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Title: ACYLATION OF NATURALLY OCCURRING AND SYNTHETIC 1-DEOXYSPHINGANINES BY CERAMIDE SYNTHASE: FORMATION OF N-PALMIMTOYL-AMINOPENTOL (PAP1) PRODUCES A TOXIC METABOLITE OF HYDROLYZED FUMONISIN (AP1), AND A NEW .... INHIBITOR

Author
item HUMPF, HANS-ULRICH - UNIVERSITAT WURZBURG, GR
item SCHMELZ, EVA-MARIA - BIOCM/EMORY U SCH MED,ATL
item Meredith, Filmore
item VESPER, HUBERT - BIOCM/EMORY U SCH MED,ATL
item VALES, TERESA - BIOCM/EMORY U SCH MED,ATL
item WANG, ELAINE - BIOCM/EMORY U SCH MED,ATL
item MENALDINO, DAVID - CHEM/EMORY U SCH MED,ATL
item LIOTTA, DENNIS - CHEM/EMORY U SCH MED, ATL
item MERRILL, JR, ALFRED - BIOCM/EMORY U SCH MED,ATL

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/23/1998
Publication Date: N/A
Citation: N/A

Interpretive Summary: Toxic substances, named fumonisins are produced by a fungus Fusarium moniliforme. These toxins are produced on corn and corn products and are health risks for animals and humans. Changes in the levels of sphingoid bases in cells due to the inhibition of certain enzymes (ceramide synthase) allow them to be used as a bio-marker to monitor fumonisin toxicity. This study reports on the effect of increases in the bio-marker produced by several chemical compounds that are structurally similar to fumonisin. The bio-marker enzyme was inhibited by the fumonisin like compounds, thus increasing the sphingoid bases. From the above effects it was learned that the bio-marker enzyme does not require a specific group to be active. Two additional chemical compounds were prepared with fumonisin. These chemicals also inhibited the bio-marker enzyme at least 10 times more than fumonisin. The results indicate that fumonisin may be converted to another new category of toxic compounds that should be considered in fumonisin induced toxicity.

Technical Abstract: 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-didhyroxy-) 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 to 125 for the erythro-isomers (compared to ca 250 for D-erythro -sphinganine) and 4 to 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.