Mode of action of 4-hydroxyphenylpyruvate dioxygenase inhibition by triketone-type inhibitors.
A series of 2-(2-nitrobenzoyl)cyclohexane-1,3-dione analogues (1-9) were designed, synthesized, and evaluated for inhibition of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), a key enzyme involved in the catabolism of tyrosine which catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. The correlations between the results of enzyme inhibition, ferric chloride tests, and the conformational analysis suggested that the tight binding between triketone-type inhibitors and 4-HPPD is likely due to chelation of the enzyme-bound ferric iron with the enol tautomer of 1,3-diketone moiety of the triketones. The presence of a 2-carbonyl group in the triketone is an essential structural feature for potent 4-HPPD inhibition. Modification of the 3-carbonyl group of triketone moiety to other functionality will reduce the overall planarity and thus prevent keto-enol tautomerization, resulting in a decrease or lack of inhibition activity.
Wu
Chung-Shieh
CS
Department of Chemistry, Tunghai University, 181, Taichung-Kang Road, Section 3, Taichung, Taiwan, Republic of China 40704.
Huang
Jian-Lin
JL
Sun
Yang-Sheng
YS
Yang
Ding-Yah
DY
D015111:4-Hydroxyphenylpyruvate Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry; D002712:Chlorides; D003124:Colorimetry; D018360:Crystallography, X-Ray; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005290:Ferric Compounds / Q000737:chemistry; D007536:Isomerism; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D002614:Chelating Agents; D002712:Chlorides; D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D007659:Ketones; D015111:4-Hydroxyphenylpyruvate Dioxygenase; C024555:ferric chloride