1-DEOXY-SPHINGOID BASE AND 1-DEOXYDIHYDROCER BIOSYNTHESIS IN MAMALS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A novel sphingoid base, 1-deoxysphinganine (1-deoxySa), was recently reported (Zitomer et al., J. Biol. Chem. 284:4786, 2009) to accumulate in fumonisin B1 (FB1) treated cells in culture and in livers and kidneys from mice exposed to this mycotoxin. 1-Deoxysphinganine was shown to arise from condensation of L-alanine with palmitoyl-CoA by following the incorporation of [13C]-L-alanine or [13C]palmitate into [13C]-1-deoxySa by cells in culture. Serine palmitoyltransferase (SPT) was established to be responsible for this reaction because it was absent in a CHO cell line (LY-B) that lacks SPT activity (due to mutation of the LCB1 gene) and restored when wild-type LCB1 was stably transfected back into the cells. This sphingoid base is produced by cells in culture and animals (including humans) under normal conditions (i.e., FB1 is not required for its biosynthesis), but is metabolized to 1-deoxydihydroceramides rather than accumulating as the free sphingoid base. We have determined that glycine is utilized by SPT to synthesize 1-desoxymethyl-sphinganine (1-desoxySa), which is metabolized to 1-desoxymethyl-dihydroceramides. In contrast, L-threonine was not found to be utilized to make a sphingoid base analog. Therefore, SPT is a tri-functional enzyme with the capacity to utilize serine, alanine or glycine to synthesize three categories of sphingoid bases. Furthermore, the distribution of these products is dependent on the relative amounts of the respective precursors available at the site of synthesis. Since 1-deoxy- and 1-desoxymethyl-sphingoid bases are naturally produced by mammalian cells, and the amounts appear to be controlled by the balance of important intermediary metabolites, it seems likely that these novel lipids play significant roles in cell regulation.