima M.; ''Purification of the serine palmitoyltransferase complex responsible for sphingoid base synthesis by using affinity peptide chromatography techniques.''; PubMedEurope PMCScholia
Tomishige N, Kumagai K, Kusuda J, Nishijima M, Hanada K.; ''Casein kinase I{gamma}2 down-regulates trafficking of ceramide in the synthesis of sphingomyelin.''; PubMedEurope PMCScholia
Roeser D, Preusser-Kunze A, Schmidt B, Gasow K, Wittmann JG, Dierks T, von Figura K, Rudolph MG.; ''A general binding mechanism for all human sulfatases by the formylglycine-generating enzyme.''; PubMedEurope PMCScholia
Diringer H, Marggraf WD, Koch MA, Anderer FA.; ''Evidence for a new biosynthetic pathway of sphingomyelin in SV 40 transformed mouse cells.''; PubMedEurope PMCScholia
Oshima A, Yoshida K, Shimmoto M, Fukuhara Y, Sakuraba H, Suzuki Y.; ''Human beta-galactosidase gene mutations in morquio B disease.''; PubMedEurope PMCScholia
Idevall-Hagren O, Lü A, Xie B, De Camilli P.; ''Triggered Ca2+ influx is required for extended synaptotagmin 1-induced ER-plasma membrane tethering.''; PubMedEurope PMCScholia
Weiss B, Stoffel W.; ''Human and murine serine-palmitoyl-CoA transferase--cloning, expression and characterization of the key enzyme in sphingolipid synthesis.''; PubMedEurope PMCScholia
De Laurenzi V, Rogers GR, Hamrock DJ, Marekov LN, Steinert PM, Compton JG, Markova N, Rizzo WB.; ''Sjögren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene.''; PubMedEurope PMCScholia
Uchida Y, Hama H, Alderson NL, Douangpanya S, Wang Y, Crumrine DA, Elias PM, Holleran WM.; ''Fatty acid 2-hydroxylase, encoded by FA2H, accounts for differentiation-associated increase in 2-OH ceramides during keratinocyte differentiation.''; PubMedEurope PMCScholia
Sun W, Xu R, Hu W, Jin J, Crellin HA, Bielawski J, Szulc ZM, Thiers BH, Obeid LM, Mao C.; ''Upregulation of the human alkaline ceramidase 1 and acid ceramidase mediates calcium-induced differentiation of epidermal keratinocytes.''; PubMedEurope PMCScholia
Cosma MP, Pepe S, Annunziata I, Newbold RF, Grompe M, Parenti G, Ballabio A.; ''The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases.''; PubMedEurope PMCScholia
Simanshu DK, Kamlekar RK, Wijesinghe DS, Zou X, Zhai X, Mishra SK, Molotkovsky JG, Malinina L, Hinchcliffe EH, Chalfant CE, Brown RE, Patel DJ.; ''Non-vesicular trafficking by a ceramide-1-phosphate transfer protein regulates eicosanoids.''; PubMedEurope PMCScholia
Monti E, Preti A, Rossi E, Ballabio A, Borsani G.; ''Cloning and characterization of NEU2, a human gene homologous to rodent soluble sialidases.''; PubMedEurope PMCScholia
Laviad EL, Albee L, Pankova-Kholmyansky I, Epstein S, Park H, Merrill AH, Futerman AH.; ''Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate.''; PubMedEurope PMCScholia
Fyrst H, Saba JD.; ''Sphingosine-1-phosphate lyase in development and disease: sphingolipid metabolism takes flight.''; PubMedEurope PMCScholia
Tomiuk S, Hofmann K, Nix M, Zumbansen M, Stoffel W.; ''Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling?''; PubMedEurope PMCScholia
Merrill AH.; ''De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway.''; PubMedEurope PMCScholia
Salvioli R, Tatti M, Ciaffoni F, Vaccaro AM.; ''Further studies on the reconstitution of glucosylceramidase activity by Sap C and anionic phospholipids.''; PubMedEurope PMCScholia
Ferlinz K, Hurwitz R, Sandhoff K.; ''Molecular basis of acid sphingomyelinase deficiency in a patient with Niemann-Pick disease type A.''; PubMedEurope PMCScholia
Ichikawa S, Sakiyama H, Suzuki G, Hidari KI, Hirabayashi Y.; ''Expression cloning of a cDNA for human ceramide glucosyltransferase that catalyzes the first glycosylation step of glycosphingolipid synthesis.''; PubMedEurope PMCScholia
Sugiura M, Kono K, Liu H, Shimizugawa T, Minekura H, Spiegel S, Kohama T.; ''Ceramide kinase, a novel lipid kinase. Molecular cloning and functional characterization.''; PubMedEurope PMCScholia
Hanada K, Kumagai K, Yasuda S, Miura Y, Kawano M, Fukasawa M, Nishijima M.; ''Molecular machinery for non-vesicular trafficking of ceramide.''; PubMedEurope PMCScholia
Zhou XY, Galjart NJ, Willemsen R, Gillemans N, Galjaard H, d'Azzo A.; ''A mutation in a mild form of galactosialidosis impairs dimerization of the protective protein and renders it unstable.''; PubMedEurope PMCScholia
