Naturally Occurring <i>cis</i> -9-Docosenoic Acid from the <i>Hizikia fusiformis</i> Dietary Seaweed Inhibits Sphingomyelin Synthase

Naturally occurring inhibitors of membrane-bound enzymes offer therapeutic potential for metabolic disorders such as obesity and fatty liver disease. Sphingomyelin synthase (SMS), which converts ceramide to sphingomyelin, is a promising target in this regard. In this study, cis -9-docosenoic acid (9Z-DSA) was identified from the dietary seaweed Hizikia fusiformis ( hijiki ) as a natural SMS inhibitor. Inhibition assays using HeLa cell lysates expressing SMS1 and SMS2 a reliable model for membrane enzyme studies were analyzed by liquid chromatography–mass spectrometry (LC–MS). The nonpolar hexane extract of hijiki exhibited SMS inhibitory activity, and purification revealed 9Z-DSA (47% purity) as the active compound, with IC 50 values of 4.5 ± 1.3 μM for SMS1 and 5.8 ± 1.8 μM for SMS2. Molecular docking and dynamics simulations indicated strong binding interactions between 9Z-DSA and the SMS active sites. These findings demonstrate that 9Z-DSA functions as a natural SMS inhibitor with potential as a nutraceutical candidate for metabolic disease management.