SF2312 is a natural phosphonate inhibitor of enolase.
Nat Chem Biol
; 12(12): 1053-1058, 2016 Dec.
Article
in En
| MEDLINE
| ID: mdl-27723749
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphopyruvate Hydratase
/
Pyrrolidinones
/
Enzyme Inhibitors
/
Organophosphonates
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Nat Chem Biol
Year:
2016
Document type:
Article