Abstract
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,. N 2-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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 18-21 |
| Number of pages | 4 |
| Journal | Biochemical and Biophysical Research Communications |
| Volume | 424 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jul 20 2012 |
Bibliographical note
Funding Information:This study was supported by NIH grants CA-77528 and CA-129438 (JDS), CA-81301 (SSH), and HL-083187 (RB) . Mass spectrometry was carried out in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center , supported in part by NIH grant CA-77598 . We thank Todd Rappe, University of Minnesota NMR Center, for acquiring the NMR spectra.
Keywords
- 1,N -propanodeoxyguanosine adducts
- DNA adducts
- Sphingosine 1-phosphate
- Sphingosine 1-phosphate lyase
- Trans-2-Hexadecenal