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Mayo Clinic Study Could Lead To Safer Pesticides

Date:
October 24, 2006
Source:
Mayo Clinic
Summary:
Each year millions of dollars in crops are lost to two insects notorious for devastating farms -- the greenbug and the English grain aphid. In a new study in the October issue of Bioorganic & Medicinal Chemistry Letters, a Mayo Clinic researcher has published work that opens the door to the possibility of creating safer pesticides to control the greenbug and English grain aphid in crop farms.

Each year millions of dollars in crops are lost to two insects notorious for devastating farms: the greenbug (Schizaphis graminum) and the English grain aphid (Sitobion avenae). Although these tiny green insects are 1/16th of an inch long, they are heavyweights in the farm industry. In 2005, the Department of Agriculture reported that $100 million in crops were lost in six states to these pests.

In a new study in the October issue of Bioorganic & Medicinal Chemistry Letters, a Mayo Clinic researcher has published work that opens the door to the possibility of creating safer pesticides to control the greenbug and English grain aphid in crop farms. The key, according to the study's author, Yuan-Ping Pang, Ph.D., director of Mayo Clinic's Computer-Aided Molecular Design Laboratory, was in identifying an insect-specific enzyme that could be used as a direct target for a new insecticide that would not affect humans and animals. The research was done with the support of a powerful terascale supercomputer Dr. Pang designed to develop a three-dimensional model of an enzyme taken from the two insects. (Terascale refers to a computer so powerful it can perform one trillion operations per second.)

"We now have a blueprint that will enable the development of a new generation of pesticides that will not be toxic to humans. Ultimately, the idea would be that we would be able to eat apples without washing them -- even though it may be covered with pesticides," says Dr. Pang.

Greenbugs are found in North, Central and South America, Europe, Africa, the Middle East and Asia. Aphids have been present since 1912 in southern Europe, central Asia, the Middle East and Africa. Greenbugs are the most damaging of aphids because they suck plant juices and inject a toxin into the plant during the process, Dr. Pang says. The toxin causes more injury than the actual physical injury made by greenbugs.

To date a common method of protecting crops from greenbugs and the English grain aphid has been the use of anticholinesterase-based pesticides developed during the World War II era. These pesticides cripple an enzyme called acetylcholinesterase, which decomposes acetylcholine, a neurotransmitter in the brain that sends signals between nerve cells. Disabling acetylcholinesterase causes a chemical imbalance in the brains of insects eventually killing them. The problem is that acetylcholinesterase affects both insects and humans.

"Unfortunately current anticholinesterase-based pesticides target a common residue of acetylcholinesterases that is apparent in both insects and humans. The use of potentially dangerous pesticides developed decades ago is based on the hypothesis that these pesticides are used in low doses that humans can tolerate, but pests cannot," Dr. Pang says.

But according to a report by the Environmental Protection Agency's Office of Inspector General, some anticholinesterase pesticides can enter the brain of fetuses and young children and can destroy cells in the developing nervous system.

To date, safer and equally effective insecticides have not been designed to replace insecticides currently used by farmers, Dr. Pang says.

Anticholinesterase-based pesticides target an amino acid within the acetylcholinesterase enzyme, called serine. Serine is not unique to insects, which is why serine-based insecticides affect both humans and animals. Dr. Pang developed a computer-based three-dimensional model that identified a different amino acid called cysteine, which is unique to insects. It is located at the opening of the active site of acetylcholinesterase.

"My goal was to find an enzyme residue that is unique to insects. Doing so would allow us to design a molecule that would selectively inhibit the insect enzyme. Therefore we could conceivably create a pesticide that is only toxic to insects, not humans," Dr. Pang says.

Dr. Pang analyzed the anticholinesterase protein sequences of 72 species ranging from humans to chickens and other mammals and pests. He found a cysteine amino acid present in the acetylcholinesterase protein sequences of the greenbug and English grain aphid, but absent in comparable human and animal sequences.

Examining the three-dimensional models of both the greenbug and aphid acetylcholinesterase enzymes with the terascale supercomputer he designed was Dr. Pang's crucial next step. He discovered the pest-specific cysteine residue located at the edge of the active site of the insect acetylcholinesterase.

Acetylcholinesterase enzymes have a deep and narrow active site. A cysteine residue is located at the opening of the active site of insect acetylcholinesterases and can react with a small-molecule pesticide. In other words, the cysteine residue serves as a hook that can tether a small molecule in the active site and damage the enzyme.

However, the cysteine is not present in acetylcholinesterase in humans or animals. So the cysteine residue is essentially a species marker for developing new pesticides that would not harm humans because cysteine is not an enzyme active in humans or mammals, Dr. Pang says.

"We inspected the entire active site of the human enzyme and we couldn't find one cysteine residue," he says.

"It is conceivable that a chemically stable molecule could react with insect-specific cysteine residue and irreversibly inhibit the insect acetylcholinesterases upon binding to the active site. This leads me to believe that the cysteine residue can be used as a species marker for developing a new generation of safer pesticides that can inhibit greenbug and aphid acetylcholinesterase, but not human or animal acetylcholinesterases," Dr. Pang says.

"Protein sequences as one-dimensional information can tell us whether an amino acid we are focusing on is unique, but not whether that amino acid is located in the active site of the enzyme. We cannot target the residue if we do not know where it lies. Now, we can examine the location of the residue in three-dimensional space using terascale computers.

"This work offers a structural basis for the possible design of pesticides that are toxic to insects, but not to humans. It demonstrates the benefits in the power of molecular biology that led to the discovery of the functionally important and pest-specific cysteine residue that was hidden in a sea of protein sequences originally reported in 2002," Dr. Pang says.

This study was funded by the Mayo Foundation for Medical Education and Research.


Story Source:

The above story is based on materials provided by Mayo Clinic. Note: Materials may be edited for content and length.


Cite This Page:

Mayo Clinic. "Mayo Clinic Study Could Lead To Safer Pesticides." ScienceDaily. ScienceDaily, 24 October 2006. <www.sciencedaily.com/releases/2006/10/061012183519.htm>.
Mayo Clinic. (2006, October 24). Mayo Clinic Study Could Lead To Safer Pesticides. ScienceDaily. Retrieved September 22, 2014 from www.sciencedaily.com/releases/2006/10/061012183519.htm
Mayo Clinic. "Mayo Clinic Study Could Lead To Safer Pesticides." ScienceDaily. www.sciencedaily.com/releases/2006/10/061012183519.htm (accessed September 22, 2014).

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