Quinolinate synthase

HbT COOH Quinolinate Synthase n COOH Iirtinosuccinic Acid (NadA) Quinolinic Acid... 

HN cooh Quinolinate Synthase a Iminosuccinic Acid (NadA)... 

Quinolinic acid is generated by one of two different pathways. In one pathway, by utilizing the enzyme quinolinate synthase (EC 1.4.3.16), whose crystal structure has recently been obtained, only the broadest outlines of a possible pathway arising from a reaction between dihydroxyacetone monophosphate and iminoaspartate have been adumbrated (Scheme 12.104),... 

The 6-methylacetylamino-l,2,3,4-tetrahydroquinoline, after nitration and separation of isomers, following reduction and deprotection, gave the 7-amino-6-methylamino derivative, which cyclized with cyanogen bromide. Alkylation of the cyclization products afforded inhibitors of thymidylate synthase, 5-substituted 2-amino-l//-l-methyl-5,6,7,8-tetrahydroimidazo[4,5-g]quinolines 136, designed for use in iterative protein crystal analysis (Scheme 42) (92JMC847). 

The polyketide synthases responsible for chain extension of cinnamoyl-CoA starter units leading to flavonoids and stilbenes, and of anthraniloyl-CoA leading to quinoline and acridine alkaloids (see page 377) do not fall into either of the above categories and have now been termed Type TTT PKSs. These enzymes differ from the other examples in that they are homodimeric proteins, they utilize coenzyme A esters rather than acyl carrier proteins, and they employ a single active site to perform a series of decarboxylation, condensation, cyclization, and aromatization reactions. 

Additionally, Rivkin and co-workers synthesized a variety of 4-hydroxy-3-phenylquinolin-2-(l//)-ones under solvent free microwave conditions using an activated arylmalonate <06TL2395>. Reacting the desired substituted aniline with di-(2,4,6-trichlorophenyl)-2-phenyl-malonate at 250 °C with microwave irradiation for 15 min resulted in a variety of 4-hydroxy-3-phenylquinolin-2-(l//)-ones in good yields. They also demonstrated the utility of this method in the synthesis of type I fatty acid synthase inhibitors <06BMCL4620>. Kumar et al. have reported a variation of the Friedlander quinoline synthesis. They highlight the use of CeClj THjO as a reusable catalyst in the reaction of 2-... 

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. 

However, arguing against the quinolinate hypothesis is evidence that quinolinate levels are not elevated in the CSF or striatum of HD patients (Reynolds et al., 1988). An interesting observation regarding the aspiny striatal cells that are spared in HD is that these neurons contain NADPH diaphorase (NO synthase) (Ferrante et al., 1985). Although these neurons are resistant to NMDA-mediated toxicity (Koh and Choi, 1988), they are likely to release NO and thus could serve as killer cells for other neurons in the local environment. This hypothesis is tentative since there is presently no conclusive evidence linking NO to the neuronal damage in HD. 

Reich, S.H., Fuhry, M.A.M., Nguyen, D., Pino, M.J., Welsh, K.M., et al. (1992) Design and synthesis of novel 6,7-imidazotetrahydro-quinoline inhibitors of thymidylate synthase using iterative protein crystal structure analysis. J. Med. Chem. 35 847-858. 

The enzyme strictosidine synthase (EC 4.3.3.2) is responsible for the stereospecific coupling of tryptamine and secologanin, yielding strictosidine (Fig. 12). This glucoalkaloid is the precursor for all terpenoid indole and related alkaloids, including among others the Cinchona quinoline alkaloids. Hampp and Zenk (707) isolated and purified this enzyme to homogeneity from a cell suspension culture of R. serpentina. The enzyme could successfully be immobilized on CNBr-activated Sepharose 4B, as was reported for this enzyme isolated from Catharanthus roseus (102,708). It proved to be more stable than the C. roseus enzyme the half-life of the immobilized enzyme was 100 days at a temperature of 37°C. 

As an alternative to nicotinamide, quinolinic acid (a degradation product of tryptophan) may be used to form nicotinic acid mononucleotide (NaMN). Quinolinic acid contains two carboxyl groups one of which is cleaved off during the reaction. All known NMNATs may use NaMN to form a dinucleotide and the subsequent reaction with ATP then yields nicotinic acid adenine dinucleotide, NAAD. This intermediate is the substrate of NAD synthase, an enzyme... 

Lukton D, Mackie JE, Lee JS, Marks GS, Ortiz de Montellano PR (1988) 2,2-Dialkyl-l,2-dihydro-quinolines cytochrome P-450 catalyzed N-alkyl-porphyrin formation, ferrochelatase inhibition, and induction of 5-aminolevulinic acid synthase activity. Chem Res Toxicol 1 208-215... 

Lucas S, Negri M, Heim R, Zimmer C, Hartmann RW (2011) Pine-tuning the selectivity of aldosterone synthase inhibitors structure-activity and structure-selectivity insights from studies of heteroaryl substituted l,2,5,6-tetrahydropyrrolo[3,2,l-ij]quinolin-4-one derivatives. J Med Chem 54 2307-2319... 

Cinchona officinalis Catharanthus roseus Tryptophan decarboxylase (TDC), Strictosidine synthase (STR) Increased quinoline alkaloids in root culture... 

Interesting correlation between distribution of the strictosidine synthase activity and alkaloid content in the 6-month C. ledgeriana plants was found by Aerts et al. The enzyme was active in the top of stems, in young leaflets, and in the roots, and these parts also contained the highest concentration of the alkaloids. Quinoline alkaloids were accumulated in the roots, whereas cinchophyllines in aerial part of plants [218]. Similarly high activity of strictosidine synthase in the germinating Cinchona seeds and cell cultures has been reported [219]. Four isoforms of strictosidine synthase have been isolated and purified from the suspension culture of C. robusta [220]. 

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