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Researchers have obtained the first three-dimensional crystal structure of the non-haem, iron-containing enzyme, hydroxyethylphosphonate dioxygenase (HEPD) from the Streptomyces soil microbe. The study could lead to new agricultural technology, catalysts, and even novel antibiotics. An unusual collaboration between chemists, biochemists and microbiologists, at the Institute for Genomic Biology (IGB) at the University of Illinois at Urbana-Champaign has led to new understanding of how a soil bacterium uses chemical weapons to fight off its competitors. Its arsenal relies on a chemical pathway involving an enzyme that can do what no other known enzyme can do - break non-activated carbon-carbon bonds in a single step. Chemist Wilfred van der Donk, microbiologist William Metcalf, and structural biologist Satish Nair, and colleagues first reported the enzyme, HEPD, in the journal Nature Chemical Biology in 2007. This month, their crystal structure of the enzyme appears in parent journal Nature, and offers a putative mechanism for the enzyme's mode of action. "Our team discovered this very implausible chemical reaction," van der Donk explains, "And the more we learned about it the more unusual it became. The enzyme is unusual because it breaks a carbon-carbon bond without needing anything except oxygen." HEPD catalyses a critical step in the biochemical pathway that produces phosphinothricin (PT). This is a microbial metabolite used as a natural antibiotic by Streptomyces against competitors in the soil. Technologists have recruited the same compound as a widely used agricultural herbicide. Indeed, it is a component of the two top-selling herbicides in the USA (Liberty and Basta). The compound is most effective when used in conjunction with genetically modified crops carrying the PT-resistance gene, which is itself derived from Streptomyces. Transgenic corn and other crops can withstand PT-based herbicides that kill only the weeds that would otherwise grow tall among their stems. As part of ongoing efforts to investigate such compounds, the researchers at Illinois are focusing on natural products with carbon-phosphorus bonds. These include the phosphonates, which contain C-P bonds, and phosphinates, which have C-P-C bonds. Such compounds are already known to agriculture and medicine. Indeed organic compounds of these classes include the herbicide glyphosate, the osteoporosis treatment alendronate, the antimalarial drug fosmidomycin and the antibiotics fosfomycin, dehydrophos and plumbemycin. Phosphonates and phosphinates, whether naturally derived or synthetic, are good substrates for the HEPD and related enzymes. They can act as inhibitors of the enzyme, which could make them attractive candidates for the development of new antibiotics against bacteria that use such enzymes, explains van der Donk. Moreover, understanding how bacteria synthesize and use these compounds might also shed light on how other bacteria can develop resistance to antibiotics and perhaps allow drug designers to investigate alternative approaches to new drugs that resist resistance. "Knowing how a compound is made may allow you to make an analogue that can overcome that resistance," van der Donk says, "That's the game that's been played with penicillin for the last 40 years. Every time a bacterial strain becomes resistant to one penicillin, scientists tinker with the structure so that the organism is susceptible again." Team member Houjin Zhang, a biochemistry postdoctoral researcher, obtained the crystallographic structure of HEPD. The study revealed that, unlike countless other dioxygenase enzymes, HEPD needs no cofactors to carry out its task. Seemingly, it exploits an iron(II) grouping that reacts with oxygen to produce an Fe(III) superoxide species. It is this non-haem iron complex that tears apart otherwise unreactive bonds in the organophosphorus substrates, such as HEP. The researchers hope the new findings will spur the development of much smaller, cheaper and more efficient synthetic catalysts that can also sever C-C bonds in one step. "Every time we find something new in nature it's an inspiration to see if we can copy that reactivity with a small molecule," van der Donk said.
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