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Insights gained from
molecular modeling may lead to better insecticides
Barlow, Life Sciences Editor
courtesy of Jerome Baudry
|The modeled structure of the CYP6B8 protein
in the corn earworm (Helicoverpa
zea). A potential substrate binding cavity, in green, where
insecticides or plant defense chemicals can be detoxified,
is shown above the heme, the small complex that includes the
red sphere at its center.
Ill. — One of the most damaging crop pests, the corn earworm, may be outwitting
efforts to control it by making structural changes in a single metabolic
protein, but new insights uncovered by molecular modeling could pave
the way for more efficient insecticides, say researchers at the University
of Illinois at Urbana-Champaign.
In a study that compared the ability of corn earworms (Helicoverpa zea)
and black swallowtail butterflies (Papilio polyxenes) to neutralize
insecticides and plant defense allelochemicals that target insect herbivores,
researchers focused on the insects’ primary detoxifying cytochrome
study appears online this week in advance of regular publication in
the Proceedings of the National Academy of Sciences.
Earworms, which can feed on hundreds of different kinds of plants, have
evolved generalist counter-defense P450 proteins that can process more
diverse arrays of harmful agents than can similar proteins in black
swallowtails, which consume a restricted diet of only two plant families.
Predictive three-dimensional modeling of the structures of the proteins
detoxifying allelochemicals and insecticides has indicated vivid differences
in the catalytic sites of CYP6B1, the P450 in black swallowtails, and
CYP6B8, the P450 protein in earworms.
Because the corn earworm’s metabolic protein is more flexible,
it can bind to and detoxify six different kinds of plant defense chemicals
as well as three common insecticides, said Jerome Baudry, a senior research
scientist in the School of Chemical
Sciences at Illinois. "This generalist insect has adapted to
the natural chemical defenses of plants so that it can feed on a wider
variety of plants," he said.
The P450 studied in the specialist is significantly more constrained.
It contains a more rigid catalytic pocket that restricts the range of
plant chemicals and insecticides that can enter and be processed, Baudry
While the specialization allows for much higher rates of detoxification
of chemicals that black swallowtails normally encounter, they can handle
few other toxins. In the study, the CYP6B1 protein metabolized only
two plant defense chemicals and one insecticide.
"This is the first clear demonstration that resistance to plant
allelochemicals and insecticides can be acquired by changes within a
single P450 catalytic site," said Mary A. Schuler, a professor
of cell and structural biology. "If you can identify the P450 responsible for metabolizing insecticides
and find a way to inactivate its catalytic site, you kill the P450 and
prevent it from detoxifying insecticides."
Accomplishing that, however, won’t be easy because there is at
least one other P450 in corn earworms that also handles insecticides,
she said. "To truly hit the earworms, you would need to find one
inhibitor that can kill both enzymes. Ultimately, it may be possible
to use a synergistic approach that would kill more insects using significantly
lower levels of insecticides, thereby reducing the toxicity of insecticides
in the environment," she said.
Structural differences of the P450s involved in these chemical detoxifications
result from changes in the arrangement of amino acids within the catalytic
sites. In the black swallowtail’s version, aromatic rings protrude
into the substrate binding site, creating a rigid space in which allelochemicals
or insecticides must fit exactly – like keys going into locks,
Baudry said. The amino acid residues in the catalytic site stabilize
the toxic substrate so it is optimally bonded with the protein’s
heme, an iron-containing pigment in the catalytic site that mediates
oxidation of the chemical to a non-toxic product.
In the earworm protein, many of the aromatic rings are missing, creating
a much more accessible and flexible catalytic site. As a result, toxins
of many different shapes and sizes can enter and be detoxified. Since
the toxins are not as rigidly restricted, they are not detoxified quite
as efficiently as some of the toxins encountered by the specialist P450.
"The corn earworm thus is jack of many trades but master of none,
but this biochemical ability allows it to acquire new host plants and
overcome new pesticides with relative ease," said co-investigator
May R. Berenbaum, the head of the entomology department at Illinois and an expert on allelochemicals.
Xianchun Li, a doctoral student in entomology, also was a coauthor of
the paper and a major contributor to the research.
The study was funded by grants from the U.S. Department of Agriculture
to Schuler and Berenbaum, a grant from the National Institutes of Health
to Schuler, and a China Natural Science Foundation grant to Li.