Regulation of quinolinic acid synthesis by mitochondria and o-methoxybenzoylalanine.
o-Methoxybenzoylalanine, a selective kynureninase inhibitor, caused unexpected accumulation of 3-hydroxyanthranilic acid (3OH-ANA), the product of kynureninase activity and the precursor of quinolinic acid (QUIN) in liver homogenates incubated with 3OH-kynurenine (3OH-KYN). In order to explain this observation, we investigated the interaction(s) of o-methoxybenzoylalanine with 3-hydroxyanthranilic acid dioxygenase, the enzyme responsible of QUIN formation. When the purified enzyme, or partially purified cytosol preparations were used, oMBA did not affect 3-hydroxyanthranilic acid dioxygenase activity. The addition of purified mitochondria to 3-hydroxyanthranilic acid dioxygenase preparations reduced the enzymatic activity and the synthesis of QUIN. In the presence of mitochondria oMBA further reduced QUIN synthesis. The administration of oMBA reduced QUIN content in both blood and brain of mice. Our results suggest that mitochondrial protein(s) interact(s) with soluble 3-hydroxyanthranilic acid dioxygenase and cause(s) modifications in the enzyme resulting in a decrease in its activity. These modifications also allow the enzyme to interact with oMBA, thus leading to a further reduction in QUIN synthesis.
Chiarugi
A
A
Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy.
Moroni
F
F
D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D049308:Dioxygenases; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006867:Hydrolases / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D017378:Quinolinic Acid / Q000378:metabolism*
C095159:2-methoxybenzoylalanine; D004791:Enzyme Inhibitors; D010105:Oxygenases; D049308:Dioxygenases; D050561:3-Hydroxyanthranilate 3,4-Dioxygenase; D006867:Hydrolases; C021480:kynureninase; D017378:Quinolinic Acid; D000409:Alanine