Acylation of naturally occurring and synthetic 1-deoxysphinganines by ceramide synthase. Formation of N-palmitoyl-aminopentol produces a toxic metabolite of hydrolyzed fumonisin, AP1, and a new category of ceramide synthase inhibitor.
Fumonisin B1 (FB1) is the predominant member of a family of mycotoxins produced by Fusarium moniliforme (Sheldon) and related fungi. Certain foods also contain the aminopentol backbone (AP1) that is formed upon base hydrolysis of the ester-linked tricarballylic acids of FB1. Both FB1 and, to a lesser extent, AP1 inhibit ceramide synthase due to structural similarities between fumonisins (as 1-deoxy-analogs of sphinganine) and sphingoid bases. To explore these structure-function relationships further, erythro- and threo-2-amino, 3-hydroxy- (and 3, 5-dihydroxy-) octadecanes were prepared by highly stereoselective syntheses. All of these analogs inhibit the acylation of sphingoid bases by ceramide synthase, and are themselves acylated with Vmax/Km of 40-125 for the erythro-isomers (compared with approximately 250 for D-erythro-sphinganine) and 4-6 for the threo-isomers. Ceramide synthase also acylates AP1 (but not FB1, under the conditions tested) to N-palmitoyl-AP1 (PAP1) with a Vmax/Km of approximately 1. The toxicity of PAP1 was evaluated using HT29 cells, a human colonic cell line. PAP1 was at least 10 times more toxic than FB1 or AP1 and caused sphinganine accumulation as an inhibitor of ceramide synthase. These studies demonstrate that: the 1-hydroxyl group is not required for sphingoid bases to be acylated; both erythro- and threo-isomers are acylated with the highest apparent Vmax/Km for the erythro-analogs; and AP1 is acylated to PAP1, a new category of ceramide synthase inhibitor as well as a toxic metabolite that may play a role in the diseases caused by fumonisins.
Humpf
H U
HU
Lehrstuhl für Lebensmittelchemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany.
Schmelz
E M
EM
Meredith
F I
FI
Vesper
H
H
Vales
T R
TR
Wang
E
E
Menaldino
D S
DS
Liotta
D C
DC
Merrill
A H
AH
D000215:Acylation; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism*; D037341:Fumonisins; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D009183:Mycotoxins / Q000737:chemistry / Q000378:metabolism*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
D002264:Carboxylic Acids; D037341:Fumonisins; D009183:Mycotoxins; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; C110744:aminopentol; D019308:Palmitic Acid; C056933:fumonisin B1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D013110:Sphingosine; C005682:safingol