| Autor: |
Saman Salari, Hiu‐Fung Lee, Youla S. Tsantrizos, Jaeok Park |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
FEBS Open Bio, Vol 14, Iss 8, Pp 1320-1339 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2211-5463 |
| DOI: |
10.1002/2211-5463.13853 |
| Popis: |
Mevalonate kinase is a key regulator of the mevalonate pathway, subject to feedback inhibition by the downstream metabolite farnesyl pyrophosphate. In this study, we validated the hypothesis that monophosphonate compounds mimicking farnesyl pyrophosphate can inhibit mevalonate kinase. Exploring compounds originally synthesized as allosteric inhibitors of farnesyl pyrophosphate synthase, we discovered mevalonate kinase inhibitors with nanomolar activity. Kinetic characterization of the two most potent inhibitors demonstrated Ki values of 3.1 and 22 nm. Structural comparison suggested features of these inhibitors likely responsible for their potency. Our findings introduce the first class of nanomolar inhibitors of human mevalonate kinase, opening avenues for future research. These compounds might prove useful as molecular tools to study mevalonate pathway regulation and evaluate mevalonate kinase as a potential therapeutic target. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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