4-halo-3-hydroxyanthranilic acids: potent competitive inhibitors of 3-hydroxy-anthranilic acid oxygenase in vitro.
The mechanism of action of three potent inhibitors of 3-hydroxyanthranilic acid oxygenase (3HAO), the enzyme responsible for the production of the endogenous excitotoxin quinolinic acid, was examined in vitro. Using either liver homogenate or purified 3HAO, and following the rapid synthesis of the immediate enzymatic product alpha-amino-beta-carboxymuconic acid omega-semialdehyde spectrophotometrically, 4-halogenated (F, Cl, Br) 3-hydroxyanthranilic acids were found to inhibit enzymatic activity in a reversible fashion. Because of the very tight binding of the drugs to 3HAO, reversibility was detected only after warming the protein-inhibitor complexes at 37 degrees. Further studies showed that enzyme inhibition was competitive in nature (apparent Ki values: 190, 6 and 4 nM for the F-, Cl- and Br-compounds, respectively), and suggested that the drugs are metabolized by the enzyme. Specific, reversible, and tightly binding 3HAO inhibitors can be expected to become valuable tools for the study of quinolinate neurobiology. The drugs could also be of interest for the diagnostics and therapeutics of brain diseases which have been speculatively linked to a pathological overabundance of quinolinic acid.
Walsh
J L
JL
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore 21228.
Todd
W P
WP
Carpenter
B K
BK
Schwarcz
R
R
D015095:3-Hydroxyanthranilic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008956:Models, Chemical; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D017378:Quinolinic Acid; D011805:Quinolinic Acids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D011805:Quinolinic Acids; D015095:3-Hydroxyanthranilic Acid; C026381:4-chloro-3-hydroxyanthranilic acid; C070327:4-bromo-3-hydroxyanthranilic acid; C070326:4-fluoro-3-hydroxyanthranilic acid; D010088:Oxidoreductases; C026382:3-hydroxyanthranilic acid oxidase; D017378:Quinolinic Acid