Kynurenine cyclization

Metabolic product of Tryptophan via Kynurenine cyclization by Kynurenine Aminotransferases I II (KATI KATII)... 

The principal reason that DMT must be administer parenterally is its rapid and efficient metabolism. It can be oxidized to the N-oxide. It can be cyclized to b-carbolines, both with and without an N-methyl group. It can be N-dealkylated to form NMT and simple tryptamine itself. Best known is its oxidative destruction, by the monoamine oxidase system, to the inactive indoleacetic acid. There is a wild biochemical conversion process known for tryptophan that involves an enzymatic conversion to kynurenine by the removal of the indole-2-carbon. A similar product, N,N-dimethylkynuramine or DMK, has been seen with DMT, when it was added to whole human blood in vitro. 

The result of this is that at low rates of flux through the kynurenine pathway, which result in concentrations of aminocarhoxymuconic semialdehyde below that at which picolinate carboxylase is saturated, most of the flux will be byway of the enzyme-catalyzed pathway, leading to oxidation. There will be Utde accumulation of aminocarhoxymuconic semialdehyde to undergo nonenzymic cyclization. As the rate of formation of aminocarhoxymuconic semialdehyde increases, and picolinate carboxylase nears saturation, there will be an increasing amount available to undergo the nonenzymic reaction and onward metabolism to NAD. Thus, there is not a simple stoichiometric relationship between tryptophan and niacin, and the equivalence of the two coenzyme precursors will vary as the amount of tryptophan to be metabolized and the rate of metabolism vary. 

Wiss (937, 938) fractionated crude liver extracts to give a kynureninase fraction which would form anthranilic acid, but not kynurenic acid, and a transaminase fraction which would not form anthranilic acid, but formed kynurenic acid provided an a-keto acid was present. o-Aminobenzoyl-pyruvic acid, the keto acid corresponding to kynurenine, is known to cyclize spontaneously to kynurenic acid (622), and the absence of ammonia production and requirement for an a-keto acid (c/. also 434) suggests that... 

Formation of Qa via aerobic degradation ofTrp (Kyn pathway) includes five enzymatic steps (1) oxidation of Trp to N-formyl kynurenine (FKyn) by Trp 2,3-dioxygenase (TRDOX), (2) deformylation of FKyn by kynurenine formamidase (KYNFA), (3) oxidation of Kyn to 3-hydroxykynurenine (HKyn) by kynurenine 3-monooxygenase (KYNOX), (4) conversion of HKyn into 3-hydroxyanthranilate (HAnt) by kynureninase (KYNSE), and (5) oxidation of HAnt by 3-hydroxyanthranilate 3,4-dioxygenase (HADOX) to a-amino-/3-carboxymuconic semialdehyde (ACMS) followed by its spontaneous cyclization to Qa (Scheme 2). This pathway and all respective... 

Fig. 244. Degradation of L-tryptophan via kynurenine and 3-hydroxyanthranilic acid 1 Tryptophan 2,3-dioxygenase (tryptophan pyrrolase, C 2.5) 2 formamidase 3 kynurenine 3-monooxygenase 4 kynureninase 5 3-hydroxyanthranilate 3,4-dioxygenase 6 aminocarhoxy-muconate semialdehyde decarboxylase 7 aminomuconate semialdehyde dehydrogenase 8 0x0-glutarate dehydrogenase system 9 spontaneous cyclization...

Degradation of L-tryptophan in most organisms proceeds via L-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxyanthranilic acid and quinolinic acid to acetyl Co A and CO2 (Fig. 244). Anthranilic acid formed as an intermediate may be recycled to L-tryptophan (see above). The ring of 3-hydroxyanthranilic acid is cleaved by a dioxygenase (C 2.5). The x-amino-/3-carboxymuconic acid-e-semialdehyde formed either undergoes a cis trans isomerization of the Zl -double bond and cyclization to quinolinic acid, a compound synthesized in microorganisms and plants from aspartic acid and D-glyceraldehyde-3-phosphate (D 16.2). On the other hand o -amino-/3-carboxymuconic acid-e-aldehyde may be de-carboxylated and is then the immediate precursor of NH3, acetic acid and COg. 

Kynurenine Metaholism. Kynurenine may be metabolized in five ways acetylation to iV -acetylkynurenine,i decarboxylation to kynuramine, oxidation to 3-hydroxykynurenine, cyclization to a quinoline derivative, and cleavage to yield anthranilic acid." The oxidation, cyclization, and cleavage reactions are components of major pathways of tryptophan metabolism. Ommochrome is composed of a series of heterocyclic condensed ring systems that have been shown to be derived from tryptophan via kynurenine. The individual steps in the enzymatic formation of the pigments have not separated. ... 

This pathway occurs in a incomplete form in the vertebrate organism. In certain bacteria it is an important pathway for the total oxidation of tryptophan. The quinolinic pathway arises by transamination of kynurenine and hydroxykynurenine. The resulting products qiontaneously cyclize to form kynurenic and xanthurenic acids. 

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