Synthesis and application of a photocaged-l-lactate for studying the biological roles of l-lactate
Abstract l-Lactate, once considered a metabolic waste product of glycolysis, is now recognized as a vitally important metabolite and signaling molecule in multiple biological pathways. However, exploring l-lactate’s emerging intra- and extra-cellular roles is hindered by a lack of tools to perturb l...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01495-1 |
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| Summary: | Abstract l-Lactate, once considered a metabolic waste product of glycolysis, is now recognized as a vitally important metabolite and signaling molecule in multiple biological pathways. However, exploring l-lactate’s emerging intra- and extra-cellular roles is hindered by a lack of tools to perturb l-lactate concentration intracellularly and extracellularly. Photocaged compounds are a powerful way to introduce bioactive molecules with spatiotemporal precision using illumination. Here, we report the development of a photocaged derivative of l-lactate, 4-methoxy-7-nitroindolinyl-l-lactate (MNI-l-lac), that releases l-lactate upon illumination. We validated MNI-l-lac in cell culture by demonstrating that the photorelease of l-lactate elicits a response from genetically encoded extra- and intracellular l-lactate biosensors (eLACCO1, eLACCO2.1, R-iLACCO1.2). To demonstrate the utility of MNI-l-lac, we employed the photorelease of l-lactate to activate G protein-coupled receptor 81 (GPR81), as revealed by the inhibition of adenylyl cyclase activity and concomitant decrease of cAMP. These results indicate that MNI-l-lac may be useful for perturbing the concentration of endogenous l-lactate in order to investigate l-lactate’s roles in metabolic and signaling pathways. |
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| ISSN: | 2399-3669 |