George Carman is a Theobald Smith Society Past President (1997-1998) and Waksman Honorary Lecturer (1996). His lab at the Rutgers Center for Lipid Research recently looked closely at the antidepressant drug sertraline and its possible use to remediate lipid-based disease.
Phosphatidic acid phosphatase (PAP) is an evolutionarily conserved eukaryotic enzyme that plays a key role in lipid homeostasis and is an important target for regulation to alleviate metabolic disorders associated with disturbances in phosphatidic acid and diacylglycerol levels. Sertraline is a novel noncompetitive inhibitor of the Saccharomyces cerevisiae PAP enzyme Pah1 with an inhibition constant (Ki) of 13.5 μM, 7-fold lower than the commonly used PAP inhibitor propranolol. Sertraline also inhibits the PAP activity of the human lipin 1 isoforms (α, β, and γ), with IC50 values approximately 2-fold lower than propranolol. The inhibition of PAP activity by sertraline in yeast cells leads to a decrease in triacylglycerol content and an increase in phospholipid content, consistent with the role of PAP in regulating the balance between these lipid classes.
They speculate that sertraline and/or structural analogs might be used to effect remediation of lipid-based disease based on PAP inhibition in humans to minimize latent Mycobacterium tuberculosis infection, alleviate intestinal inflammation-driven colon cancer development, suppress SARS-CoV-2 replication, and/or as an anti-mycotic.
Stukey GJ, Breuer MR, Burchat N, Jog R, Schultz K, Han GS, Sachs MS, Sampath H, Marmorstein R, Carman GM. The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatases. J Lipid Res. 2025 Jan;66(1):100711. doi: 10.1016/j.jlr.2024.100711. Epub 2024 Nov 20. PMID: 39577771; PMCID: PMC11721541. https://www.jlr.org/article/S0022-2275(24)00216-5/fulltext
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