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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

Permanent URL:
http://handle.nal.usda.gov/10113/53693
Abstract:
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.
Author(s):
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.
Subject(s):
alanine , cell lines , cytotoxicity , dissociation , enzyme inhibition , enzyme inhibitors , fumonisin B1 , hepatocytes , hepatotoxicity , hexosyltransferases , kidney cells , liquid chromatography , mammals , mass spectrometry , nephrotoxicity , phosphatidylcholine-choline acyltransferase , serine , sphingomyelins , transfection
Note:
Includes references
Source:
Journal of biological chemistry 2009 Feb. 20, v. 284, no. 8
Language:
English
Publisher:
American Society for Biochemistry and Molecular Biology
Year:
2009
Collection:
Journal Articles, USDA Authors, Peer-Reviewed
File:
Download [PDF File]
Rights:
Works produced by employees of the U.S. Government as part of their official duties are not copyrighted within the U.S. The content of this document is not copyrighted.