Katsuichiro Komatsu

Visualization of electrostatic recognition by enzymes for their ligands and cofactors

Abstract Electrostatic potentials for several enzymes and their guest molecules such as ligands and/or cofactors are individually calculated and illustrated as colour codes on their tertiary structures using a raster graphics technique. Two kinds of potential surface were illustrated on the molecular surface of the guest molecule. One is due to the host enzyme (H-on-G potential surface) and the other is due to the guest molecule itself (G-on-G potential surface). Remarkable mutual complementarities between the H-on-G and G-on-G potential surfaces were found in most cases. These give a semi-quantitative indication of the important role of electrostatic recognition in enzymes.

Electrostatic Complementarities between Guest Ligands and Host Enzymes

A method is described for visualizing electrostatic complementarity between a guest ligand and a host enzyme by using molecular graphics and drawing a correlation map. First, two kinds of electrostatic potentials were calculated and illustrated on the surface of the guest molecule. One is due to the host enzyme and the other is due to the guest molecule itself. Second, the correlation between these two molecular surfaces was calculated and illustrated. Simultaneously, the correlation map was given with a well-defined correlation coefficient. This method provides a helpful tool for understanding the specific electrostatic recognition geometrically and quantitatively.

Inhibition of bacterial undecaprenyl pyrophosphate synthase by small fungal molecules.

Viridicatumtoxin and spirohexaline, small fungal molecules with a tetracyclic scaffold and an additional spirobicyclic ring in common, were found to inhibit bacterial undecaprenyl pyrophosphate (UPP) synthase with IC50 values of 4 and 9 μm, respectively. These molecules showed weak inhibitory activity against catalytically related enzymes such as bacterial octaprenyl pyrophosphate synthase and yeast dehydrodolichyl pyrophosphate synthase, indicating that the compounds preferentially inhibit UPP synthase. They showed antimicrobial activity, particularly against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, molecular modeling strongly suggested that the hydrophobic spirobicyclic ring of viridicatumtoxin interacts with three hydrophobic clefts of the active site in MRSA UPP synthase.