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Mayo Researcher Discovers Target Site for Developing Mosquito Pesticides

21.12.2006
A Mayo Clinic researcher has discovered a target site within malaria-carrying mosquitoes that could be used to develop pesticides that are toxic to the Anopheles gambiae mosquito and other mosquito species. It would not affect humans and other mammals. If supported by further studies, the findings could offer a safer and more effective control of mosquito-borne diseases such as malaria.

Yuan-Ping Pang, Ph.D., a chemist and expert in computer-aided molecular design at Mayo Clinic, identified two unique amino acid residues called cysteine (286) and arginine (339). These exist in three mosquito species and the German cockroach.

Dr. Pang’s findings are significant because the residues could potentially be used as a target site for a pesticide that would incapacitate only insects that carry these residues, which do not exist in mammals. The findings appear in the current issue of PLoS ONE, a new, peer-reviewed, open-access journal published by the Public Library of Science.

“These findings suggest that new pesticides can be designed to target only the mosquito enzyme. Such pesticides could be used in small quantities to harm mosquitoes, but not mammals,” Dr. Pang says. “We’ve developed a blueprint for a pesticide that could i ncapacitate malaria-carrying mosquitoes. We are currently making a prototype of the new pesticide.”

Most pesticides today work by crippling the serine residue, which is another amino acid of the enzyme acetylcholinesterase and is located at the active site of the enzyme. This serine residue is present in both insects and mammals and therefore, any pesticide targeting this amino acid affects both insects and mammals.

Acetylcholinesterase is a vital enzyme to both insects and mammals. It breaks down the neurotransmitter acetylcholine, which is a primary neurotransmitter in the brain that is associated with memory and cognition.

Dr. Pang, director of Mayo Clinic’s Computer-Aided Molecular Design Laboratory, studied the genetic makeup of all known acetylcholinesterases in 73 species, including humans. He identified residues that only exist in the mosquito version of the acetylcholinesterase. To identify which of these residues is susc eptible to pesticides, he developed a three-dimensional model of mosquito acetylcholinesterase. With this three-dimensional model in hand, Dr. Pang learned how residues function in a way never before possible.

He found that the cysteine and arginine residues were located at the opening of the active site of the mosquito acetylcholinesterase. An active site is a pocket in an enzyme where a fast chemical reaction takes place to break down a molecule or build a new molecule.

Previous studies by Dr. Pang and researchers elsewhere found that the cysteine residue acts as a hook that could tether a small molecule in the active site of an enzyme and permanently damage the enzyme. This led Dr. Pang to believe the cysteine and arginine residues could be targeted by a pesticide that would not affect humans and other mammals.

“While a three-dimensional model of the mosquito enzyme acetylcholinesterase has been reported by other scientists, no mosqu ito-specific residue at the active site of acetylcholinesterase has been reported until now,” Dr. Pang says. “These findings suggest that a chemically stable molecule (to be used as a safer pesticide) could be made to react with the cysteine residue in the mosquito enzyme acetylcholinesterase and irreversibly inhibit the enzyme.”

The three-dimensional model Dr. Pang developed was created with a powerful computing system called a terascale system. He built the system with 590 personal computers. Terascale refers to computational power measured in the unit of teraflops, which is a processor capable of a speed of one trillion floating-point operations per second. A single teraflops computer is comparable to a computer that can search at least 50,000 Manhattan phonebooks in one second. Terascale systems are among the most powerful computers available today.

Dr. Pang published similar findings in October 2006 in which he described a potenti ally safer and more effective method for controlling crop-destroying aphids. The study was published in the journal Bioorganic & Medicinal Chemistry Letters.

Amy Reyes | alfa
Further information:
http://www.mayo.edu
http://dx.doi.org/10.1371/journal.pone.0000058

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