Basler E, Grompe M, Parenti G, Yates J, Ballabio A.; ''Identification of point mutations in the steroid sulfatase gene of three patients with X-linked ichthyosis.''; PubMedEurope PMCScholia
Fugmann T, Hausser A, Schöffler P, Schmid S, Pfizenmaier K, Olayioye MA.; ''Regulation of secretory transport by protein kinase D-mediated phosphorylation of the ceramide transfer protein.''; PubMedEurope PMCScholia
Bonten E, van der Spoel A, Fornerod M, Grosveld G, d'Azzo A.; ''Characterization of human lysosomal neuraminidase defines the molecular basis of the metabolic storage disorder sialidosis.''; PubMedEurope PMCScholia
Li J, Yen TY, Allende ML, Joshi RK, Cai J, Pierce WM, Jaskiewicz E, Darling DS, Macher BA, Young WW.; ''Disulfide bonds of GM2 synthase homodimers. Antiparallel orientation of the catalytic domains.''; PubMedEurope PMCScholia
Noël H, Plante L, Bleau G, Chapdelaine A, Roberts KD.; ''Human placental steroid sulfatase: purification and properties.''; PubMedEurope PMCScholia
Saito S, Matsui H, Kawano M, Kumagai K, Tomishige N, Hanada K, Echigo S, Tamura S, Kobayashi T.; ''Protein phosphatase 2Cepsilon is an endoplasmic reticulum integral membrane protein that dephosphorylates the ceramide transport protein CERT to enhance its association with organelle membranes.''; PubMedEurope PMCScholia
Asp NG, Dahlqvist A, Koldovský O.; ''Human small-intestinal beta-galactosidases. Separation and characterization of one lactase and one hetero beta-galactosidase.''; PubMedEurope PMCScholia
Nakahara K, Ohkuni A, Kitamura T, Abe K, Naganuma T, Ohno Y, Zoeller RA, Kihara A.; ''The Sjögren-Larsson syndrome gene encodes a hexadecenal dehydrogenase of the sphingosine 1-phosphate degradation pathway.''; PubMedEurope PMCScholia
Wu J, Hansen GH, Nilsson A, Duan RD.; ''Functional studies of human intestinal alkaline sphingomyelinase by deglycosylation and mutagenesis.''; PubMedEurope PMCScholia
Alderson NL, Rembiesa BM, Walla MD, Bielawska A, Bielawski J, Hama H.; ''The human FA2H gene encodes a fatty acid 2-hydroxylase.''; PubMedEurope PMCScholia
Kitamura T, Takagi S, Naganuma T, Kihara A.; ''Mouse aldehyde dehydrogenase ALDH3B2 is localized to lipid droplets via two C-terminal tryptophan residues and lipid modification.''; PubMedEurope PMCScholia
Wenger DA, Rafi MA, Luzi P.; ''Molecular genetics of Krabbe disease (globoid cell leukodystrophy): diagnostic and clinical implications.''; PubMedEurope PMCScholia
Roberts R, Sciorra VA, Morris AJ.; ''Human type 2 phosphatidic acid phosphohydrolases. Substrate specificity of the type 2a, 2b, and 2c enzymes and cell surface activity of the 2a isoform.''; PubMedEurope PMCScholia
Seyrantepe V, Landry K, Trudel S, Hassan JA, Morales CR, Pshezhetsky AV.; ''Neu4, a novel human lysosomal lumen sialidase, confers normal phenotype to sialidosis and galactosialidosis cells.''; PubMedEurope PMCScholia
Eng CM, Resnick-Silverman LA, Niehaus DJ, Astrin KH, Desnick RJ.; ''Nature and frequency of mutations in the alpha-galactosidase A gene that cause Fabry disease.''; PubMedEurope PMCScholia
Matern H, Boermans H, Lottspeich F, Matern S.; ''Molecular cloning and expression of human bile acid beta-glucosidase.''; PubMedEurope PMCScholia
Zito E, Fraldi A, Pepe S, Annunziata I, Kobinger G, Di Natale P, Ballabio A, Cosma MP.; ''Sulphatase activities are regulated by the interaction of sulphatase-modifying factor 1 with SUMF2.''; PubMedEurope PMCScholia
Zhang Z, Mandal AK, Mital A, Popescu N, Zimonjic D, Moser A, Moser H, Mukherjee AB.; ''Human acid ceramidase gene: novel mutations in Farber disease.''; PubMedEurope PMCScholia
Vacaru AM, Tafesse FG, Ternes P, Kondylis V, Hermansson M, Brouwers JF, Somerharju P, Rabouille C, Holthuis JC.; ''Sphingomyelin synthase-related protein SMSr controls ceramide homeostasis in the ER.''; PubMedEurope PMCScholia
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
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Rhodopsin-like receptors (class A/1) are the largest group of GPCRs and are the best studied group from a functional and structural point of view. They show great diversity at the sequence level and thus, can be subdivided into 19 subfamilies (Subfamily A1-19) based on a phylogenetic analysis (Joost P and Methner A, 2002). They represent members which include hormone, light and neurotransmitter receptors and encompass a wide range of functions including many autocrine, paracrine and endocrine processes.
