51534-41-9Relevant academic research and scientific papers
The sphingolipid degradation product trans-2-hexadecenal forms adducts with DNA
Upadhyaya, Pramod,Kumar, Ashok,Byun, Hoe-Sup,Bittman, Robert,Saba, Julie D.,Hecht, Stephen S.
, p. 18 - 21 (2012)
Sphingosine 1-phosphate, a bioactive signaling molecule with diverse cellular functions, is irreversibly degraded by the endoplasmic reticulum enzyme sphingosine 1-phosphate lyase, generating trans-2-hexadecenal and phosphoethanolamine. We recently demonstrated that trans-2-hexadecenal causes cytoskeletal reorganization, detachment, and apoptosis in multiple cell types via a JNK-dependent pathway. These findings and the known chemistry of related α,β-unsaturated aldehydes raise the possibility that trans-2-hexadecenal may interact with additional cellular components. In this study, we show that it reacts readily with deoxyguanosine and DNA to produce the diastereomeric cyclic 1,. N2-deoxyguanosine adducts 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8. R-hydroxy-6. R-tridecylpyrimido[1,2-a]purine-10(3. H)one and 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8. S-hydroxy-6. S-tridecylpyrimido[1,2-a]purine-10(3. H)one. Thus, our findings suggest that trans-2-hexadecenal produced endogenously by sphingosine 1-phosphate lyase can react directly with DNA forming aldehyde-derived DNA adducts with potentially mutagenic consequences.
Characterization of homologous sphingosine-1- phosphate lyase isoforms in the bacterial pathogen Burkholderia pseudomallei
McLean, Christopher J.,Marles-Wright, Jon,Custodio, Rafael,Lowther, Jonathan,Kennedy, Amanda J.,Pollock, Jacob,Clarke, David J.,Brown, Alan R.,Campopiano, Dominic J.
, p. 137 - 150 (2017/01/25)
Sphingolipids (SLs) are ubiquitous elements in eukaryotic membranes and are also found in some bacterial and viral species. As well as playing an integral structural role, SLs also act as potent signaling molecules involved in numerous cellular pathways and have been linked to many human diseases. A central SL signaling molecule is sphingosine-1-phosphate (S1P), whose breakdown is catalyzed by S1P lyase (S1PL), a pyridoxal 5?-phosphate (PLP)-dependent enzyme that catalyzes the cleavage of S1P to (2E)-hexadecenal (2E-HEX) and phosphoethanolamine. Here, we show that the pathogenic bacterium, Burkholderia pseudomallei K96243, encodes two homologous proteins (S1PL2021 and S1PL2025) that display moderate sequence identity to known eukaryotic and prokaryotic S1PLs. Using an established MS-based methodology, we show that recombinant S1PL2021 is catalytically active. We also used recombinant human fatty aldehyde dehydrogenase to develop a spectrophotometric enzymecoupled assay to detect 2E-HEX formation and measure the kinetic constants of the two B. pseudomallei S1PL isoforms. Furthermore, we determined the X-ray crystal structure of the PLP-bound form of S1PL2021 at 2.1 ? resolution revealing that the enzyme displays a conserved structural fold and active site architecture comparable with known S1PLs. The combined data suggest that B. pseudomallei has the potential to degrade host SLs in a S1PL-dependent manner.-McLean, C., J. Marles-Wright, R. Custodio, J. Lowther, A. J. Kennedy, J. Pollock, D. J. Clarke, A. R. Brown, and D. J. Campopiano. Characterization of homologous sphingosine-1-phosphate lyase isoforms in the bacterial pathogen Burkholderia pseudomallei.
Creation of a S1P Lyase bacterial surrogate for structure-based drug design
Argiriadi, Maria A.,Banach, David,Radziejewska, Elzbieta,Marchie, Susan,Dimauro, Jennifer,Dinges, Jurgen,Dominguez, Eric,Hutchins, Charles,Judge, Russell A.,Queeney, Kara,Wallace, Grier,Harris, Christopher M.
, p. 2293 - 2296 (2016/04/20)
S1P Lyase (SPL) has been described as a drug target in the treatment of autoimmune diseases. It plays an important role in maintaining intracellular levels of S1P thereby affecting T cell egress from lymphoid tissues. Several groups have already published approaches to inhibit S1P Lyase with small molecules, which in turn increase endogenous S1P concentrations resulting in immunosuppression. The use of structural biology has previously aided SPL inhibitor design. Novel construct design is at times necessary to provide a reagent for protein crystallography. Here we present a chimeric bacterial protein scaffold used for protein X-ray structures in the presence of early small molecule inhibitors. Mutations were introduced to the bacterial SPL from Symbiobacterium thermophilum which mimic the human enzyme. As a result, two mutant StSPL crystal structures resolved to 2.8 ? and 2.2 ? resolutions were solved and provide initial structural hypotheses for an isoxazole chemical series, whose optimization is discussed in the accompanying paper.
