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    Structure–activity relationship of sphingomyelin analogs with sphingomyelinase from Bacillus cereus

    Year: 2012

    Journal: Biochimica et Biophysica Acta, 2012, 1818 (3), 474-480, 20131009

    Authors: Christian Sergelius, Sanna Niinivehmas, Terhi Maula, Mayuko Kurita, Shou Yamaguchi, Tetsuya Yamamoto, Shigeo Katsumura, Olli T. Pentikäinen, J. Peter Slotte

    Organizations: Biochemistry, Department of Biosciences, Åbo Akademi University, Turku, Finland; Department of Biological and Environmental Science, P.O. Box 35, FI-40014 University of Jyväskylä, Finland; School of Science & Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda City, Hyogo 669-1337, Japan

    The aim of this study was to examine how structural properties of different sphingomyelin (SM) analogs affected their substrate properties with sphingomyelinase (SMase) from Bacillus cereus. Using molecular docking and dynamics simulations (for SMase–SM complex), we then attempted to explain the relationship between SM structure and enzyme activity. With both micellar and monolayer substrates, 3O-methylated SM was found not to be degraded by the SMase. 2N-methylated SM was a substrate, but was degraded at about half the rate of its 2NH–SM control. PhytoPSM was readily hydrolyzed by the enzyme. PSM lacking one methyl in the phosphocholine head group was a good substrate, but PSM lacking two or three methyls failed to act as substrates for SMase. Based on literature data, and our docking and MD simulations, we conclude that the 3O-methylated PSM fails to interact with Mg2 + and Glu53 in the active site, thus preventing hydrolysis. Methylation of 2NH was not crucial for binding to the active site, but appeared to interfere with an induced fit activation of the SMase via interaction with Asp156. An OH on carbon 4 in the long-chain base of phytoPSM appeared not to interfere with the 3OH interacting with Mg2 + and Glu53 in the active site, and thus did not interfere with catalysis. Removing two or three methyls from the PSM head group apparently increased the positive charge on the terminal N significantly, which most likely led to ionic interactions with Glu250 and Glu155 adjacent to the active site. This likely interaction could have misaligned the SM substrate and hindered proper catalysis.