title: 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.
abstract: 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.
authors.affiliation: Univ. Paris-Sud, Laboratoire de Chimie Bioorganique et Bioinorganique, ICMMO, UMR8182, LabEx LERMIT, Orsay F-91405, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Desvergnes
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Courtiol-Legourd
authors.forename: Racha
authors.initials: R
authors.lastname: Daher
authors.forename: Maciej
authors.initials: M
authors.lastname: Dabrowski
authors.forename: Laurent
authors.initials: L
authors.lastname: Salmon
authors.forename: Michel
authors.initials: M
authors.lastname: Therisod
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004925:Escherichia / Q000201:enzymology; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors*; D005956:Glucose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D008314:Malonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008359:Mannose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D015394:Molecular Structure; D015003:Yeasts / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D008314:Malonates; C030290:malonic acid; D005634:Fructose-Bisphosphate Aldolase; D008359:Mannose-6-Phosphate Isomerase; D005956:Glucose-6-Phosphate Isomerase