ABSTRACT
A review, outlining the origins and subsequent development of the triketone class of herbicidal 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors.
Subject(s)
4-Hydroxyphenylpyruvate Dioxygenase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Herbicides/chemistry , Ketones/chemistry , 4-Hydroxyphenylpyruvate Dioxygenase/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Herbicides/chemical synthesis , Herbicides/pharmacology , Ketones/chemical synthesis , Ketones/pharmacology , Structure-Activity RelationshipABSTRACT
Cytosine deamination is a major promutagenic process, generating G:U mismatches that can cause transition mutations if not repaired. Uracil is also introduced into DNA via nonmutagenic incorporation of dUTP during replication. In bacteria, uracil is excised by uracil-DNA glycosylases (UDG) related to E. coli UNG, and UNG homologs are found in mammals and viruses. Ung knockout mice display no increase in mutation frequency due to a second UDG activity, SMUG1, which is specialized for antimutational uracil excision in mammalian cells. Remarkably, SMUG1 also excises the oxidation-damage product 5-hydroxymethyluracil (HmU), but like UNG is inactive against thymine (5-methyluracil), a chemical substructure of HmU. We have solved the crystal structure of SMUG1 complexed with DNA and base-excision products. This structure indicates a more invasive interaction with dsDNA than observed with other UDGs and reveals an elegant water displacement/replacement mechanism that allows SMUG1 to exclude thymine from its active site while accepting HmU.
