4J1W

Crystal Structure of Fe(II)-HppE with alternative substrate (R)-1-HPP

Summary for 4J1W

• Entry DOI: 10.2210/pdb4j1w/pdb
• Related: 1ZZ7 1ZZ8 3SCF 3SCG 4J1X
• Descriptor: Epoxidase, FE (II) ION, [(1R)-1-hydroxypropyl]phosphonic acid, ... (5 entities in total)
• Functional Keywords: hydroxypropylphosphonic acid epoxidase, 1, 2-phosphono migration, mononuclear non-heme iron enzyme, metal binding protein, cupin fold, phosphono migration
• Biological source: Streptomyces wedmorensis
• Total number of polymer chains: 3
• Total formula weight: 65039.52

Authors

Drennan, C.L.,Dey, M. (deposition date: 2013-02-03, release date: 2013-04-03, Last modification date: 2024-02-28)

Primary citation

Chang, W.C.,Dey, M.,Liu, P.,Mansoorabadi, S.O.,Moon, S.J.,Zhao, Z.K.,Drennan, C.L.,Liu, H.W.
Mechanistic studies of an unprecedented enzyme-catalysed 1,2-phosphono-migration reaction.
Nature, 496:114-118, 2013

PubMed Abstract: (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 oxygenation 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 (1R)-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.

PubMed: 23552950
DOI: 10.1038/nature11998

Experimental method

X-RAY DIFFRACTION (2.72 Å)