Featured Research

from universities, journals, and other organizations

Key Mechanism Of DDT Resistance Found In Malarial Mosquitoes

Date:
June 18, 2008
Source:
University of Illinois at Urbana-Champaign
Summary:
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.

Molecular modeling shows how the DDT molecule (aqua, white and bronze spheres) is predicted to interact with the active site of two P450 proteins, CYP6Z1 (tan) and CYP6Z2 (green). An amino acid, Arginine 208 (purple), blocks the active site of CYP6Z2, preventing DDT from docking with it. This model accurately predicted that CYP6Z1 could metabolize DDT, whereas CYP6Z2 could not.
Credit: Sanjeewa Rupasinghe and Michael Hallock, U. of I

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 the week of June 16 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.

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.

The researchers' 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.


Story Source:

The above story is based on materials provided by University of Illinois at Urbana-Champaign. Note: Materials may be edited for content and length.


Cite This Page:

University of Illinois at Urbana-Champaign. "Key Mechanism Of DDT Resistance Found In Malarial Mosquitoes." ScienceDaily. ScienceDaily, 18 June 2008. <www.sciencedaily.com/releases/2008/06/080616170758.htm>.
University of Illinois at Urbana-Champaign. (2008, June 18). Key Mechanism Of DDT Resistance Found In Malarial Mosquitoes. ScienceDaily. Retrieved September 14, 2014 from www.sciencedaily.com/releases/2008/06/080616170758.htm
University of Illinois at Urbana-Champaign. "Key Mechanism Of DDT Resistance Found In Malarial Mosquitoes." ScienceDaily. www.sciencedaily.com/releases/2008/06/080616170758.htm (accessed September 14, 2014).

Share This



More Plants & Animals News

Sunday, September 14, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Conservationists Face Uphill PR Battle With New Shark Rules

Conservationists Face Uphill PR Battle With New Shark Rules

Newsy (Sep. 14, 2014) — New conservation measures for shark fishing face an uphill PR battle in the fight to slow shark extinction. Video provided by Newsy
Powered by NewsLook.com
Shocker: Journalists Are Utterly Addicted To Coffee

Shocker: Journalists Are Utterly Addicted To Coffee

Newsy (Sep. 13, 2014) — A U.K. survey found that journalists consumed the most amount of coffee, but that's only the tip of the coffee-related statistics iceberg. Video provided by Newsy
Powered by NewsLook.com
'Magic Mushrooms' Could Help Smokers Quit

'Magic Mushrooms' Could Help Smokers Quit

Newsy (Sep. 11, 2014) — In a small study, researchers found that the majority of long-time smokers quit after taking psilocybin pills and undergoing therapy sessions. Video provided by Newsy
Powered by NewsLook.com
Spinosaurus Could Be First Semi-Aquatic Dinosaur

Spinosaurus Could Be First Semi-Aquatic Dinosaur

Newsy (Sep. 11, 2014) — New research has shown that the Spinosaurus, the largest carnivorous dinosaur, might have been just as well suited for life in the water as on land. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

    Technology News



    Save/Print:
    Share:  

    Free Subscriptions


    Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

    Get Social & Mobile


    Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

    Have Feedback?


    Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
    Mobile iPhone Android Web
    Follow Facebook Twitter Google+
    Subscribe RSS Feeds Email Newsletters
    Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins