1-Deoxysphingolipids

Class of toxic sphingolipids involved in neurological and metabolic disorders November 2019 vanc 6 The 1-deoxysphingolipids (1-deoxySLs) are a recently identified class of atypical sphingolipids (SLs). Mwinyi J, Boström A, Fehrer I, Othman A, Waeber G, Marti-Soler H, Vollenweider P, Marques-Vidal P, Schiöth HB, von Eckardstein A, Hornemann T Plasma 1-deoxysphingolipids are early predictors of incident type 2 diabetes mellitus PLOS ONE 12 5 e0175776 2017-05-04 28472035 5417440 10.1371/journal.pone.0175776 free 2017PLoSO..1275776M Lone MA, Santos T, Alecu I, Silva LC, Hornemann T 1-Deoxysphingolipids Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1864 4 512–521 April 2019 30625374 10.1016/j.bbalip.2018.12.013 243591778 They are produced via a non-canonical biosynthetic pathway, and their defining feature, the absence of a C1 hydroxyl group (C1-OH), prevents their further conversion into complex sphingolipids. Under normal conditions, sphingolipids are synthesized through a reaction catalyzed by the enzyme serine-palmitoyltransferase (SPT), which condenses serine with palmitoyl-CoA. Hornemann T, Alecu I, Hagenbuch N, Zhakupova A, Cremonesi A, Gautschi M, Jung HH, Meienberg F, Bilz S, Christ E, Baumgartner MR, Hochuli M Disturbed sphingolipid metabolism with elevated 1-deoxysphingolipids in glycogen storage disease type I - A link to metabolic control Molecular Genetics and Metabolism 125 1–2 73–78 September 2018 30037504 10.1016/j.ymgme.2018.07.003 51711727 However, when SPT utilizes alternative amino acid substrates such as alanine or glycine instead of serine, it leads to the formation of 1-deoxySLs. Unlike canonical sphingolipids, 1-deoxysphingolipids cannot be degraded via standard catabolic pathways. As a result, they accumulate to high levels and have been implicated in a range of neurological and metabolic disorders. Structure There are two types of 1-deoxySLs: 1-deoxysphinganine and 1-deoxymethylsphinganine. 1-Deoxysphinganine yes Spisulosine.svg 1-Deoxysphinganine (2S,3R)-2-Aminooctadecan-3-ol Spisulosine 196497-48-0 correct FDA ZX5D253CYY 9925886 CCCCCCCCCCCCCCC[C@H]([C@H](C)N)O 1S/C18H39NO/c1-3-4-5-6-7-8-9-10-11-12-13-14-15-16-18(20)17(2)19/h17-18,20H,3-16,19H2,1-2H3/t17-,18+/m0/s1 YRYJJIXWWQLGGV-ZWKOTPCHSA-N C 18 H 39 N O It is an amino alcohol and a bioactive sphingoid. Its distinctive trait is that the terminal hydroxy group has been replaced by hydrogen. It possesses antineoplastic properties, appearing to inhibit the proliferation of some kinds of cancer. Sánchez AM, Malagarie-Cazenave S, Olea N, Vara D, Cuevas C, Díaz-Laviada I Spisulosine (ES-285) induces prostate tumor PC-3 and LNCaP cell death by de novo synthesis of ceramide and PKCzeta activation European Journal of Pharmacology 584 2–3 237–245 April 2008 18343365 10.1016/j.ejphar.2008.02.011 This sphingoid base can be found, in general, in low levels, in animal cells, Christie WW Long-Chain (Sphingoid) Bases https://www.lipidmaps.org/resources/lipidweb/index.php?page=lipids/sphingo/lcb/index.htm#deoxsph LIPID MAPS Lipidomics Gateway 2019-10-24 and at higher concentrations in the cell membranes of certain bacteria, including Bacteroides species common to the animal gut microbiome—suggesting this as a potential source of these compounds in circulation. Brown EM, Ke X, Hitchcock D, Jeanfavre S, Avila-Pacheco J, Nakata T, Arthur TD, Fornelos N, Heim C, Franzosa EA, Watson N, Huttenhower C, Haiser HJ, Dillow G, Graham DB, Finlay BB, Kostic AD, Porter JA, Vlamakis H, Clish CB, Xavier RJ Bacteroides-Derived Sphingolipids Are Critical for Maintaining Intestinal Homeostasis and Symbiosis Cell Host & Microbe 25 5 668–680.e7 May 2019 31071294 6544385 10.1016/j.chom.2019.04.002 It was found for the first time in a marine organism, in which context it is known as spisulosine. https://pubchem.ncbi.nlm.nih.gov/compound/9925886 Spisulosine PubChem U.S. National Library of Medicine 2019-10-24 It is known by other names such as ES-285. The molecular weight of this compound is 285,5 g/mol and its molecular formula is C18H39NO, which means it has 18 carbons.https://www.caymanchem.com/product/13511 