Novel inhibitors of mitochondrial sn-glycerol 3-phosphate dehydrogenase
| Autor: | Adam L. Orr, Melissa R. Sarantos, Deepthi Ashok, Martin D. Brand, Tong Shi, Akos A. Gerencser, Robert E. Hughes, Ryan Ng |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Enzyme Metabolism
lcsh:Medicine Dehydrogenase Mitochondrion Biochemistry Energy-Producing Processes Mice Drug Discovery Enzyme Inhibitors Inner mitochondrial membrane lcsh:Science Energy-Producing Organelles chemistry.chemical_classification Multidisciplinary Molecular Structure Lipids Oxygen Metabolism Enzymes Mitochondrial Membranes Carbohydrate Metabolism Metabolic Pathways Research Article Glycerol phosphate shuttle Bioenergetics Biology Models Biological Fluorescence Glycerides Inhibitory Concentration 50 Structure-Activity Relationship Chemical Biology Animals Muscle Skeletal Enzyme Kinetics Glycerol-3-Phosphate Dehydrogenase (NAD+) lcsh:R Succinates Lipid Metabolism Amides Cytosol Metabolism Enzyme Glycerol-3-phosphate dehydrogenase chemistry Small Molecules Benzimidazoles lcsh:Q NAD+ kinase Neuroscience |
| Zdroj: | PLoS ONE, Vol 9, Iss 2, p e89938 (2014) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Mitochondrial sn-glycerol 3-phosphate dehydrogenase (mGPDH) is a ubiquinone-linked enzyme in the mitochondrial inner membrane best characterized as part of the glycerol phosphate shuttle that transfers reducing equivalents from cytosolic NADH into the mitochondrial electron transport chain. Despite the widespread expression of mGPDH and the availability of mGPDH-null mice, the physiological role of this enzyme remains poorly defined in many tissues, likely because of compensatory pathways for cytosolic regeneration of NAD⁺ and mechanisms for glycerol phosphate metabolism. Here we describe a novel class of cell-permeant small-molecule inhibitors of mGPDH (iGP) discovered through small-molecule screening. Structure-activity analysis identified a core benzimidazole-phenyl-succinamide structure as being essential to inhibition of mGPDH while modifications to the benzimidazole ring system modulated both potency and off-target effects. Live-cell imaging provided evidence that iGPs penetrate cellular membranes. Two compounds (iGP-1 and iGP-5) were characterized further to determine potency and selectivity and found to be mixed inhibitors with IC₅₀ and K(i) values between ∼1-15 µM. These novel mGPDH inhibitors are unique tools to investigate the role of glycerol 3-phosphate metabolism in both isolated and intact systems. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|