Sphingomyelin synthesis, inhibition

Park TS, Panek RL, Rekhter MD, Mueller SB, Rosebury WS, Robertson A, Hanselman JC, Kindt E, Homan R, Karathanasis SK. Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoEl knockout mice. Atherosclerosis 2006 189 264-272. 

This asymmetric Mannich-type reaction was successfully applied to the synthesis of (1 J ,31 )-N-(3-hydroxy-l-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12), which is the first compound that specifically inhibits sphingomyelin synthesis in mammalian cells, and is also expected to act as a drug that inhibits intracellular trafficking of sphingolipids (Scheme 3.27). ... 

It should be noted here that the synthesis of sphingomyelin, the lipid whose synthesis and breakdown are most intricately involved in the process of apoptosis, is dependent on the presence of PC, since the final step in SM synthesis involves the exchange of the phosphocholine head group from PC to ceramide (see Eigure 1). Theoretically, therefore, inhibition of PC synthesis may lead to an inhibition of SM generation and an accumulation of pro-apoptotic ceramides. On the other hand, an increased breakdown of SM by SMases as frequently observed in apoptotic cells, was shown to increase the conversion of PC to anti-apoptotic DAG (Sillence and Allan, 1998, for anti-apoptotic action of DAG see below). 

Darroch PI, Dagan A, Granot T, He X, Gatt S, Schuchman EH. A Upid analogue that inhibits sphingomyelin hydrolysis and synthesis, increases ceramide, and leads to cell death. J. Lipid Res. 2005 46 2315-2324. 

Soeda S, Tsuji Y, Ochiai T, Mishima K, Iwasaki K, et al. Inhibition of sphingomyelinase activity helps to prevent neuron death caused by ischemic stress. Neurochem. Int. 2004 45 619-626. Hakogi T, Taichi M, Katsumura S. Synthesis of a nitrogen analogue of sphingomyelin as a sphingomyelinase inhibitor. Org. Lett. 2003 5 2801-2804. 

Fusarium with the synthesis of sphingomyelins, inhibit the enzyme ceramide synthase,... 

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