Institut de Chimie Moléculaire et des Matériaux d'Orsay

Laboratoire de Chimie Bioorganique et Bioinorganique - LCBB

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Subject 1
Inhibitors of sugar-metabolizing enzymes

C. Blonski, L. Salmon, R. Labruère et M. Therisod

Keywords:
-hydroxamic acids, aldolases, metalloenzymes, aldose-ketose isomerases, enzyme kinetic, competitive inhibition, slow-binding inhibition, monosaccharide, enzyme specificity.

Objectives:
-to study the structural and mechanistic aspects of enzymes involved in the metabolism of sugars.
-in the case of metalloenzymes: to study the role of metallic cofactors.
-to validate some of these enzymes as potential therapeutic targets.
-to find new molecules with therapeutic interest (antibiotics, antifongals, antiparasitics, antitumorals...).

Enzymes studied:
-phosphoglucose, phosphomannose et phosphoribose isomerases.
-class I and II fructose-1,6-diphosphate aldolases.
-enolase.

Strategy:
1-design and synthesis of new competitive inhibitors as substrates or transition state analogues.
2-comparative studies of the inhibition properties of the synthetized molecules towards enzymes from pathogenic organisms and mammals.
3-comparative studies of the biological properties of the synthesized molecules (collaboration).
4-comparative cristallographic studies of the enzyme-inhibtor complexes (collaboration).
5-theoritical studies for the design of specific molecules of the target enzymes (collaboration).

Collaborations:
-Dr. Nohad Gresh, Université de Paris V, Paris, France.
-Pr. Constance J. Jeffery, University of Illinois at Chicago, Chicago, USA.
-Pr. Sherry L. Mowbray, Uppsala University, Uppsala, Suède.
-Dr. Mary Fillon-Jackson, Colorado State University, Fort Collins, USA.
-Pr. Jürgen Sygusch, University of Montreal, Montreal, Canada.