Institut de Chimie Moléculaire et des Matériaux d'Orsay

Laboratoire de Chimie Bioorganique et Bioinorganique - LCBB

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Subject 2
New metal complexes and interactions with biomolecules
F. Avenier, S. Pethe, F. Ramiandrasoa, R. Ricoux and J.-P. Mahy
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a) Design of new catalysts by protein engineering
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b) Synthesis of antimalarial drugs and study of their mechanism of action.


a) Design of new catalysts by protein engineering
F. Avenier, J.-P. Mahy, S. Pethe and R. Ricoux

Keywords:

-peroxidases; P450 cytochromes; metalloporphyrines; microperoxidase 8; hemoabzymes; catalytic antibodies; selective oxydation; electrocatalysis; nitric oxide; N-hydroxyguanidines; NO synthase; iron-nitrosyl complexes.

Objectives:
1-elucidation of the mechanism of interaction of various chemical compounds with hemoproteins like hemoglobine, P450 cytochromes, prostaglandine H synthase, NO- synthase, "in vitro ", thereafter "in vivo ".
2-determination of the mechanism of action and active site topology of hemoproteins still rather unknown like prostaglandine H synthetase.
3-elaboration of simple systems based on metalloporphyrins for the achievement of selective and efficient different types of reactions, like the oxidation of alkanes and alkenes:
a) iron tetraarylporphyrins or microperoxydase 8 associated to oxene donors in homogeneous organic medium (iodosobenzene, hydrogen peroxide, alkyl hydroperoxydes),
b) artificial hemoproteins, built either from anti-porphyrin antibodies, or by covalent link of metalloporphyrins on anti-substrat antibodies,
c) iron tetraarylporphyrins or microperoxydase 8 bound to electrode: bioelectrocatalysis of selective oxidation reactions,
d) bioconversions catalyzed by peroxydases.

Enzymes studied:
-hemoglobine, P450 cytochromes, prostaglandine H synthase, peroxydases, microperoxydase 8.

Strategy:
1- synthesis of new metalloporphyrins.
2-study of the coordination chemistry of these metalloproteins and comparaison to the coordination chemistry of the hemoproteins in order to explain the interactions of hemoproteins with endogenic or exogenic (like medecines) compounds; elaboration of biomimetic systems associating metalloporphyrins to oxene donors (iodosobenzene, hydrogen peroxide, alkyl hydroperoxydes) efficient in selective oxidation reactions.
3-fixation of these metalloporphyrins to:
a) carrier proteins used for the production of antigens which are thereafter injected to mouses in order to obtain anti-porphyrin antibodies. The obtained iron or manganese porphyrin-antibody complexes are then used as catalysts for selective oxidation reactions,
b) functionalized polymers, at the electrodes surface, so as to achieve electrocatalysis in selective oxidation reactions.

Collaborations:
- Dr Marcel Delaforge, Dr Jacques Grassi & Dr. Didier Boquet, CEA Saclay, Gif-sur-Yvette, France.
- Dr. Béatrice Golinelli & Dr. Marcel Knossow, UMR 9920 CNRS, Gif-sur-Yvette, France.
- Dr. Dominique Mandon, CNRS, Strasbourg, France.
- Dr. Pierrette Battioni & Dr Jean-Luc Boucher, UMR 8601, Université Paris V, France.
- Pr. Bob Crichton , Université de Louvain La Neuve, Belgique.
- Pr. Steve Benkovic, Pennstate University, U. S. A.
- Pr. John Shelnutt, New Mexico, U. S. A.
- Dr. Sophie Leconte, LADIR, CNRS Thiais, France.



b) Synthesis of antimalarial drugs and study of their mechanisme of action:
J.-P. Mahy, S. Pethe, et F. Ramiandrasoa