'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.
Witte
John F
JF
Arthur F. Scott Laboratory of Chemistry, Reed College, Portland, OR 97202-8199, USA.
Bray
Kathryn E
KE
Thornburg
Chelsea K
CK
McClard
Ronald W
RW
D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018716:Molecular Mimicry; D015394:Molecular Structure; D009962:Orotate Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011742:Pyrimidine Nucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology
D004791:Enzyme Inhibitors; D011742:Pyrimidine Nucleotides; D009962:Orotate Phosphoribosyltransferase