Details

Autor(en) / Beteiligte

• Zitomer, Nicholas C
• Mitchell, Trevor
• Voss, Kenneth A
• Bondy, Genevieve S
• Pruett, Sarah T
• Garnier-Amblard, Ethel C
• Liebeskind, Lanny S
• Park, Hyejung
• Wang, Elaine
• Sullards, M. Cameron
• Merrill, Alfred H. Jr
• Riley, Ronald T

Titel

Ceramide synthase inhibition by fumonisin B₁ causes accumulation of 1-deoxy-sphinganine: A novel category of bioactive 1-deoxy-sphingoid bases and 1-deoxy-dihydroceramides biosynthesized by mammalian cell lines and animals

Ist Teil von

• The Journal of biological chemistry, 2009, Vol.284 (8), p.4786-4795

Ort / Verlag

American Society for Biochemistry and Molecular Biology

Erscheinungsjahr

2009

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Fumonisin B₁ (FB₁) is a mycotoxin that inhibits ceramide synthases (CerS) and causes kidney and liver toxicity and other disease. Inhibition of CerS by FB₁ increases sphinganine (Sa), Sa 1-phosphate, and a previously unidentified metabolite. Analysis of the latter by quadrupole-time-of-flight mass spectrometry assigned an m/z = 286.3123 in positive ionization mode, consistent with the molecular formula for deoxysphinganine (C₁₈H₄₀NO). Comparison with a synthetic standard using liquid chromatography, electrospray tandem mass spectrometry identified the metabolite as 1-deoxysphinganine (1-deoxySa) based on LC mobility and production of a distinctive fragment ion (m/z 44, CH₃CH=NH⁺₂) upon collision-induced dissociation. This novel sphingoid base arises from condensation of alanine with palmitoyl-CoA via serine palmitoyltransferase (SPT), as indicated by incorporation of L-[U-¹³C]alanine into 1-deoxySa by Vero cells; inhibition of its production in LLC-PK₁ cells by myriocin, an SPT inhibitor; and the absence of incorporation of [U-¹³C]palmitate into 1-[¹³C]deoxySa in LY-B cells, which lack SPT activity. LY-B-LCB1 cells, in which SPT has been restored by stable transfection, however, produce large amounts of 1-[¹³C]deoxySa. 1-DeoxySa was elevated in FB₁-treated cells and mouse liver and kidney, and its cytotoxicity was greater than or equal to that of Sa for LLC-PK₁ and DU-145 cells. Therefore, this compound is likely to contribute to pathologies associated with fumonisins. In the absence of FB₁, substantial amounts of 1-deoxySa are made and acylated to N-acyl-1-deoxySa (i.e. 1-deoxydihydroceramides). Thus, these compounds are an underappreciated category of bioactive sphingoid bases and "ceramides" that might play important roles in cell regulation.