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J Am Chem Soc. 2013 Jun 5;135(22):8153-6. doi: 10.1021/ja403441x. Epub 2013 May 23.

Reaction of HppE with substrate analogues: evidence for carbon-phosphorus bond cleavage by a carbocation rearrangement.

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Division of Medicinal Chemistry, College of Pharmacy, and Department of Chemistry and Biochemistry, University of Texas at Austin , Austin, Texas 78712, United States.


(S)-2-hydroxypropylphosphonic acid ((S)-2-HPP) epoxidase (HppE) is an unusual mononuclear non-heme iron enzyme that catalyzes the oxidative epoxidation of (S)-2-HPP in the biosynthesis of the antibiotic fosfomycin. Recently, HppE has been shown to accept (R)-1-hydroxypropylphosphonic acid as a substrate and convert it to an aldehyde product in a reaction involving a biologically unprecedented 1,2-phosphono migration. In this study, a series of substrate analogues were designed, synthesized, and used as mechanistic probes to study this novel enzymatic transformation. The resulting data, together with insights obtained from density functional theory calculations, are consistent with a mechanism of HppE-catalyzed phosphono group migration that involves the formation of a carbocation intermediate. As such, this reaction represents a new paradigm for biological C-P bond cleavage.

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