Selected Update: Lipid metabolism: Orm SPOTS demand

Posted: April 14, 2010 at 8:15 am

Story Summary: Breslow et al. investigated Orm function in the yeast Saccharomyces cerevisiae, using a genetic analysis that compares the phenotypic profiles of double mutants to identify pathways in which the individual mutant genes function. This suggests that Orm proteins negatively regulate sphingolipid biosynthesis, which was confirmed by global lipidomic analysis: deletion of Orm1 and Orm2 causes higher flux throughout the sphingolipid biosynthetic pathway. A novel protein complex, the serine palmitoyltransferase, Orm1 and Orm2, Tsc3 and Sac1 (SPOTS) complex, was identified using binding assays. The identification of several phosphorylated Orm species, and the use of the serine palmitoyltransferase inhibitor myriocin, provided further mechanistic clues. Comparisons of growth rate and metabolite levels between Orm1- and Orm2-deleted and wild-type yeast, with or without myriocin, indicated that cells use progressive inactivation of Orm1 and Orm2 to maintain sphingolipid output as serine palmitoyltransferase activity is inhibited. Phosphomutant Orm1 and Orm2 were able to interact with each other and with serine palmitoyltransferase, but blocked the normal regulation of SPOTS oligomerization and disrupted sphingolipid homeostasis. The authors suggest that the SPOTS complex dynamically coordinates the localization and activity of sphingolipid metabolism enzymes in response to cellular demand. Now the focus turns to whether misregulation of this axis can directly cause asthma….Read the Full Story

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