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Review
. 2024 Dec;476(12):1833-1843.
doi: 10.1007/s00424-024-03018-8. Epub 2024 Sep 19.

Atypical sphingosine-1-phosphate metabolites-biological implications of alkyl chain length

Melanie Glueck  1   2 , Alexandra Lucaciu  1   3 , Julien Subburayalu  4   5 , Roxane Isabelle Kestner  1   3 , Waltraud Pfeilschifter  1   6 , Rajkumar Vutukuri  7 , Josef Pfeilschifter  8
Affiliations
Review

Atypical sphingosine-1-phosphate metabolites-biological implications of alkyl chain length

Melanie Glueck et al. Pflugers Arch. 2024 Dec.

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive lipid signaling molecule with pleiotropic implications by both auto- and paracrine signaling. Signaling occurs by engaging five G protein-coupled receptors (S1P1-5) or intracellular pathways. While the extensively studied S1P with a chain length of 18 carbon atoms (d18:1 S1P) affects lymphocyte trafficking, immune cell survival and inflammatory responses, the biological implication of atypical S1Ps such as d16:1 or d20:1 remains elusive. As S1P lipids have far-reaching implications in health and disease states in mammalian organisms, the previous contrasting results may be attributed to differences in S1P's alkyl chain length. Current research is beginning to appreciate these less abundant atypical S1P moieties. This review provides an up-to-date foundation of recent findings on the biological implications of atypical S1P chain lengths and offers a perspective on future research endeavors on S1P alkyl chain length-influenced signaling and its implications for drug discovery.

Keywords: Chain lengths; Myristoyl CoA; Palmitoyl CoA; Serine palmitoyl transferase; Sphingolipids; Sphingosine-1-phosphate (S1P); Stearoyl CoA.

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Conflict of interest statement

Declarations. Ethics approval: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
A Biosynthesis of atypical sphingosine-1-phosphate metabolites. De novo sphingolipid biosynthesis is initiated in the smooth endoplasmic reticulum. Here the α-aminocarbonic acid serine and the lipids decanoyl-CoA, lauroyl-CoA, myristoyl-CoA, palmitoyl-CoA, stearoyl-CoA, and arachidoyl-CoA are enzymatically processed by the key enzyme serine palmitoyltransferase (SPT) to 3-keto-sphinganine with varying LCBs. The further enzymatic reactions include a reduction to dihydrosphingolipid with varying LCBs, followed by a synthase reaction to dihydroceramide and a desaturase reaction to ceramide, followed by a deacylation by ceramidase to form sphingosine. Sphingosine is phosphorylated by sphingosine kinases to S1P with varying LCBs. Enzymatic activities of SPT for these metabolites were taken from Raman et al. [56]. B The enzyme SPT is composed of two large subunits (SPTLC1 and SPTLC2 or SPTLC3) and one small subunit (SPTssa or SPTssb). The subunit composition of SPT dictates the fatty-acyl-CoA substrates utilized. SPTLC1/3/SPTssa can use myristoyl-CoA, resulting in d16 bases. A SPTssb mutation increases the affinity of SPT towards C18 acyl-CoA substrates and significantly elevates C20 LCB production in the mutant brain and eye (Zhao et al., 2015). Kd- Dissociation constant
Fig. 2
Fig. 2
Identification of atypical sphingosine-1-phosphate metabolites in several organs and their implications in health and diseases. Reduced levels of d20:1 have been reported in whole brain homogenate and mouse brain microvessels in a septic encephalopathy mouse model (Vutukuri et al., 2018). It was also shown that significantly elevated C20 LCBs in the mutant mouse brain and eye play a detrimental role resulting in neurodegenerative effects (Zhao et al., 2015). Elevated C20 LCBs have been regarded as predictive biomarkers of cardiovascular events independently from conventional cardiovascular risk factors (Othman et al., 2015). The new atlas of murine sphingolipids displayed that d18:1 sphingosine (SPH) is the most abundant mammalian SPH and showed a very characteristic peak value in the skin for d16:1 SPH (Muralidharan et al., 2021). Glueck et al. confirmed the levels of C16:1 in human kidney samples and investigated the role of d16:1 S1P in renal cell carcinoma (RCC) Glueck et al. [17]. Reduced levels of d16:1 have also been shown in vascular cognitive impairment Chua et al. [10]
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