Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Team Finds Key Mechanism Of DDT Resistance In Malarial Mosquitoes

17.06.2008
University of Illinois researchers have identified a key detoxifying protein in Anopheles mosquitoes that metabolizes DDT, a synthetic insecticide used since World War II to control the mosquitoes that spread malaria.

The new findings, described this week in the Proceedings of the National Academy of Sciences, reveal that a protein produced at elevated levels in DDT-resistant Anopheles gambiae mosquitoes actually metabolizes the insecticide.

Anopheles gambiae as a species includes many closely related mosquito strains that transmit the malarial parasite to humans and other animals. The A. gambiae genome, isolated from an insecticide-susceptible strain, was first published in 2002.

The protein that metabolized DDT, CYP6Z1, belongs to a class of cytochrome P450 monooxygenases (P450s) that are known to be important detoxifying agents in many species. Many studies in a variety of insect species have shown that P450s play key roles in insect defenses against plant toxins.

... more about:
»CYP6Z1 »DDT »P450 »gambiae »insecticide »metabolize »mosquito »species

Using molecular modeling techniques based on the three-dimensional structure of a similar protein found in humans, principal investigator Mary A. Schuler and postdoctoral researchers Ting-Lan Chiu and Sanjeewa Rupasinghe were able to visualize the likely orientation of the molecules that allowed CYP6Z1 to bind to, and inactivate, DDT. Their model predicted that the active site of CYP6Z1 could accommodate a single molecule of DDT and inactivate it by adding oxygen to a chlorinated side group on the DDT molecule.

Their model of a similar protein, CYP6Z2, which is also produced at elevated levels in some DDT-resistant Anopheles mosquito strains, predicted that it was structurally incapable of binding – and hence inactivating – DDT.

Biochemical studies conducted by postdoctoral researcher Zhimou Wen confirmed that CYP6Z1 did in fact inactivate DDT while CYP6Z2 did not.

“To understand the relationship of different P450s, you really need to look at three-dimensional active site predictions in order to see what are critical variations between evolutionarily related P450s,” Schuler said.

“The configuration of the CYP6Z1 active site is open enough so that DDT can come in close enough to the reactive center to be oxygenated and, therefore, disabled.”

Schuler is a professor of cell and developmental biology, of biochemistry, of plant biology and of entomology and is affiliated with the Institute for Genomic Biology.

Malaria infects between 300 million and 500 million people a year, according to the World Health Organization, and is the leading cause of disease-related sickness and death in the world. Although banned in the United States, DDT is used in mosquito-control programs in many other parts of the world.

Schuler chose the CYP6Z1 protein for further study from a list of P450 genes that were transcriptionally elevated in resistant mosquitoes because its gene structure closely resembled other P450s that she and entomology department head May Berenbaum had studied in pest insects in the United States. Much earlier work by Schuler, Berenbaum and their colleagues had identified the CYP6 family of related P450s as an important part of insects’ defense against plant toxins and some insecticides. Efficient expression of these proteins allows insects to survive on host plants normally toxic to other species, and confers resistance to some insecticides.

“In the mosquito genome you’ve got somewhat over a hundred P450 genes, and if you can identify which ones are responsible for DDT resistance, there are many things you can do to control this pest species,” Schuler said. “And if you can effectively block the actions of proteins that metabolize DDT then you can prevent the resistance levels from becoming elevated in natural populations.”

By comparing models developed for the CYP6Z1 proteins in “sensitive” and “resistant” strains of A. gambiae mosquitoes, the researchers found that, from a three-dimensional perspective, the CYP6Z1 proteins were not appreciably different from one another. Variations dID occur, but often these were on the surface of the protein in regions not important for DDT metabolism.

“With biochemical analysis showing that the CYP6Z1 protein can metabolize DDT quite efficiently, you have to ask: What’s the difference between the sensitive strain and the resistant strain?” Schuler said. “It has to be that these transcripts and their proteins are over-expressed in the resistant strains and, as a consequence, are allowing them to exhibit this resistance.”

It is probable that exposure to potent, naturally occurring plant toxins or to synthetic insecticides causes the insects to step up production of certain P450 proteins, such as CYP6Z1, that subsequently aid in the detoxification of these compounds, Schuler said. Other studies have shown that insects encountering high levels of plant toxins in their food sources have higher levels of detoxifying proteins in their bodies, allowing them to withstand exposure to a broad range of insecticides, she said.

"There’s a lot out there that still has to be learned about mosquito populations in the wild,” she said.

Diana Yates | University of Illinois
Further information:
http://www.illinois.edu

Further reports about: CYP6Z1 DDT P450 gambiae insecticide metabolize mosquito species

More articles from Life Sciences:

nachricht Good preparation is half the digestion
15.11.2018 | Max-Planck-Institut für Stoffwechselforschung

nachricht How the gut ‘talks’ to brown fat
16.11.2018 | Technische Universität München

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

Im Focus: Coping with errors in the quantum age

Physicists at ETH Zurich demonstrate how errors that occur during the manipulation of quantum system can be monitored and corrected on the fly

The field of quantum computation has seen tremendous progress in recent years. Bit by bit, quantum devices start to challenge conventional computers, at least...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Massive impact crater from a kilometer-wide iron meteorite discovered in Greenland

15.11.2018 | Earth Sciences

When electric fields make spins swirl

15.11.2018 | Physics and Astronomy

Discovery of a cool super-Earth

15.11.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>