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).
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).
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).
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 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).
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 lysosomal 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).
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).
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).
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 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.
Beta-galactosidase can hydrolyse a galactose moeity from globosides to form cerebrosides. Here, lactosylceramide is hydrolysed to glucosylceramide (Asp et al. 1969).
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).
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).
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).
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).
Sulfatase-modifying factor 2 (SUMF2, also called C-alpha-formylglycine-generating enzyme 2, pFGE) is the paralogue of SUMF1. While SUMF1 can modify a critical residue on arylsulfatases to confer activity to them, SUMF2 lacks this ability (Mariappan et al. 2005) and instead, SUMF2 can inhibit the action of SUMF1 by dimerising with it (Zito et al. 2005). SUMF2 can interact with sulfatases with and without SUMF1 (Zito et al. 2005).
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.
Ceramide glucosyltransferase (UGCG) catalyses the first glycosylation step in glycosphingolipid biosynthesis by the transfer of glucose to ceramide (Ichikawa et al. 1996).
Ceramide kinase (CERK) mediates the phosphorylation of ceramide (CERA) to the lipid second messenger, ceramide 1-phosphate (C1P) (Sugiura et al. 2002).
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).
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).
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).
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).
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). Yeast SPTLC has a third small subunit (Tsc3) associated that is required for maximal SPT activity (Gable et al. 2000). Analyses of complexes from cultured human cells and placenta suggested that the SPTLC heterodimers might associate into larger complexes (Hanada et al. 2000; Weiss and Stoffel 1997; Hornemann et al. 2006, 2007). Two novel small subunits (SPTSSA and SPTSSB) were identified, both of which enhance SPTLC activity >10-fold when bound to either of the SPTLC heterodimers (Han et al. 2009). Orosomucoid (ORM) proteins, first identified in yeast, associate with and negatively regulate SPTLC activity (Breslow et al. 2010, Han et al. 2010). The 3 human ORM proteins similarly bind and negatively regulate SPTLC activity (Breslow et al. 2010).
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).
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).
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 to sphingosine 1-phosphate (S1P) (Liu et al. 2000, Nava et al. 2000, Pitson et al. 2000).
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).
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.
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.
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).
The cytosolic enzyme sphingosine kinase 1 (SPHK1) catalyzes the phosphorylation of sphingosine (SPG) to sphingosine 1-phosphate (S1P) (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 (S1P) to form phosphoethanolamine (PETA) and hexadec-2-enal (HD2NAL) (Van Veldhoven et al. 2000; Fyrst and Saba 2008).
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).
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).
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).
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).
“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) 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).
