Quinolinic acid formation

Saito K, Q owley JS, Markey SP, Heyes MP (1993) A mechauism for increased quinolinic acid formation following acute systemic immune stimulation. J Biol Chem 268 15496-15503. 

Heyes MP, Chen CY, Major EO, Saito K (1997) Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. Biochem J 326 351-356. 

The results with Neurospora led Bonner and Yanofsky (94) to suggest that the conversion of hydroxyanthranilic acid to nicotinic acid went by way of Intermediates A and B of diagram 21. Quinolinic acid formation was thought to be a shunt or side reaction of intermediate A, slow conversion to nicotinic acid possibly providing an alternative pathway. A similar conclusion was drawn from experiments in the rat (971), and it is now generally agreed that the conversion of quinolinic acid to nicotinic acid is at best of the order of a side reaction (e.g., 685, 754, and in man, 397, 696). 

This intermediate appears to be important in the formation of a number of pyridinecarboxylic acids. Figure 2 depicts the formation of quinolinic acid from compound 1. Quinolinic acid formation is a spontaneous reaction and does not reqmre enzymes. Only one of several Neurospora mutants can use quinolinic acid in place of nicotinic acid, and in this mutant the activity is very low. Quinolinic acid is also a very poor growth factor. The dicarboxylic acid appears to be a by-product of tryptophan metabolism and not an intermediate in nicotinic acid formation. Although quinolinic... 

The primary oxidation product of 3-hydroxyanthranilic acid is the precursor of two pyridine compounds, quinolinic and picolinic acids (Mehler, 1956). The structure of the oxidation product is supported by this information, since a chemically plausible mechanism can be devised to acccount for these reactions. The formation of quinolinic acid is a nonenzymic, first-order reaction. The reaction rate is a function of temperature but not of the composition of the medium except for low pH. At low pH values a rapid, irreversible elimination of ammonia and carbon dioxide competes with quinolinic acid formation. At higher pH values the reaction may be considered as beginning with an isomerization of the double bond, leading to the formation of a compound with cu-carboxyl groups. This structure would ordinarily be the less favorable form. 

Quinoline.—The formation of c[uinoline by Skratip s reaction may be explained as follows - The sulphuric acid converts the glycerol into aciolein, which then combines w-ith the aniline to form acrolein-aniline. The latter on o.xidation with nitrobenzene yields quinoline. 

Faced with the inapplicability of the standard basic conditions required for the Pfitzinger condensation in the context of their study, Lackey and Stembach developed a modified protocol which allows for the formation of quinolinic acids under acidic conditions. ... 

Combes quinoline synthesis. Formation of quinolines by condensation of (i-di ketones with primary arylamines followed by acid-catalyzed ring closure of the intermediate Schiff base. 

Knorr quinoline synthesis. Formation of a-hydroxyquinolines from (3-ketoesters and aryla-mines above 100C. The intermediate anilide undergoes cyclization by dehydration with concentrated sulfuric acid. 

Niementowski quinoline synthesis. Formation of y-hydroxyquinoline derivatives from anthranilic acids and carbonyl compounds. 

The phenoxazine can then participate in reversible oxidation-reduction reactions, and moreover by transamination and cyclization of one side chain, in a manner analogous to xanthurenic acid formation discussed below, can give a pyridinophenoxazine derivative which equally undergoes reversible oxidation-reduction, and which, being a derivative of 8-hydroxy-quinoline, would bind metals strongly (see also 122a). 

Behavioral disorders such as anorexia, sleep disturbances, and pain insensitivity associated with hyperammonemia have been attributed to increased tryptophan transport across the blood-brain barrier and the accumulation of its metabolites. Two of the tryptophan-derived metabolites are serotonin and quinolinic acid (discussed later). The latter is an excitotoxin at the N-methyl-D-aspartate (NMDA) glutamate receptors. Thus, the mechanism of the ammonium-induced neurological abnormalities is multifactorial. Normally only small amounts of NH3 (i.e., NH4 ) are present in plasma, since NH3 is rapidly removed by reactions in tissues of glutamate dehydrogenase, glutamine synthase, and urea formation. 

This enzyme has been overexpressed but not purified due to instability. The mechanism for the formation of quinolinic acid is unknown. A proposal is outlined in Fig. 4. 

Surprisingly few studies have been carried out of the formation of monoterpene alkaloids in plant tissue culture. Indeed the only work published appears to be that by Dohnal (89,243) from over 20 years ago. Using Tecoma stans cultures grown on media supplemented with mevalonic acid, lysine, or quinolinic acid, alkaloid production was very limited or nonexis-... 

These results strongly indicate a dependency between ricinine biosynthesis and the pyridine nucleotide cycle. The similarity in incorporation of members of this cycle into ricinine" is explained by allowing each member to be diverted directly into a pathway leading to ricinine this explanation covers the observation that excess exogenous NAD increases the incorporation of quinolinic acid into ricinine" since this precursor can simply be shunted along one of these diversions if the formation of NAD is blocked by its presence in large excess. 

Oxidation affects both rings of the quinoline system. Alkaline permanganate causes oxidative cleavage of the benzene ring in quinoline and 2-substituted quinolines to give pyridine-2,3-dicarboxylic acid 39 (R = H quinolinic acid). In contrast, acidic permanganate oxidizes the pyridine ring with formation of A-acylanthranilic acid 40 ... 

---