Potent inhibition of macrophomate synthase by reaction intermediate analogs.
Potent inhibitors for macrophomate synthase, which has recently been found to catalyze a highly unusual five-step chemical transformation, were explored. Among 11 oxalacetate analogs tested, only three analogs had moderate to relatively strong inhibitory activities (I50 1.3-8.1 mM). On the other hand, among 35 bicyclic intermediate analogs synthesized, two diacids were found to be the most potent inhibitors (I50 0.80, 0.84 mM) which had a much higher affinity than that of the natural substrate 2-pyrone. (-)-Enantiomers of the diacids showed 30 times stronger activity (I50 0.34, 0.41 mM) than (+)-ones. The I50/Km values (0.20, 0.24) showed their potent inhibitions. Competitive inhibitions were observed in two representative inhibitors.
Oikawa
H
H
Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Sapporo, Japan. hoik@chem.agr.hokudai.ac.jp
Yagi
K
K
Ohashi
S
S
Watanabe
K
K
Mie
T
T
Ichihara
A
A
Honma
M
M
Kobayashi
K
K
D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010071:Oxaloacetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D010071:Oxaloacetates; D011753:Pyrones; C408144:macrophomate synthase