The sphingolipid degradation product trans-2-hexadecenal forms adducts with DNA.
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-8R-hydroxy-6R-tridecylpyrimido[1,2-a]purine-10(3H)one and 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8S-hydroxy-6S-tridecylpyrimido[1,2-a]purine-10(3H)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.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Pramod
P
Upadhyaya
Ashok
A
Kumar
Hoe-Sup
HS
Byun
Robert
R
Bittman
Julie D
JD
Saba
Stephen S
SS
Hecht
D000446:Aldehyde-Lyases / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D003849:Deoxyguanosine / Q000737:chemistry*; D008246:Lysophospholipids / Q000096:biosynthesis / Q000737:chemistry*; D016296:Mutagenesis; D013107:Sphingolipids / Q000737:chemistry*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry
C576057:3-(2-deoxypentofuranosyl)-5,6,7,8-tetrahydro-8-hydroxy-6-tridecylpyrimido(1,2-a)purine-10(3H)one; D000447:Aldehydes; D018736:DNA Adducts; D008246:Lysophospholipids; D013107:Sphingolipids; C060506:sphingosine 1-phosphate; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D003849:Deoxyguanosine; D013110:Sphingosine; C519712:2-hexadecenal