Oxidation defense in mosquitoes benefits malaria parasite

Scientists from two universities in Italy and Virginia Tech in the United States have determined the structure of a protein that is responsible for the production xanthurenic acid (XA) in Anopheles gambiae, the malaria carrying mosquitoes. XA plays a key role in the sexual reproduction of the malaria parasite (Plasmodium falciparum) in A. gambiae mosquitoes. Interfering with the formation of XA could be an avenue for development of drugs and insecticides to block malaria transmission. Millions of people worldwide are infected with malaria.

The research will be presented in the Proceedings of the National Academy of Science (PNAS) on-line as early as April 3 and in print April 11, 2006 (“Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase” by Franca Rossi, Silvia Garavaglia, and Giovanni Battista Giovenzana, of the DiSCAFF-Drug and Food Biotechnology Center at the University of Piemonte Orientale ’Amedeo Avogadro’; Bruno Arca’ of the Department of Biological Structure and Function at the University of Napoli ’Federico II’; Jianyong Li of the Department of Biochemistry at Virginia Tech, and Menico Rizzi, also of the University of Piemonte Orientale).

The synthesis of XA is one of the biochemical defenses against oxidative stress resulting from 3-hydroxykynurenine (3-HK) accumulation in mosquitoes and possibly other species as well. “3-HK is oxidized easily under physiological condition, stimulating the production of reactive oxygen species, which can damage cells,” said Li.

Mammals have various biochemical pathways of disposing of 3-HK, which mosquitoes lack. Research by Li’s group at Virginia Tech on Aedes aegypti mosquitoes determined that “mosquitoes have developed an efficient strategy to prevent the accumulation of 3-HK by converting the chemically reactive 3-HK to the chemically stable XA via transaminase-mediated reactions,” said Li.

The protein described in the PNAS article is responsible for this transforming of 3-HK into XA in the malaria vector Anopheles gambiae, where XA also helps the malarial parasite reproduce. So stopping the oxidative defense could stop the parasite as well as make the insect a victim of oxidative stress.

Rizzi’s group at the University of Piemonte Orientale focuses on the structural characterization of enzymes involved in tryptophan degradation in mosquitoes, which results in the synthesis of XA. “Deciphering the molecular architecture of each enzyme in this pathway will be used for the structure-based rational design of potent and highly selective inhibitors of potential interest as innovative antimalarial agents,” said Rizzi

Li’s group at Virginia Tech biochemically characterizes enzymes involved in conversion to XA, including trptophan, the initial precursor of the process.

The researchers have collaborated since 2003.

“The use of protein crystallography in combination with biochemical studies and medicinal chemistry, represents a highly multidisciplinary approach that could lead to the identification of novel agents for the treatment of malaria,” said Rizzi.

The PNAS article describes what an International team of scientists learned about the structure of Anopheles gambiae 3-HK transaminase. The research will continue on the rational design of a small molecule that could be synthesized, and that would allow the malaria cycle to be interrupted, therefore representing a novel avenue for the treatment of malaria.