Ceramide synthase inhibition by fumonisin B1 causes accumulation of 1-deoxysphinganine: a novel category of bioactive 1-deoxysphingoid bases and 1-deoxydihydroceramides biosynthesized by mammalian cell lines and animals.
Fumonisin B(1) (FB(1)) is a mycotoxin that inhibits ceramide synthases (CerS) and causes kidney and liver toxicity and other disease. Inhibition of CerS by FB(1) 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 (C(18)H(40)NO). 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, CH(3)CH=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-(13)C]alanine into 1-deoxySa by Vero cells; inhibition of its production in LLC-PK(1) cells by myriocin, an SPT inhibitor; and the absence of incorporation of [U-(13)C]palmitate into 1-[(13)C]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-[(13)C]deoxySa. 1-DeoxySa was elevated in FB(1)-treated cells and mouse liver and kidney, and its cytotoxicity was greater than or equal to that of Sa for LLC-PK(1) and DU-145 cells. Therefore, this compound is likely to contribute to pathologies associated with fumonisins. In the absence of FB(1), 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.
Zitomer
Nicholas C
NC
Toxicology and Mycotoxin Research Unit, USDA-ARS, Athens, Georgia 30604, USA.
Mitchell
Trevor
T
Voss
Kenneth A
KA
Bondy
Genevieve S
GS
Pruett
Sarah T
ST
Garnier-Amblard
Ethel C
EC
Liebeskind
Lanny S
LS
Park
Hyejung
H
Wang
Elaine
E
Sullards
M Cameron
MC
Merrill
Alfred H
AH
Riley
Ronald T
RT
D000818:Animals; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D037341:Fumonisins / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000201:enzymology*; D051379:Mice; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013552:Swine; D014709:Vero Cells
C514304:1-deoxysphingosine; D004791:Enzyme Inhibitors; D037341:Fumonisins; C056933:fumonisin B1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D013110:Sphingosine