Innovative analytical tactics toward the discovery of seaweed bio-actives for obesity control

Abstract: Over the past 40 years, obesity has become a major global epidemic and is a leading preventable cause of death, closely linked to metabolic syndrome and fatty liver disease. Altered lipid metabolism plays a crucial role in these conditions, primarily regulated by sphingomyelin synthase (SMS) enzymes, particularly SMS1 and SMS2. The upregulation of SMS enzymes is one of the key contributors to obesity. This study focuses on discovering anti-obesity agents from natural products, using an LC/MS-based screening method.
The objective is to discover natural bioactive compounds as anti-obesity agents from seaweed extracts by using an LC/MS-based method. In this study, we established a sensitive LC/MS-based method for monitoring the SMS activity using HeLa cells. Further, validated the method by in-vitro and in-silico studies with a natural inhibitor ginkgolic acid (GA), which showed IC₅₀ of 5.5 μM and 3.6 μM for SMS1 and SMS2 enzymes respectively. Binding energies for GA with SMS1 and SMS2 are −6.6 kcal/mol and −8.2 kcal/mol respectively.
The developed method was applied to screen the various seaweed extracts for the discovery of a potent SMS inhibitor. Our findings revealed that seaweed wakame hexane extract showed strong inhibition against both SMS1 and SMS2. Further analysis led to the identification and characterization of the active compound as a long-chain fatty acid (LCFA), which is responsible for SMS inhibition. LCFA (FA 20:5) demonstrated IC₅₀ values of 10 μM for SMS1 and 6.5 μM for SMS2. To support these results in-silico analyses revealed strong binding interactions of FA 20:5 with SMS1 and SMS2 are -7.1 kcal/mol and -6.4 kcal/mol, respectively.
This study provides a new, sensitive method for screening SMS inhibitors. The discovery of potent inhibitors from wakame seaweed offers the potential for developing plant-based nutraceuticals to combat obesity, aligning with the AOCS Analytical Division's focus on advancing lipid-related research.