title: Fumonisins and fumonisin analogs as inhibitors of ceramide synthase and inducers of apoptosis.
abstract: Sphingoid bases are growth inhibitory and pro-apoptotic for many types of cells when added to cells exogenously, and can be elevated to toxic amounts endogenously when cells are exposed to inhibitors of ceramide synthase. An important category of naturally occurring inhibitors are the fumonisins, which inhibit ceramide synthase through structural similarities with both the sphingoid base and fatty acyl-CoA co-substrates. Fumonisins cause a wide spectrum of disease (liver and renal toxicity and carcinogenesis, neurotoxicity, induction of pulmonary edema, and others), and most-possibly all-of the pathophysiologic effects of fumonisins are attributable to disruption of the sphingolipid metabolism. The products of alkaline hydrolysis of fumonisins (which occurs during the preparation of masa flour for tortillas) are aminopentols that also inhibit ceramide synthase, but more weakly. Nonetheless, the aminopentols (and other 1-deoxy analogs of sphinganine) are acylated to derivatives that inhibit ceramide synthase, perhaps as product analogs, elevate sphinganine, and kill the cells. Somewhat paradoxically, fumonisins sometimes stimulate growth and inhibit apoptosis, possibly due to elevation of sphinganine 1-phosphate, which is known to have these cellular effects. These findings underscore the complexity of sphingolipid metabolism and the difficulty of identifying the pertinent mediators unless a full profile of the potentially bioactive species is evaluated.
authors.affiliation: School of Biology, Georgia Institute of Technology, Atlanta, GA 30332-0230, USA.
authors.forename: Kena
authors.initials: K
authors.lastname: Desai
authors.forename: M Cameron
authors.initials: MC
authors.lastname: Sullards
authors.forename: Jeremy
authors.initials: J
authors.lastname: Allegood
authors.forename: Elaine
authors.initials: E
authors.lastname: Wang
authors.forename: Eva M
authors.initials: EM
authors.lastname: Schmelz
authors.forename: Michaela
authors.initials: M
authors.lastname: Hartl
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Humpf
authors.forename: D C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Qiong
authors.initials: Q
authors.lastname: Peng
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Merrill
mesh_terms: D000818:Animals; D017209:Apoptosis; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D037341:Fumonisins / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D006028:Glycosphingolipids / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D003313:Zea mays / Q000382:microbiology
chemical_list: D002264:Carboxylic Acids; D002273:Carcinogens; D004791:Enzyme Inhibitors; D037341:Fumonisins; D006028:Glycosphingolipids; D013107:Sphingolipids; C110744:aminopentol; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D013110:Sphingosine; C005682:safingol