[afro-nets] Novel Avenue For The Treatment Of Malaria

[Leela McCullough <leela@healthnet.org>]

Novel Avenue For The Treatment Of Malaria
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http://www.medicalnewstoday.com/medicalnews.php?newsid=40891

Article Date: 05 Apr 2006

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 Na-
tional Academy of Science (PNAS) in print on 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) accu-
mulation 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 de-
veloped 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 Anophe-
les gambiae, where XA also helps the malarial parasite repro-
duce. 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 trypto-
phan 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 de-
sign of potent and highly selective inhibitors of potential in-
terest 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 bio-
chemical 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 scien-
tists 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 represent-
ing a novel avenue for the treatment of malaria.

--
Contact: Susan Trulove
mailto:STrulove@vt.edu

--
Leela McCullough, Ed.D.
Director of Information Services

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