[28] Sphingosine-1-phosphate lyase

doi:10.1016/S0076-6879(00)11087-0

Methods in Enzymology

Volume 311, 2000, Pages 244-254

https://doi.org/10.1016/S0076-6879(00)11087-0 Get rights and content

Publisher Summary

Sphingoid bases are a group of related aliphatic 2-amino-l,3-diols and characteristic constituents of sphingolipids. The most prevalent base in mammals is sphingenine [_D(+)-erythro-2-amino-4-trans-l,3-octadecadecenediol; sphingosine]. The saturated analog, sphinganine (dihydrosphingosine), and the 4-hydroxyderivative of it, 4D-hydroxysphinganine (phytosphingosine), are less common but are major sphingoid bases in other organisms such as plants, invertebrata, fungi, and protozoa. All sphingoid bases found in nature possess the 2D, 3D-configuration, better known as “_D-erythro” (in the case of sphingenine or sphinganine), and generally contain 18 carbon atoms. The catabolic removal of sphingoid bases involves a phosphorylation of the primary hydroxyl group, followed by cleavage of the generated phosphorylated sphingoid base (PSB) between the carbon atoms carrying the amino and the secondary hydroxyl groups. The phosphorylation is catalyzed by sphingosine kinase. Mammalian tissues contain a cytosolic and a (presumably plasma) membrane-associated sphingosine kinase, the latter one being responsible for the major portion of the overall tissue activity. The cleavage reaction is catalyzed by sphingosine-1-phosphate lyase (sphingosine-phosphate lyase), also named “dihydrosphingosine-1-phosphate aldolase” or “sphinganine-l-phosphate alkanal lyase” (EC 4.1.2.27). In yeast, this reaction would be the rate-limiting step in sphingolipid breakdown. Interest in PSBs has increased substantially as these zwitterionic lipids appear to evoke different cellular responses. Hence, in addition to being catabolic intermediates, PSBs (especially sphingenine phosphate) are now considered to be inter- and/or intracellular messengers. Whether sphingosine-phosphate lyase plays a role in the attenuation of bioactive sphingenine phosphate has not been critically evaluated, but in mammalian cells a plasma membrane-bound sphingosine phosphatase activity would be involved in the inactivation process.