1-Deoxysphinganine (m18:0) (CAS 196497-48-0) www.caymanchem.com 2019-10-24 1-Deoxymethylsphinganine yes 1-Deoxymethylsphinganine 1-Deoxymethylsphinganine.svg (2R)-1-Aminoheptadecan-2-ol 1-Deoxymethylsphinganine (m17:0) 1219484-98-6 70678793 CCCCCCCCCCCCCCC[C@H](CN)O 1S/C17H37NO/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-17(19)16-18/h17,19H,2-16,18H2,1H3/t17-/m1/s1 UGVBFHUWZNNKIK-QGZVFWFLSA-N C 17 H 37 N O It is a bioactive sphingoid which derives from the sphinganine. It is formed by a sphingoid and an amino alcohol and it constitutes the conjugated base of 1-deoxymethylsphinganine (1+).https://pubchem.ncbi.nlm.nih.gov/compound/70678793 1-Deoxymethylsphinganine PubChem U.S. National Library of Medicine 2019-10-24 Its role is accepting a hydron from a donor via its organic amino compound; it is a Brønsted base.https://www.ebi.ac.uk/chebi/chebiOntology.do?chebiId=CHEBI:67187 1-deoxymethylsphinganine (CHEBI:67187) www.ebi.ac.uk 2019-10-24 It is also known as deoxymethyl-SA, (2R)-1-aminoheptadecan-2-ol and 1-desoxymethylsphinganine. The molecular weight of this compound is 271,48 g/mol and its molecular formula is C17H37NO, which means it has 17 carbons. In relation to its appearance, it has a powder form. Other physical and chemical properties are not certainly known.https://avantilipids.com/ 1-desoxymethylsphinganine Avanti Polar Lipids 2019-10-24 Localization Sphingolipid metabolism is based in compartmentalization. In this way, possible cycles of opposite anabolism and catabolism reactions are avoided. The ER is the compartment where the synthesis of ceramide is produced. Then, it will move to the Golgi apparatus. If the ceramide transporter protein is involved, it will go to the TGN to form sphingomyelin. If the vesicles are the ones in charge of transport, it will reach the cis zone to become glucosylceramide. Instead, deoxySL transport and localization in cells is not known for sure. It is true that several studies has proved some of his intracellular behaviours. What allows to understand the distribution in the cell of 1-deoxysphingolipids is the comparison between the behavior of fluorescent analogs of the SLs (C6-NBD-(dh)-Cer) and the 1-deoxySLs (C6-NBD-deoxy(dh)-Cer). The fact that C6-NBD-deoxy(dh)-Cer is not located in the same compartments as C6-NBD-(dh)-Cer indicates that the absence of C1-OH interferes in the protein and vesicular traffic. On the other side, it's been found that 1-deoxySLs gave a signal in the mitochondria and remained prominent by using alkyne-1-deoxySA, as well as the co-location in the RE and Golgi markers. The signal was absent in the lysosomes and in the plasma membrane. A specific change in 1-deoxySLs causes variations in mitochondrial morphology, as well as variations of the same type in the RE when de concentrations are toxic. Metabolism thumb|Differences depending on the substrate used by serine-palmitoyltransferase (SPT) Synthesis 1-DeoxySLs has a similar pattern to sphingolipids during de novo synthesis. The reaction is catalyzed by the enzyme serine palmitoyltransferase (SPT) but instead of condensing palmitoyl-CoA and L-serine, the amino acid substrate is replaced by L-alanina or L-glycine. Duan J, Merrill AH 1-Deoxysphingolipids Encountered Exogenously and Made de Novo: Dangerous Mysteries inside an Enigma The Journal of Biological Chemistry 290 25 15380–15389 June 2015 25947379 4505451 10.1074/jbc.R115.658823 free This atypical sphingolipids are formed as the result of a mutated SPT (SPTLC1/SPTLC2) with alternative activities. It has also produced by wild-type of SPT Merrill AH, Carman GM Introduction to Thematic Minireview Series: Novel Bioactive Sphingolipids The Journal of Biological Chemistry 290 25 15362–15364 June 2015 25947376 4505448 10.1074/jbc.R115.663708 free under unfavorable conditions where the synthesis of L-serine is diminished and / or the biosynthesis of alanine and glycine is too high. Vidal-Puig A, Cuenca R Lipotoxicidad, obesidad y enfermedades metabólicas Lipotoxicity, obesity and metabolic diseases Spanish Revista de la Sociedad Española de Bioquímia y Biología