The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatases
Phosphatidic acid phosphatase (PAP) is an evolutionarily conserved eukaryotic enzyme that catalyzes the Mg2+-dependent dephosphorylation of phosphatidic acid to produce diacylglycerol. The product and substrate of PAP are key intermediates in the synthesis of triacylglycerol and membrane phospholipi...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002165 |
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| author | Geordan J. Stukey Matthew R. Breuer Natalie Burchat Ruta Jog Kollin Schultz Gil-Soo Han Matthew S. Sachs Harini Sampath Ronen Marmorstein George M. Carman |
| author_facet | Geordan J. Stukey Matthew R. Breuer Natalie Burchat Ruta Jog Kollin Schultz Gil-Soo Han Matthew S. Sachs Harini Sampath Ronen Marmorstein George M. Carman |
| author_sort | Geordan J. Stukey |
| collection | DOAJ |
| description | Phosphatidic acid phosphatase (PAP) is an evolutionarily conserved eukaryotic enzyme that catalyzes the Mg2+-dependent dephosphorylation of phosphatidic acid to produce diacylglycerol. The product and substrate of PAP are key intermediates in the synthesis of triacylglycerol and membrane phospholipids. PAP activity is associated with lipid-based cellular defects indicating the enzyme is an important target for regulation. We identified that the antidepressant sertraline is a novel inhibitor of PAP. Using Saccharomyces cerevisiae Pah1 as a model PAP, sertraline inhibited the activity by a noncompetitive mechanism. Sertraline also inhibited the PAP activity of human lipin 1 (α, β, and γ), an orthologue of Pah1. The inhibitor constants of sertraline for the S. cerevisiae and human PAP enzymes were 7-fold and ∼2-fold, respectively, lower than those of propranolol, a commonly used PAP inhibitor. Consistent with the inhibitory mechanism of sertraline and propranolol, molecular docking of the inhibitors predicts that they interact with non-catalytic residues in the haloacid dehalogenase-like catalytic domain of Pah1. The Pah1-CC (catalytic core) variant, which lacks regulatory sequences, was inhibited by both drugs in accordance with molecular docking data. That Pah1 is a physiological target of sertraline in S. cerevisiae is supported by the observations that the overexpression of PAH1 rescued the sertraline-mediated inhibition of pah1Δ mutant cell growth, the lethal effect of overexpressing Pah1-CC was rescued by sertraline supplementation, and that a sublethal dose of the drug resulted in a 2-fold decrease in TAG content. |
| format | Article |
| id | doaj-art-a0d0d4faeb0e471c90f37024511a8b06 |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-a0d0d4faeb0e471c90f37024511a8b062025-01-30T05:12:38ZengElsevierJournal of Lipid Research0022-22752025-01-01661100711The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatasesGeordan J. Stukey0Matthew R. Breuer1Natalie Burchat2Ruta Jog3Kollin Schultz4Gil-Soo Han5Matthew S. Sachs6Harini Sampath7Ronen Marmorstein8George M. Carman9Department of Food Science, Rutgers University, New Brunswick, NJ, USA; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USADepartment of Biology, Texas A&M University, College Station, TX, USARutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USA; Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USADepartment of Food Science, Rutgers University, New Brunswick, NJ, USA; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USAAbramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Graduate Group in Biochemistry & Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Food Science, Rutgers University, New Brunswick, NJ, USA; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USADepartment of Biology, Texas A&M University, College Station, TX, USARutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USA; Department of Nutritional Sciences, Rutgers University, New Brunswick, NJ, USAAbramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biochemistry & Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Food Science, Rutgers University, New Brunswick, NJ, USA; Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ, USA; For correspondence: George M. CarmanPhosphatidic acid phosphatase (PAP) is an evolutionarily conserved eukaryotic enzyme that catalyzes the Mg2+-dependent dephosphorylation of phosphatidic acid to produce diacylglycerol. The product and substrate of PAP are key intermediates in the synthesis of triacylglycerol and membrane phospholipids. PAP activity is associated with lipid-based cellular defects indicating the enzyme is an important target for regulation. We identified that the antidepressant sertraline is a novel inhibitor of PAP. Using Saccharomyces cerevisiae Pah1 as a model PAP, sertraline inhibited the activity by a noncompetitive mechanism. Sertraline also inhibited the PAP activity of human lipin 1 (α, β, and γ), an orthologue of Pah1. The inhibitor constants of sertraline for the S. cerevisiae and human PAP enzymes were 7-fold and ∼2-fold, respectively, lower than those of propranolol, a commonly used PAP inhibitor. Consistent with the inhibitory mechanism of sertraline and propranolol, molecular docking of the inhibitors predicts that they interact with non-catalytic residues in the haloacid dehalogenase-like catalytic domain of Pah1. The Pah1-CC (catalytic core) variant, which lacks regulatory sequences, was inhibited by both drugs in accordance with molecular docking data. That Pah1 is a physiological target of sertraline in S. cerevisiae is supported by the observations that the overexpression of PAH1 rescued the sertraline-mediated inhibition of pah1Δ mutant cell growth, the lethal effect of overexpressing Pah1-CC was rescued by sertraline supplementation, and that a sublethal dose of the drug resulted in a 2-fold decrease in TAG content.http://www.sciencedirect.com/science/article/pii/S0022227524002165phosphatidic acid phosphatasePah1lipin 1diacylglyceroltriacylglycerolsertraline |
| spellingShingle | Geordan J. Stukey Matthew R. Breuer Natalie Burchat Ruta Jog Kollin Schultz Gil-Soo Han Matthew S. Sachs Harini Sampath Ronen Marmorstein George M. Carman The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatases Journal of Lipid Research phosphatidic acid phosphatase Pah1 lipin 1 diacylglycerol triacylglycerol sertraline |
| title | The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatases |
| title_full | The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatases |
| title_fullStr | The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatases |
| title_full_unstemmed | The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatases |
| title_short | The antidepressant drug sertraline is a novel inhibitor of yeast Pah1 and human lipin 1 phosphatidic acid phosphatases |
| title_sort | antidepressant drug sertraline is a novel inhibitor of yeast pah1 and human lipin 1 phosphatidic acid phosphatases |
| topic | phosphatidic acid phosphatase Pah1 lipin 1 diacylglycerol triacylglycerol sertraline |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002165 |
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