‘Irreversible’ slow-onset inhibition of orotate phosphoribosyltransferase by an amidrazone phosphate transition-state mimic

A mimic of the putative transition-state intermediate has been synthesized and found to be a very slow-onset inhibitor of yeast orotate phosphoribosyltransferase. The mechanism of inhibition may involve a rate-determining isomerization of the enzyme to a form receptive to the inhibitor, which then remains tightly bound.