Molecular (SEEBM) [Internet] 190 17–22 December 2016 https://sebbm.es/wp-content/uploads/190-bioquimica-de-la-obesidad.pdf www.sebbm.es 2019-10-25 The result of the reaction with L-alanine forms 1-deoxysphinganine (1-deoxySA; m18:0), while the use of glycerin forms 1-deoxymethylsphinganine (1-deoxymethylSA; m17:0). Both molecules are 1-deoxySLs. Degradation Atypical sphingolipids' lack of C1-OH (hydroxyl group) of sphinganine its the cause they accumulate in the cytoplasm and cannot be degraded.November 2019 These headless sphingolipids are not able to be phosphorylated and they can neither converted into complex lipids as sphingomyelins and glycosphingolipids (galactosylceramides, gangliosides, cerebrosides ...). Instead, they have toxic effects to the cell.https://www.caymanchem.com/news/deoxysphingolipids Deoxysphingolipids www.caymanchem.com 2019-10-18 Despite previous opinions that 1-deoxySLs are dead-end metabolites, new researches prove the opposite. Its concentrations decrease over time because atypical sphingolipids convert into downstream products, which normally are polyunsaturated and polyhydroxylated. The main reason for this transformation is detoxification. The enzymes involved in this process produce the change within several days, making it a slow conversion. This take places in two stages: Firstly, the hydroxylation of compounds begins by cytochrome P450 enzymes. Alecu I, Othman A, Penno A, Saied EM, Arenz C, von Eckardstein A, Hornemann T Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway Journal of Lipid Research 58 1 60–71 January 2017 27872144 5234722 10.1194/jlr.M072421 free Secondly, hydrophilic moieties join up to the compounds in order to increase water solubility. As a result, the excretion through urine occurs and compounds can be removed. Either CYP4A or CYP4F are the enzymes involved in the downstream metabolism of 1-deoxySLs. It is not yet known which one takes place in the process but, it is more likely to be CYP4F as in mouse experiments this enzyme is responsible for 1-deoxySLs formation. Physico-chemical properties Currently, there is still much to elucidate regarding the properties of 1-deoxysphingolipids. However, studies have already contributed with clarifications on their biophysical properties and resulting biological impact. Systematic studies on the properties of each 1-deoxysphingolipid are still needed but, we already have some important hints. The most remarkable structural differences between canonical sphingolipids and 1-deoxysphingolipids occur at the level of the sphingoid base, namely the lack of C1-OH and the double bond position and configuration. The missing C1 hydroxyl group is an important characteristic that influences the molecule's intra and intermolecular interactions, as its ability to form intra and intermolecular H-bond networks decreases with a consequent impact on membranes biophysical properties and integrity. Vattulainen E, Matsufuji T, Kinoshita M, Matsumori N, Slotte J On the Importance of the C(1)–OH and C(3)–OH Functional Groups of the Long-Chain Base of Ceramide for Interlipid Interaction and Lateral Segregation into Ceramide-Rich Domains Langmuir 34 51 15864–15870 2018 30507134 10.1021/acs.langmuir.8b03237 Santos T, Vaz A, Ventura AE, Saied EM, Arenz C, Fedorov A, Prieto M, Silva LC Canonical and 1-Deoxy(methyl) Sphingoid Bases: Tackling the Effect of the Lipid Structure on Membrane Biophysical Properties Langmuir 36 21 6007–6016 2020 32369370 10.1021/acs.langmuir.0c01000 The lack of the canonical trans double bond impacts the main transition temperature of the lipid. The more bulky cis double bound present at a deeper position of the sphingoid base increases the surface area of the lipid further reducing the strength of the H-bond network formed with the neighbouring molecules potentially disrupting membrane stability and function. González-Ramírez EJ, García-Arribas AB, Artetxe I, Shaw WA, Goñi FM, Alonso A, Jiménez-Rojo N (1-Deoxy)ceramides in bilayers containing sphingomyelin and cholesterol Colloids and Surfaces B: Biointerfaces 243 114155 2024 39137529 