Cytosolic PRKD1, 2 and 3 (protein kinase D1, D2 and D3) catalyze the phosphorylation of serine residue 132 of isoform 2 of ceramide transfer protein (COL4A3BP-2, CERT). Protein kinase D (PRKD) is as a crucial regulator of secretory transport at the trans-Golgi network (TGN). Phosphorylation of COL4A3BP-2 reduces its ceramide transfer activity. PRKDs may therefore act as regulators of lipid homeostasis (Fugmann et al. 2007).
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).
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.
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).
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).
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).
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).
Ceramide-1-phosphate transfer protein (GLTPD1) mediates the intracellular transfer of ceramide-1-phosphate (C1P) between the cell membrane and organelle membranes. C1P is an activator of group IVA cytosolic phospholipase (PLA2G4A), the rate-limiting releaser of arachidonic acid used for pro-inflammatory eicosanoid production, which contributes to disease pathogenesis. To avoid the effects of chronic inflammation, cells require efficient targeting, trafficking and presentation of C1P to specific cellular sites. GLTPD1 is localised in the cytosol but can associate with plamsa, Golgi and nuclear membranes (Simanshu et al. 2013).
Glycolipid transfer protein (GLTP) is a monomeric, soluble protein that can mediate the intermembrane transport of glycosphingolipids (GSLs) (Malinina et al. 2004, Malinina et al. 2006, Tuuf & Mattjus 2007). GLTPs could serve as potential regulators of cell processes mediated by GSLs such as differentiation and proliferation to invasive adhesion, neurodegeneration and apoptosis. This reaction shows one example of GSL transfer from the plasma membrane to ER membrane.
Fatty aldehyde dehydrogenase family 3 member A2, isoform 1 (ALDH3A2-1) in the endoplasmic reticulum membrane can catalyse the oxidation of long-chain aliphatic aldehydes to fatty acids (Kelson et al. 1997; Rizzo et al. 2001). Structural studies suggest that the enzyme is a homodimer (Keller et al. 2010), and expression studies of the homologous mouse proteins in cultured cells indicate that ALDH3A2 isoform 1 to the endoplasmic reticulum while isoform 2 is localized to peroxisomes (Ashibe et al. 2007). The sphingosine 1-phosphate (S1P) degradation product hexadec-2-enal (HD2NAL) can be oxidised to hexadecenoic acid (palmitic acid, PALM) (Nakahara et al. 2012). Defective ALDH3A2 results in Sjoegren-Larsson syndrome (SLS; MIM:270200), a neurocutaneous disorder characterised by a combination of severe mental retardation, spastic di- or tetraplegia and congenital ichthyosis. Accumulation of the S1P metabolite HD2NAL contributes to the pathogenesis of SLS (De Laurenzi et al. 1996, Sillen et al. 1998).
In mammals, 2-hydroxysphingolipids are abundant in the brain as components of the major myelin lipids galactosylceramides and sulfatides. 2-hydroxylation of sphingolipids can occur during de novo ceramide synthesis and is catalysed by fatty acid 2-hydroxylase (FA2H), an ER membrane-associated enzyme (Alderson et al. 2004, Uchida et al. 2007).
Aldehyde dehydrogenases (ALDHs) detoxify toxic aldehydes by oxidation to the corresponding carboxylic acids. Long-chain aliphatic aldehydes are largely produced by catabolic metabolism of several lipids, including ether glycerolipids, fatty alcohols, sphingolipids and wax esters. Some medium-chain aliphatic aldehydes, such as hexanal, octanal and 4-hydroxy-2-nonenal (4HNE) are produced via lipid peroxidation during oxidative stress. Aldehyde dehydrogenase family 3 member B1 (ALDH3B1) is able to oxidise both medium- and long-chain aldehydes. C16 aldehydes such as hexadecanal (HXAL) generated through sphingolipid metabolism on the plasma membrane can be oxidised to palmitic acid (PALM) (Kitamura et al. 2013). 4HNE, amongst other reactive medium-chain aldehydes, can be detoxified by oxidation to 4-hydroxynonenoic acid (4HNA) by ALDH3B1, suggesting a potential physiological role for ALDH3B1 against oxidative stress (not shown here) (Marchitti et al. 2010).
2-hydroxyacylsphingosine 1-beta-galactosyltransferase (UGT8) catalyses the transfer of galactosyl moiety from UDP-galactose (UDP-Gal) to ceramide (CERA), a key step in the biosynthesis of galactocerebrosides (GalCer), which are abundant sphingolipids of the myelin membrane of the CNS and PNS (Kapitonov & Yu 1997, Liu et al. 2013).
