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Design Novel Selective Inhibitors of Class II Fructose‐1,6‐bisphosphate Aldolase
Author(s) -
Wang Liangchen,
Labbé Geneviève,
Krismanich Anthony,
Dmitrienko Gary I.,
Guillemette J. Guy
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.792.5
Subject(s) - aldolase a , fructose bisphosphate aldolase , biochemistry , aldolase b , stereochemistry , chemistry , active site , enzyme , biology
Fructose‐1,6‐bisphosphate (FBP) aldolase (E.C. ) catalyzes the reversible aldol condensation of dihydroxyacetonephosphate (DHAP) and glyceraldehyde‐3‐phosphate in glycolysis, gluconeogenesis and Calvin cycle. FBP aldolases are categorized into two groups based on different catalytic mechanisms: Class I aldolases form a Schiff‐base intermediate with the substrate through an active site lysine residue, whereas Class II aldolases contain a divalent metal which coordinates and stabilizes the carbanion intermediate. Noticeably, Class II aldolase does not exist in animals or plants, making this enzyme a potential drug target for pathogenic microbial organisms such as Mycobacterium tuberculosis , Magnaporthe grisea , Pseudomonas aeruginosa and Bacillus anthracis . Our research group has found that a commercially available antidote for heavy metal poisoning is a good competitive inhibitor of Class II FBP aldolase. In order to improve the binding affinity of this inhibitor for the enzyme activate site, new molecules based upon this compound were designed, synthesized and tested against recombinant Class II FBP aldolases from aforementioned microorganisms using kinetic assays developed by our group. This research is supported by NSERC (J.G.G. and G.I.D.)