10.1016/j.colsurfb.2024.114236 free Santos T, Saied EM, Arenz C, Fedorov A, Prieto M, Silva LC The long chain base unsaturation has a stronger impact on 1-deoxy(methyl)-sphingolipids biophysical properties than the structure of its C1 functional group Biochimica et Biophysica Acta (BBA) - Biomembranes 1863 8 183628 2021 33915167 10.1016/j.bbamem.2021.183628 These structural differences reduce the ability of the lipid to segregate laterally and form ordered domains important for many biological functions. This can contribute to the development and progression of pathological scenarios. Function Up until now, sphingolipids functions have not been yet known. In any case, its danger contributes to the development of several neuropathies and diseases. Esaki K, Sayano T, Sonoda C, Akagi T, Suzuki T, Ogawa T, Okamoto M, Yoshikawa T, Hirabayashi Y, Furuya S L-Serine Deficiency Elicits Intracellular Accumulation of Cytotoxic Deoxysphingolipids and Lipid Body Formation The Journal of Biological Chemistry 290 23 14595–14609 June 2015 25903138 4505526 10.1074/jbc.M114.603860 free Toxicity There are some diseases which causes are due to the formation of 1-deoxySLs and doxSA. Alecu I, Tedeschi A, Behler N, Wunderling K, Lamberz C, Lauterbach MA, Gaebler A, Ernst D, Van Veldhoven PP, Al-Amoudi A, Latz E, Othman A, Kuerschner L, Hornemann T, Bradke F, Thiele C, Penno A Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction Journal of Lipid Research 58 1 42–59 January 2017 27881717 5234710 10.1194/jlr.M068676 free For example, HSAN1 is caused because of the formation of this atypical and neurotoxic sphingolipid metabolites (doxSA and 1-deoxySLs). Moreover, it has been found that patients with type 2 diabetes, autonomic neuropathy type 1 (HSAN1) and hereditary sensory have elevated number of this kind of sphingolipids in their plasma. Othman A, Bianchi R, Alecu I, Wei Y, Porretta-Serapiglia C, Lombardi R, Chiorazzi A, Meregalli C, Oggioni N, Cavaletti G, Lauria G, von Eckardstein A, Hornemann T Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats Diabetes 64 3 1035–1045 March 2015 25277395 10.2337/db14-1325 free free 10281/55627 There are some investigations Othman A, Rütti MF, Ernst D, Saely CH, Rein P, Drexel H, Porretta-Serapiglia C, Lauria G, Bianchi R, von Eckardstein A, Hornemann T Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome? Diabetologia 55 2 421–431 February 2012 22124606 10.1007/s00125-011-2384-1 free https://www.zora.uzh.ch/id/eprint/63201/4/Othman_et_al_Diabetologia_final.pdf that affirm that plasma concentrations in patients with diabetes or the metabolic syndrome were higher than the control group's concentrations. The increase of 1-deoxySLs in metabolic disorders is curiously related to a fatty acid and carbohydrate metabolic dysregulation, that also affects to L-serine metabolism. We are capable to synthesize an alkyne analog of 1-deoxysphinganine (doxSA), which is the metabolic precursor of all deoxySLs. Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A, Brown RH, Hornemann T, Eichler FS Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1 The Journal of Clinical Investigation 121 12 4735–4745 December 2011 22045570 3225995 10.1172/JCI57549 This is useful for us to trace the metabolism of deoxySLs. With this information, now we are able to know that the metabolism of this lipid is restricted to only some lipid species. Considering the fact that we do not know much of the 1-deoxySL, there are some investigations Fridman V, Suriyanarayanan S, Novak P, David W, Macklin EA, McKenna-Yasek D, Walsh K, Aziz-Bose R, Oaklander AL, Brown R, Hornemann T, Eichler F Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1 Neurology 92 4 e359–e370 January 2019 30626650 6345118 10.1212/WNL.0000000000006811 that try to find a possible treatment for the diseases caused by this sphingolipid. In some of the experiments, there are hypothesis about a possible diabetic neuropathy treatment. This one consists in an oral L-serine supplementation since it has been demonstrated that this substance lowered 1-deoxySL concentrations in plasma. References July 2025 Category:Lipids