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.
MeSH terms
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Humans
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Models, Molecular
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Molecular Structure
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Organophosphonates / chemistry
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Organophosphonates / pharmacology*
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Phosphopyruvate Hydratase / antagonists & inhibitors*
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Phosphopyruvate Hydratase / metabolism
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Pyrrolidinones / chemistry
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Pyrrolidinones / pharmacology*
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Structure-Activity Relationship
Substances
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(1,5-dihydroxy-2-oxopyrrolidin-3-yl)phosphonic acid
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Enzyme Inhibitors
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Organophosphonates
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Pyrrolidinones
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Phosphopyruvate Hydratase
Associated data
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PubChem-Substance/317230099
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PubChem-Substance/317230108
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PubChem-Substance/317230109
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PubChem-Substance/317230110
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PubChem-Substance/317230111
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PubChem-Substance/317230112
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PubChem-Substance/317230113
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PubChem-Substance/317230114
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PubChem-Substance/317230115
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PubChem-Substance/317230100
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PubChem-Substance/317230101
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PubChem-Substance/317230102
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PubChem-Substance/317230103
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PubChem-Substance/317230104
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PubChem-Substance/317230105
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PubChem-Substance/317230106
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PubChem-Substance/317230107