SF2312 is a natural phosphonate inhibitor of enolase
| Autor: | Gilbert R. Lee, Florian L. Muller, John M. Asara, Todd M. Link, Federica Pisaneschi, Barbara Czako, Y. Alan Wang, Duoli Sun, William G. Bornmann, Yu Hsi Lin, Ronald A. DePinho, Paul G. Leonard, David Maxwell, Maria Emilia Di Francesco, Naima Hammoudi, Nikunj Satani, Basvoju A. Bhanu Prasad, Zhenghong Peng |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Enolase Organophosphonates Cancer therapy Article Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Glioma medicine Humans Enzyme Inhibitor Glycolysis Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure biology Cell Biology medicine.disease Phosphonate Molecular biology Pyrrolidinones Metabolic pathway 030104 developmental biology Enzyme chemistry Biochemistry Enzyme inhibitor Phosphopyruvate Hydratase biology.protein |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| DOI: | 10.1038/nchembio.2195 |
| Popis: | Despite being crucial for energy generation in most forms of life, few if any microbial antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme enolase 2 (ENO2) for the treatment of cancers with deletion of ENO1 (encoding enolase 1), we modeled the synthetic tool compound inhibitor phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. A ring-stabilized analog of PhAH, in which the hydroxamic nitrogen is linked to Cα by an ethylene bridge, was predicted to increase binding affinity by stabilizing the inhibitor in a bound conformation. Unexpectedly, a structure-based search revealed that our hypothesized backbone-stabilized PhAH bears strong similarity to SF2312, a phosphonate antibiotic of unknown mode of action produced by the actinomycete Micromonospora, which is active under anaerobic conditions. Here, we present multiple lines of evidence, including a novel X-ray structure, that SF2312 is a highly potent, low-nanomolar inhibitor of enolase. |
| Databáze: | OpenAIRE |
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