Champaign, Illinois
June 10, 2009
A soil microbe that uses chemical
warfare to fight off competitors employs an unusual chemical
pathway in the manufacture of its arsenal, researchers report,
making use of an enzyme that can do what no other enzyme is
known to do: break a non-activated carbon-carbon bond in a
single step.
 Their
study, appearing this week in the journal
Nature, provides the
first three-dimensional structure of the enzyme,
hydroxyethylphosphonate dioxygenase (HEPD) and proposes a
mechanism by which it performs its task.
 University
of Illinois researchers first reported the enzyme in Nature
Chemical Biology in 2007, said Wilfred van der Donk (photo
right), an author on both papers with microbiologist William
Metcalf (photo left).
"Our team discovered this very implausible chemical reaction,"
van der Donk said. "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."
The study is important because HEPD catalyzes a critical step in
the chemical pathway that produces phosphinothricin (PT), a
bacterial compound that is widely used as an agricultural
herbicide. This compound, which is a component of two
top-selling weed killers (Liberty and Basta), is effective when
used with transgenic crops that have a PT-resistance gene
inserted into their DNA. The resistance gene also comes from the
bacteria that produce PT. It allows the bacteria (which belong
to the genus Streptomyces) to emit the antibiotic to kill off
their competitors without killing themselves. Similarly, corn
and other crops that contain the resistance gene are able to
withstand PT-based herbicides that kill the weeds around them.
The new findings are part of an ongoing exploration at Illinois
of naturally produced molecules that contain carbon-phosphorus
(C-P) bonds. Although little understood, these phosphonates
(which contain C-P bonds) and phosphinates (with C-P-C bonds)
are already widely used in agriculture and medicine. This class
of compounds includes the herbicide glyphosate, the osteoporosis
treatment alendronate, the antimalarial drug fosmidomycin and
the antibiotics fosfomycin, dehydrophos and plumbemycin.
 Whether
man-made or naturally produced, phosphonates and phosphinates
are structurally similar to other compounds used by enzymes in
nature. They sometimes bind to the same enzymes and thus can
inhibit ordinary cellular processes in bacteria or other
organisms. This makes them attractive candidates for the
development of new antibiotics, said van der Donk, a principal
investigator on the study with Metcalf and biochemistry
professor Satish Nair (photo right).
Understanding how bacteria synthesize these compounds also
enables the scientists to predict how bacteria might develop
resistance to any new drugs that are developed, he said.
"Knowing how a compound is made may allow you to make an analog
that can overcome that resistance," van der Donk said. "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."
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.
The findings are the result of an unusual collaboration between
chemists, biochemists and microbiologists, van der Donk said,
all of them affiliates of the Institute for Genomic Biology
(IGB) at Illinois. The team included chemistry postdoctoral
associate Robert Cicchillo; biochemistry postdoctoral researcher
Houjin Zhang, who produced the first crystallographic structure
of HEPD; microbiology graduate student Joshua Blodgett;
chemistry graduate student John Whitteck; and chemistry
postdoctoral researcher Gongyong Li. The new study is part of
the Mining Microbial Genomes for Novel Antibiotics theme at IGB. |
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