Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction

摘要

磷霉素(一种用来治疗糖尿病足部感染和减少rn尿道感染的抗生素)生物合成中的最后步是rn被“非血红素铁依赖型酶”(S)-2-hydroxypro-rnpyphosphonate((S)-2-HPP)环氧酶(HppE)rn催化的。该反应涉及一个不寻常的脱氢反应，rn在其中(S)-2-HPP的仲醇被转化成磷霉素的环rn氧化物环。本文作者发现，该酶还能催化一个rn“1，2-磷酰基迁移”反应，这是个在生物学rn上前所未有的化学转变。这一发现有可能为含rn磷酸盐的新颖天然产物及新型磷酸盐衍生物的rn生产铺平道路。%(S)-2-hydroxypropylphosphonate ((S)-2-HPP) epoxidase (HppE) is a mononuclear non-haem-iron-dependent enzyme responsible for the final step in the biosynthesis of the clinically useful antibiotic fosfomycin. Enzymes of this class typically catalyse oxy-genation reactions that proceed via the formation of substrate radical intermediates. By contrast, HppE catalyses an unusual dehydrogenation reaction while converting the secondary alcohol of (S)-2-HPP to the epoxide ring of fosfomycin. Here we show that HppE also catalyses a biologically unprecedented 1,2-phosphono migration with the alternative substrate (-R)-1-HPP. This transformation probably involves an intermediary carbocation, based on observations with additional substrate analogues, such as (IR)-1-hydroxyl-2-aminopropylphosphonate, and model reactions for both radical- and carbocation-mediated migration. The ability of HppE to catalyse distinct reactions depending on the regio- and stereochemical properties of the substrate is given a structural basis using X-ray crystallography. These results provide compelling evidence for the formation of a substrate-derived cation intermediate in the catalytic cycle of a mononuclear non-haem-iron-dependent enzyme. The underlying chemistry of this unusual phosphono migration may represent a new paradigm for the in vivo construction of phosphonate-containing natural products that can be exploited for the preparation of new phosphonate derivatives.