HYDROXYPROPYLPHOSPHONIC ACID EPOXIDASE (HPPE) BOUND WITH SUBSTRATE ANALOGS

Cornell University, Ithaca NY

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The biosynthetic pathway of the antibiotic fosfomycin is intriguing in that it creates a natural product with a carbon-phosphorus bond and utilizes enzymes whose reactions have no precedent in biology. To investigate this unusual pathway and to probe the unique epoxidation reaction catalyzed by the final biosynthetic enzyme, HppE from Streptomyces wedmorensis, we previously obtained four X-ray structures: the apoenzyme at 2.0 [unreadable] resolution;a native Fe(II)-bound form at 2.4 [unreadable] resolution;a tris-(hydroxymethyl)aminomethane-Co(II)-enzyme complex structure at 1.8 [unreadable] resolution, and a substrate-Co(II)-enzyme complex structure at 2.5 [unreadable] resolution (in press). Our current studies aim to further elucidate the regiospecific and stereospecific mechanism of fosfomycin biosynthesis using substrates and substrate analogs bound to HppE.