ALDH3B2 (aldehyde dehydrogenase family 3 member B2), associated with cytosolic lipid droplets, catalyzes the NAD-dependent oxdidation of HXAL (hexadecanal) to PALM (palmitate). A geranylgeranylated cysteine residue mediates the enzyme's association with the lipid droplet (Kitamura et al. 2013, 2015).
Gangliosides are part of the larger family of glycosphingolipids and are components of the synaptic plasma membrane involved in synaptic plasticity, signal transduction and endocytosis, processes for CNS development. Complex gangliosides (G) can be mono- (M), di- (D), and tri- (T) sialic acid-containing glycosphingolipids generated by sequential glycosylations in the ER and Golgi. Beta-1,4 N-acetylgalactosaminyltransferase 1 (B4GALNT1), a homodimeric protein (Li et al. 2000) residing on the Golgi membrane, catalyses the transfer of N-acetyl-galactosamine (GalNAc) into GM3, GD3 (and globotriaosylceramide, not shown here) by a beta-1,4 linkage (Nagata et al. 1992). Defects in B4GALNT1 can cause spastic paraplegia 26 (SPG26), a neurodegenerative disorder characterised by a slow, gradual, progressive weakness and spasticity of the lower limbs (Boukhris et al. 2013).
Mammalian cells ubiquitously express three extended-synaptotagmins 1 to 3 (ESYT1-3) which function as Ca2+-regulated endoplasmic reticulum-plasma membrane (ER-PM) tethers. They form homo- and hetero-meric complexes on the ER membrane (heterotrimer shown in this example), are dependent on PI(4,5)P2 in plasma membranes and regulated by cytosolic Ca2+ via the Ca2+-sensing property of ESYT1. An increase in Ca2+ levels contributes to ER-PM tethering, allowing ESYTs to play a putative role in transport of lipids such as glycerophospholipids (GPL) between the two membranes (Giordano et al. 2013, Idevall-Hagren et al. 2015).
Globosides are a type of glycosphingolipid with more than one sugar as the side chain of ceramide, usually a combination of N-acetylgalactosamine, D-glucose or D-galactose. They are components of cellular membranes, especially of the kidneys, red blood cells, blood serum, liver and spleen. Globoside synthesis (and therefore accummulation) increases in pathological conditions including neurodegenerative disorders, immune diseases and cancer. UDP-GalNAc:beta-1,3-N-acetylgalactosaminyltransferase 1 (B3GALNT1, B3GALT3) is a Golgi membrane-associated protein that can add N-acetylgalactosamine (GalNAc) to globotriaosylceramide (Gb3Cer) to form Gb4Cer (Okajima et al. 2000, Amado et al. 1998).
Sphingolipids such as sphingomyelin (SM) are important components of cellular membranes and dynamic regulators of a wide range of cellular processes in most organisms. Ceramides constitute the backbone of all sphingolipids and are synthesised on the cytosolic surface of the endoplasmic reticulum (ER) then transported to the Golgi for conversion to SM. The ER-membrane resident protein sphingomyelin synthase-related protein 1 (SAMD8) catalyses the synthesis of the SM analogue ceramide phosphoethanolamine (CPE) in the ER lumen. SAMD8 only produces trace amounts of CPE but blocking its catalytic activity causes a substantial rise in ER ceramide levels and a structural collapse of the early secretory pathway. SAMD8 is therefore a key regulator of ceramide homeostasis, functioning as a sensor rather than a converter of ceramides in the ER (Vacaru et al. 2009).
Sphingosine 1-phosphate (S1P) is a signaling molecule that regulates many physiological processes in development and the immune system. S1P is produced inside cells so must be secreted to exert its effects through its receptors. Protein spinster homolog 2 (SPNS2) is a S1P transporter involved in S1P secretion and regulation of its levels (Nagahashi et al. 2013).
The cytosolic enzyme sphingosine kinase 2 (SPHK2) catalyzes the phosphorylation of sphingosine (SPG) to sphingosine 1-phosphate (S1P) (Liu et al. 2000). In contrast to pro-survival SPHK1, the BH3-only protein SPHK2 inhibits cell growth and enhances apoptosis (Maceyka et al. 2005).
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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).