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Sphingosine 1-phosphate in sepsis and beyond: Its role in disease tolerance and host defense and the impact of carrier molecules
2021, Cellular Signalling
Sphingosine 1-phosphate (S1P) is an important immune modulator responsible for physiological cellular responses like lymphocyte development and function, positioning and emigration of T and B cells and cytokine secretion. Recent reports indicate that S1P does not only regulate immunity, but can also protect the function of organs by inducing disease tolerance. S1P also influences the replication of certain pathogens, and sphingolipids are also involved in pathogen recognition and killing. Certain carrier molecules for S1P like serum albumin and high density lipoproteins contribute to the regulation of S1P effects. They are able to associate with S1P and modulate its signaling properties. Similar to S1P, both carrier molecules are also decreased in sepsis patients and likely contribute to sepsis pathology and severity.
In this review, we will introduce the concept of disease tolerance and the involvement of S1P. We will also discuss the contribution of S1P and its precursor sphingosine to host defense mechanisms against pathogens. Finally, we will summarize current data demonstrating the influence of carrier molecules for differential S1P signaling. The presented data may lead to new strategies for the prevention and containment of sepsis.
Agonist-induced activation of the S1P receptor 2 constitutes a novel osteoanabolic therapy for the treatment of osteoporosis in mice
2019, Bone
Citation Excerpt :
We also identified clear associations of serum S1P and bone health in over 4000 human subjects [4]. The pharmacological S1P lyase inhibitor 4-deoxypyridoxine (DOP) that we employed but also several others of this group such as 2-acetyl-4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)imidazole (THI) and the novel LX2931 ((1E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime) that is tested as candidate drug for rheumatoid arthritis in a phase 2 clinical trial, block S1P lyase activity by competing with vitamin B6 at the pyridoxal-5′-phosphate binding domain of the enzyme [11,12]. Accordingly, side effects from interference with a number of other vitamin B6-dependent enzymes are expected.
Osteoporosis is a worldwide epidemic but pharmacological agents to stimulate new bone formation are scarce. We have shown that increasing tissue levels of sphingosine-1-phosphate (S1P) by blocking its degradation by the S1P lyase has pronounced osteoanabolic effect in mouse osteoporosis models by stimulating osteoblast differentiation through the S1P receptor 2 (S1P2). However, S1P lyase inhibitors have side effects complicating potential clinical use. Here, we tested whether direct S1P2 engagement by the S1P2 agonist CYM5520 exerted osteoanabolic potential in estrogen deficiency-induced osteopenia in mice. We compared its efficacy to LX2931, a novel S1P lyase inhibitor currently tested in rheumatoid arthritis.
CYM5520, LX2931 or vehicle were administered to ovariectomized mice for 6 weeks beginning 5 weeks after ovariectomy, Bone mass, cellular composition and mechanical strength were assessed by microCT, histomorphometry and three point bending tests. Plasma markers of bone metabolism were analyzed by ELISA.
Therapeutic treatment with CYM5520 and LX2931 clearly increased long bone and vertebral bone mass to impressive 3–5 fold over vehicle in osteopenic ovariectomized mice. As expected, lymphopenia was a side effect of LX2931, whereas none occurred with CYM5520. Consistent with an osteoanabolic effect, CYM5520 increased osteoblast number, osteoid surface and alkaline phosphatase area 2–3 fold over vehicle. Plasma concentrations of the osteoanabolic marker procollagen I C-terminal propeptide were also elevated by CYM5520 and LX2931. LX2931 but not yet CYM5520 increased cortical thickness and mechanical strength without affecting mineral density.
Treatment with a pharmacological S1P2 agonist corrected ovariectomy-induced osteopenia in mice by inducing new bone formation thus constituting a novel osteoanabolic approach to osteoporosis.
Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase
2017, Advances in Biological Regulation
Cellular level of sphingosine-1-phosphate (S1P), the simplest bioactive sphingolipid, is tightly regulated by its synthesis catalyzed by sphingosine kinases (SphKs) 1 & 2 and degradation mediated by S1P phosphatases, lipid phosphate phosphatases, and S1P lyase. The pleotropic actions of S1P are attributed to its unique inside-out (extracellular) signaling via G-protein-coupled S1P1-5 receptors, and intracellular receptor independent signaling. Additionally, S1P generated in the nucleus by nuclear SphK2 modulates HDAC1/2 activity, regulates histone acetylation, and transcription of pro-inflammatory genes. Here, we present data on the role of S1P lyase mediated S1P signaling in regulating LPS-induced inflammation in lung endothelium. Blocking S1P lyase expression or activity attenuated LPS-induced histone acetylation and secretion of pro-inflammatory cytokines. Degradation of S1P by S1P lyase generates Δ2-hexadecenal and ethanolamine phosphate and the long-chain fatty aldehyde produced in the cytoplasmic compartment of the endothelial cell seems to modulate histone acetylation pattern, which is different from the nuclear SphK2/S1P signaling and inhibition of HDAC1/2. These in vitro studies suggest that S1P derived long-chain fatty aldehyde may be an epigenetic regulator of pro-inflammatory genes in sepsis-induced lung inflammation. Trapping fatty aldehydes and other short chain aldehydes such as 4-hydroxynonenal derived from S1P degradation and lipid peroxidation, respectively by cell permeable agents such as phloretin or other aldehyde trapping agents may be useful in treating sepsis-induced lung inflammation via modulation of histone acetylation. .
