Ceramide Synthase Inhibition by Fumonisin B1 Causes Accumulation of 1-Deoxysphinganine

Abstract

13 C]deoxySa. 1-DeoxySa was elevated in FB 1 -treated cells and mouse liver and kidney, and its cytotoxicity was greater than or equal to that of Sa for LLC-PK 1 and DU-145 cells. Therefore, this compound is likely to contribute to pathologies associated with fumonisins. In the absence of FB 1 , 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. Fumonisins (FB)2 cause diseases of horses, swine, and other farm animals and are regarded to be potential risk factors for human esophageal cancer (1) and, more recently, birth defects (2). Studies of this family of mycotoxins, and particularly of the highly prevalent subspecies fumonisin B 1 (FB 1 ) (reviewed in Refs. 1 and 2), have established that FB 1, is both toxic and carcinogenic for laboratory animals, with the liver and kidney being the most sensitive target organs (3, 4). Other FB are also toxic, but their carcinogenicity is unknown.FB are potent inhibitors of ceramide synthase(s) (CerS) (5), the enzymes responsible for acylation of sphingoid bases using fatty acyl-CoA for sphingolipid biosynthesis de novo and recycling pathways (6). As a consequence of this inhibition, the substrates sphinganine (Sa) and, usually to a lesser extent, sphingosine (So), accumulate and are often diverted to sphinganine 1-phosphate (Sa1P) and sphingosine 1-phosphate (S1P), respectively (7), while the product N-acylsphinganines (dihydroceramides), N-acylsphingosines (ceramides, Cer), and more complex sphingolipids decrease (5, 7). This disruption of sphingolipid metabolism has been proposed to be responsible for the toxicity, and possibly carcinogenicity, of FB, based on mechanistic studies with cells in culture (5,(7)(8)(9). This has been borne out by a number of animal feeding studies that have correlated the elevation of Sa in blood, urine, liver, and kidney with liver and kidney toxicity (4, 7, 10, 11).Most of the mechanistic studies have focused on the accumulation of free Sa and other sphingoid bases, because these compounds are highly cytotoxic, although the large number of bioactive metabolites in this pathway make it likely that multi-

The External Aldimine Form of Serine Palmitoyltransferase

“…The eukaryotic SPT heterodimeric isozymes appear to be more complex than their bacterial homologs, since a third, tissue-specific SPT subunit has been identified recently (34). Furthermore, an abnormal, "dead end" sphingolipid product, 1-deoxysphinganine (also known as the natural product "spisulosine"), formed by SPT using L-Ala as a substrate, has been identified in mammalian cells (53,54). Whether the SPT HSAN1 mutations impact directly on substrate and product specificity requires further detailed investigation.…”

Sphingolipid and Glycosphingolipid Metabolic Pathways in the Era of Sphingolipidomics

“…They are mainly present as the N-acylated (1-deoxydihydroceramide) metabolites,(67) which will be extremely hydrophobic. It is not clear how they are catabolized since degradation of the typical sphingoid bases proceeds via the 1-phosphates.…”

Many Ceramides

“…SPT can also employ alanine as a substrate to generate a 1-deoxysphingoid backbone, an effect that is exaggerated in the SPT mutants in type I hereditary sensory and autonomic neuropathy (76), and may even employ glycine to generate a 1-de(OHmethyl)sphingoid backbone (77).…”