Synthesis and evaluation of malonate-based inhibitors of phosphosugar-metabolizing enzymes: Class II fructose-1,6-bis-phosphate aldolases, type I phosphomannose isomerase, and phosphoglucose isomerase
| Autor: | Maciej Dabrowski, Michel Therisod, Racha Daher, Laurent Salmon, Stéphanie Courtiol-Legourd, Stéphanie Desvergnes |
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| Rok vydání: | 2012 |
| Předmět: |
Escherichia
Glucose-6-phosphate isomerase Stereochemistry Clinical Biochemistry Pharmaceutical Science Models Biological Biochemistry Inhibitory Concentration 50 chemistry.chemical_compound Catalytic Domain Fructose-Bisphosphate Aldolase Yeasts Drug Discovery Animals Humans Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Mannose-6-Phosphate Isomerase Molecular Structure biology Organic Chemistry Glucose-6-Phosphate Isomerase Active site Fructose Phosphate Malonates Enzyme Activation Enzyme Malonate chemistry Enzyme inhibitor biology.protein Molecular Medicine Phosphorylation |
| Zdroj: | Bioorganic & Medicinal Chemistry. 20:1511-1520 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2011.12.050 |
| Popis: | In the design of inhibitors of phosphosugar metabolizing enzymes and receptors with therapeutic interest, malonate has been reported in a number of cases as a good and hydrolytically-stable surrogate of the phosphate group, since both functions are dianionic at physiological pH and of comparable size. We have investigated a series of malonate-based mimics of the best known phosphate inhibitors of class II (zinc) fructose-1,6-bis-phosphate aldolases (FBAs) (e.g., from Mycobacterium tuberculosis), type I (zinc) phosphomannose isomerase (PMI) from Escherichia coli, and phosphoglucose isomerase (PGI) from yeast. In the case of FBAs, replacement of one phosphate by one malonate on a bis-phosphorylated inhibitor (1) led to a new compound (4) still showing a strong inhibition (K(i) in the nM range) and class II versus class I selectivity (up to 8×10(4)). Replacement of the other phosphate however strongly affected binding efficiency and selectivity. In the case of PGI and PMI, 5-deoxy-5-malonate-D-arabinonohydroxamic acid (8) yielded a strong decrease in binding affinities when compared to its phosphorylated parent compound 5-phospho-D-arabinonohydroxamic acid (2). Analysis of the deposited 3D structures of the kinetically evaluated enzymes complexed to the phosphate-based inhibitors indicate that malonate could be a good phosphate surrogate only if phosphate is not tightly bound at the enzyme active site, such as in position 7 of compound 1 for FBAs. These observations are of importance for further design of inhibitors of phosphorylated-compounds metabolizing enzymes with therapeutic interest. |
| Databáze: | OpenAIRE |
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