Inhibition of glyoxalase I in vitro by coumarin and coumarin derivatives

Previous reports from these laboratories on the inhibition of glyoxalase I (S-lactoyl-glutathione methylglyoxal lyase, isomerizing; EC 4.4.1.5) (Glo I) have been presented for various flavones and other compounds. We report here the inhibition of Glo I by coumarin and various coumarin derivatives. Human red blood cell Glo I was purified 7000-fold and the concentration of various coumarins was determined for 50% inhibition (I50) of enzyme activity. These compounds resemble the transition state of the methylglyoxal hemimercaptal as previously reported. The I50 varies from 3.5 m̈M to 1.9 mM for the compounds tested with the parent compound coumarin having an I50 of 1.9 mM. The most inhibitory compounds had hydroxyls at various positions on the coumarin ring system and a phenyl or similar group at the 3 or 4 position on the pyrone ring. Molecular electrostatic potential maps were calculated for three of the compounds tested and they provide suggestive evidence for the inhibitory regions of the molecules.