Bacterial versus human sphingosine-1-phosphate lyase (S1PL) in the design of potential S1PL inhibitors
2016, Bioorganic and Medicinal Chemistry
A series of potential active-site sphingosine-1-phosphate lyase (S1PL) inhibitors have been designed from scaffolds 1 and 2, arising from virtual screening using the X-ray structures of the bacterial (StS1PL) and the human (hS1PL) enzymes. Both enzymes are very similar at the active site, as confirmed by the similar experimental kinetic constants shown by the fluorogenic substrate RBM13 in both cases. However, the docking scoring functions used probably overestimated the weight of electrostatic interactions between the ligands and key active-site residues in the protein environment, which may account for the modest activity found for the designed inhibitors. In addition, the possibility that the inhibitors do not reach the enzyme active site should not be overlooked. Finally, since both enzymes show remarkable structural differences at the access channel and in the proximity to the active site cavity, caution should be taken when designing inhibitors acting around that area, as evidenced by the much lower activity found in StS1PL for the potent hS1PL inhibitor D.
A facile stable-isotope dilution method for determination of sphingosine phosphate lyase activity
2016, Chemistry and Physics of Lipids
A new technique for quantifying sphingosine phosphate lyase activity in biological samples is described. In this procedure, 2-hydrazinoquinoline is used to convert (2E)-hexadecenal into the corresponding hydrazone derivative to improve ionization efficiency and selectivity of detection. Combined utilization of liquid chromatographic separation and multiple reaction monitoring-mass spectrometry allows for simultaneous quantification of the substrate S1P and product (2E)-hexadecenal. Incorporation of (2E)- d₅-hexadecenal as an internal standard improves detection accuracy and precision. A simple one-step derivatization procedure eliminates the need for further extractions. Limits of quantification for (2E)-hexadecenal and sphingosine-1-phosphate are 100 and 50 fmol, respectively. The assay displays a wide dynamic detection range useful for detection of low basal sphingosine phosphate lyase activity in wild type cells, SPL-overexpressing cell lines, and wild type mouse tissues. Compared to current methods, the capacity for simultaneous detection of sphingosine-1-phosphate and (2E)-hexadecenal greatly improves the accuracy of results and shows excellent sensitivity and specificity for sphingosine phosphate lyase activity detection.
Deficiency of sphingosine-1-phosphate lyase impairs lysosomal metabolism of the amyloid precursor protein
2014, Journal of Biological Chemistry
Progressive accumulation of the amyloid β protein in extracellular plaques is a neuropathological hallmark of Alzheimer disease. Amyloid β is generated during sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. In addition to the proteolytic processing by secretases, APP is also metabolized by lysosomal proteases. Here, we show that accumulation of intracellular sphingosine-1-phosphate (S1P) impairs the metabolism of APP. Cells lacking functional S1P-lyase, which degrades intracellular S1P, strongly accumulate full-length APP and its potentially amyloidogenic C-terminal fragments (CTFs) as compared with cells expressing the functional enzyme. By cell biological and biochemical methods, we demonstrate that intracellular inhibition of S1P-lyase impairs the degradation of APP and CTFs in lysosomal compartments and also decreases the activity of γ-secretase. Interestingly, the strong accumulation of APP and CTFs in S1P-lyase-deficient cells was reversed by selective mobilization of Ca²⁺ from the endoplasmic reticulum or lysosomes. Intracellular accumulation of S1P also impairs maturation of cathepsin D and degradation of Lamp-2, indicating a general impairment of lysosomal activity. Together, these data demonstrate that S1P-lyase plays a critical role in the regulation of lysosomal activity and the metabolism of APP.

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B. Turnover[28] Sphingosine-1-phosphate lyase

Publisher Summary

Chem. Phys. Lipids

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Chem. Phys. Lipids

J. Biol. Chem.

Chem. Phys. Lipids

Tetrahed. Lett.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Anal. Biochem.

J. Lipid Res.

Anal. Biochem.

Biochem. Biophys. Res. Commun.

J. Lipid Res.

Biochim. Biophys. Acta

FEBS Lett.

Adv. Lipid Res.

Methods Enzymol.

B. Turnover
[28] Sphingosine-1-phosphate lyase