title: Fumonisin toxicity and sphingolipid biosynthesis.
abstract: Fumonisins are inhibitors of sphinganine (sphingosine) N-acyltransferase (ceramide synthase) in vitro, and exhibit competitive-type inhibition with respect to both substrates of this enzyme (sphinganine and fatty acyl-CoA). Removal of the tricarballylic acids from fumonisin B1 reduces the potency by at least 10 fold; and fumonisin A1 (which is acetylated on the amino group) is essentially inactive. Studies with diverse types of cells (hepatocytes, neurons, kidney cells, fibroblasts, macrophages, and plant cells) have established that fumonisin B1 not only blocks the biosynthesis of complex sphingolipids; but also, causes sphinganine to accumulate. Some of the sphinganine is metabolized to the 1-phosphate and degraded to hexadecanal and ethanolamine phosphate, which is incorporated into phosphatidylethanolamine. Sphinganine is also released from cells and, because it appears in blood and urine, can be used as a biomarker for exposure. The accumulation of these bioactive compounds, as well as the depletion of complex sphingolipids, may account for the toxicity, and perhaps the carcinogenicity, of fumonisins.
authors.affiliation: Department of Biochemistry, Emory University, Atlanta, GA 30322, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Merrill
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: T R
authors.initials: TR
authors.lastname: Vales
authors.forename: E R
authors.initials: ER
authors.lastname: Smith
authors.forename: J J
authors.initials: JJ
authors.lastname: Schroeder
authors.forename: D S
authors.initials: DS
authors.lastname: Menaldino
authors.forename: C
authors.initials: C
authors.lastname: Alexander
authors.forename: H M
authors.initials: HM
authors.lastname: Crane
authors.forename: J
authors.initials: J
authors.lastname: Xia
authors.forename: D C
authors.initials: DC
authors.lastname: Liotta
authors.forename: F I
authors.initials: FI
authors.lastname: Meredith
authors.forename: R T
authors.initials: RT
authors.lastname: Riley
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D016923:Cell Death; D055572:Ceramidases; D004791:Enzyme Inhibitors / Q000633:toxicity; D037341:Fumonisins; D006801:Humans; D009183:Mycotoxins / Q000633:toxicity*; D013107:Sphingolipids / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D004791:Enzyme Inhibitors; D037341:Fumonisins; D009183:Mycotoxins; D013107:Sphingolipids; C056933:fumonisin B1; D000581:Amidohydrolases; D055572:Ceramidases