Chemistry:1-Deoxysphingolipids

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The 1-deoxysphingolipids (1-deoxySLs) are a recently identified class of atypical sphingolipids (SLs).[1][2] 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.[3] 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

1-Deoxysphinganine
Names
Preferred IUPAC name
(2S,3R)-2-Aminooctadecan-3-ol
Other names
Spisulosine
Identifiers
3D model (JSmol)
Properties
C18H39NO
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

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 Its distinctive trait is that the terminal hydroxy group has been replaced by hydrogen.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.[4]

This sphingoid base can be found, in general, in low levels, in animal cells,[5] 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.[6] It was found for the first time in a marine organism, in which context it is known as spisulosine.[7] 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.[8]

1-Deoxymethylsphinganine

1-Deoxymethylsphinganine
Names
Preferred IUPAC name
(2R)-1-Aminoheptadecan-2-ol
Other names
1-Deoxymethylsphinganine (m17:0)
Identifiers
3D model (JSmol)
Properties
C17H37NO
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

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+).[9] Its role is accepting a hydron from a donor via its organic amino compound; it is a Brønsted base.[10]

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.[11]

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.[2]

Metabolism

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.[12]

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[13] under unfavorable conditions where the synthesis of L-serine is diminished and / or the biosynthesis of alanine and glycine is too high.[14]

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.[clarification needed] 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.[15]

Despite previous opinions that 1-deoxySLs are dead-end metabolites, new researches prove the opposite.[2] 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.[16]
  • 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.[2] 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.[17][18] 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.[19][20]

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.[21]

Toxicity

There are some diseases which causes are due to the formation of 1-deoxySLs and doxSA.[22] 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.[23] There are some investigations [24] 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.[25] This is useful for us in order to trace the metabolism of deoxySLs. With this information, now we are able to know that the metabolism of this lipids is restricted to only some lipid species.

Considering the fact that we do not know much of the 1-deoxySL, there are some investigations[26] 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

  1. ↑ "Plasma 1-deoxysphingolipids are early predictors of incident type 2 diabetes mellitus". PLOS ONE 12 (5). 2017-05-04. doi:10.1371/journal.pone.0175776. PMID 28472035. Bibcode: 2017PLoSO..1275776M. 
  2. ↑ 2.0 2.1 2.2 2.3 "1-Deoxysphingolipids". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1864 (4): 512–521. April 2019. doi:10.1016/j.bbalip.2018.12.013. PMID 30625374. 
  3. ↑ "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. doi:10.1016/j.ymgme.2018.07.003. PMID 30037504. 
  4. ↑ "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. doi:10.1016/j.ejphar.2008.02.011. PMID 18343365. 
  5. ↑ "Long-Chain (Sphingoid) Bases". LIPID MAPS Lipidomics Gateway. https://www.lipidmaps.org/resources/lipidweb/index.php?page=lipids/sphingo/lcb/index.htm#deoxsph. 
  6. ↑ "Bacteroides-Derived Sphingolipids Are Critical for Maintaining Intestinal Homeostasis and Symbiosis". Cell Host & Microbe 25 (5): 668–680.e7. May 2019. doi:10.1016/j.chom.2019.04.002. PMID 31071294. 
  7. ↑ "Spisulosine". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/9925886. 
  8. ↑ "1-Deoxysphinganine (m18:0) (CAS 196497-48-0)". https://www.caymanchem.com/product/13511. 
  9. ↑ "1-Deoxymethylsphinganine". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/70678793. 
  10. ↑ "1-deoxymethylsphinganine (CHEBI:67187)". https://www.ebi.ac.uk/chebi/chebiOntology.do?chebiId=CHEBI:67187. 
  11. ↑ "1-desoxymethylsphinganine". https://avantilipids.com/. 
  12. ↑ "1-Deoxysphingolipids Encountered Exogenously and Made de Novo: Dangerous Mysteries inside an Enigma". The Journal of Biological Chemistry 290 (25): 15380–15389. June 2015. doi:10.1074/jbc.R115.658823. PMID 25947379. 
  13. ↑ "Introduction to Thematic Minireview Series: Novel Bioactive Sphingolipids". The Journal of Biological Chemistry 290 (25): 15362–15364. June 2015. doi:10.1074/jbc.R115.663708. PMID 25947376. 
  14. ↑ "Lipotoxicidad, obesidad y enfermedades metabólicas" (in Spanish). Revista de la Sociedad Española de Bioquímia y Biología Molecular (SEEBM) [Internet]. December 2016. pp. 17–22. https://sebbm.es/wp-content/uploads/190-bioquimica-de-la-obesidad.pdf. 
  15. ↑ "Deoxysphingolipids". https://www.caymanchem.com/news/deoxysphingolipids. 
  16. ↑ "Cytotoxic 1-deoxysphingolipids are metabolized by a cytochrome P450-dependent pathway". Journal of Lipid Research 58 (1): 60–71. January 2017. doi:10.1194/jlr.M072421. PMID 27872144. 
  17. ↑ "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. doi:10.1021/acs.langmuir.8b03237. PMID 30507134. 
  18. ↑ "Canonical and 1-Deoxy(methyl) Sphingoid Bases: Tackling the Effect of the Lipid Structure on Membrane Biophysical Properties". Langmuir 36 (21): 6007–6016. 2020. doi:10.1021/acs.langmuir.0c01000. PMID 32369370. 
  19. ↑ "(1-Deoxy)ceramides in bilayers containing sphingomyelin and cholesterol". Colloids and Surfaces B: Biointerfaces 243: 114155. 2024. doi:10.1016/j.colsurfb.2024.114236. PMID 39137529. 
  20. ↑ "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). 2021. doi:10.1016/j.bbamem.2021.183628. PMID 33915167. 
  21. ↑ "L-Serine Deficiency Elicits Intracellular Accumulation of Cytotoxic Deoxysphingolipids and Lipid Body Formation". The Journal of Biological Chemistry 290 (23): 14595–14609. June 2015. doi:10.1074/jbc.M114.603860. PMID 25903138. 
  22. ↑ "Localization of 1-deoxysphingolipids to mitochondria induces mitochondrial dysfunction". Journal of Lipid Research 58 (1): 42–59. January 2017. doi:10.1194/jlr.M068676. PMID 27881717. 
  23. ↑ "Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats". Diabetes 64 (3): 1035–1045. March 2015. doi:10.2337/db14-1325. PMID 25277395. 
  24. ↑ "Plasma deoxysphingolipids: a novel class of biomarkers for the metabolic syndrome?". Diabetologia 55 (2): 421–431. February 2012. doi:10.1007/s00125-011-2384-1. PMID 22124606. https://www.zora.uzh.ch/id/eprint/63201/4/Othman_et_al_Diabetologia_final.pdf. 
  25. ↑ "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. doi:10.1172/JCI57549. PMID 22045570. 
  26. ↑ "Randomized trial of l-serine in patients with hereditary sensory and autonomic neuropathy type 1". Neurology 92 (4): e359–e370. January 2019. doi:10.1212/WNL.0000000000006811. PMID 30626650. 



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