Inhibitors of Bacillus subtilis DNA polymerase III. Structure-activity relationships of 6-(phenylhydrazino)uracils.
6-(Phenylhydrazino)uracils inhibit the replication-specific enzyme DNA polymerase III of Bacillus subtilis by forming a strong, reversible complex with template-primer DNA and enzyme. The phenyl ring interacts with a hydrophobic enzyme site which, on the basis of structure-activity relationships of substituted analogues, appears to possess the following characteristics: (1) planarity or near-planarity; (2) a finite capacity to accommodate bulky substituents; and (3) location near the domain of the enzyme active site. A mutant DNA polymerase III, derived from a mutant strain of B. subtilis selected for resistance to 6-(p-hydroxyphenylazo)pyrimidines, is resistant only to inhibitors bearing p-hydroxy or amino groups and is hypersensitive to inhibitors containing nonpolar substituents; these results suggest the existence of mutable, secondary regions of the binding site which interact with para substituents and, thus, influence the strength of the primary phenyl-enzyme interaction.
D001412:Bacillus subtilis / Q000201:enzymology*; D001665:Binding Sites; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D019384:Nucleic Acid Synthesis Inhibitors; D010659:Phenylhydrazines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology
D019384:Nucleic Acid Synthesis Inhibitors; D010659:Phenylhydrazines; D014498:Uracil; D004258:DNA Polymerase III