Kynurenine Pathway

Our attention is focus on the biochemical defects of kynurenine pathway. The concentration of metabolites changes under various diseases, such as neurodegenerative disease, memory loss, chronical renal failure, eyes disease. 

The kynurenine pathway metabolites are kynurenine, kynurenic acid, xahthurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid. The more important are kynurenine (Kyn) and 3-hydroxykynurenine (30HKyn) (Fig 1). 

The kynurenine pathway accounts for most of the nonprotein tryptophan metabolism in most tissues. Several metabolites produced by this pathway have been shown... 

Kinase Domain Kinase Inhibitors Kinins Kir Channels Knockout Mice Kringle Domains K+-Sparing Diuretics Kv(3 -Subunits Kv-Channels KvLQT 1 -Channels Kynurenine Pathway L-NAME... 

Phenoxazines — The two main types of phenoxazines are the ommochromes and the microbial phenoxazines. The biosynthesis of ommochromes occurs via the kynurenine pathway. The tryptophan amino acid is converted to formylkynurenine and then to kynurenine and 3-hydroxykynurenine. Not all the steps of ommochrome synthesis are completely elucidated yet. Ommatins are dimers and ommins are oligomers of 3-hydroxykynurenine. - The papiliochromes are derived from tyrosine as well as from the tryptophan pathway. The key intermediate in the formation of papiliochromes is N-beta-alanyldopamine (NBAD). Papiliochromes are synthesized in special wing scale cells, before melanins. " "... 

Herve, C., Beyne, P., Jamault, H., and Delacoux, E., Determination of tryptophan and its kynurenine pathway metabolites in human serum by high-performance liquid chromatography with simultaneous ultraviolet and fluo-rimetric detection, ]. Chromatogr. B, 675, 157, 1996. 

Miller, C. L., Llenos, I. C., Dulay, J. R. et al. Expression of the kynurenine pathway enzyme tryptophan 2,3-dioxygenase is increased in the frontal cortex of individuals with schizophrenia. Neurobiol. Dis. 15 618-629, 2004. 

Aspects of Disorders of the Kynurenine Pathway of Tryptophan Metabolism in Man... 

Botting NP (1995) Chemistry and biochemistry of the kynurenine pathway of tryptophan metabolism. Chem Soc Rev 24, 401-412. 

The catabolism of d- and of L-tryptophan in P. aureofaciens is different.67 Only the latter isomer is catabolized by the kynurenine pathway, and it also induces the enzymes of this pathway. Added L-tryptophan may then be catabolized by this pathway. That which is will not be available for biosynthesis of pyrrolnitrin. In support, a mutant that lacks the first enzyme of this catabolic pathway showed a 30-fold increase in the production of pyrrolnitrin as compared to normal organisms.67 D-Tryptophan, not suffering catabolism in this way, will be more readily available, through slow conversion into L-tryptophan, for biosynthesis of... 

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. 

Quinolinate has been known for more than 25 years to produce HD-like pathology in rodents (e.g., Beal et al., 1986). Thus, it has been suggested that the genetic defect in HD may result in heightened neuronal susceptibility to excitotoxic injury. Guidetti et al. (2004) have shown that the levels of quinolinate (an endogenous neuroactive metabolite of the kynurenine pathway of tryptophan metabolism) and... 

The only known naturally occurring NMDA receptor antagonist in the human CNS is kynurenic acid (KYNA Stone, 1993). KYNA is one of the three neuroactive intermediate products of the kynurenine pathway. Kynurenine (KYN) is... 

The following enzymes of the kynurenine pathway are induced by pro-inflammatory cytokines such as IFN-g and TNF-a ... 

Guillemin GJ, Kerr SJ, Smythe GA, Smith DG, Kapoor V, Aimati PJ, Croitoru J, Brew BJ (2001) Kynurenine pathway metabolism in human astrocytes A paradox for neuronal protection. J Neurochem 78 842-853. 

ASPECTS OF DISORDERS OF THE KYNURENINE PATHWAY OF TRYPTOPHAN METABOLISM IN MAN... 

The series of steps that take place in vivo along this pathway, which we term the kynurenine pathway in order to distinguish it from the others, has now been elucidated through the efforts of many workers. 

Fig. 1. Kynurenine pathway for metabolic conversion of tryptophan to niacin.

The first observation on the connection of human pathological conditions with abnormal excretion of tryptophan metabolites, through the kynurenine pathway, was made in 1931 (K13). 

I.I. Newborn. It is known that some mammalian enzymes are absent in fetal life or may display a low activity only at the end of gestation whereas after birth their activity is enhanced to adult levels more or less rapidly. This is the case with tryptophan pyrrolase, a liver enzyme catalyzing the conversion of tryptophan to N -formylkynurenine, the first step of the kynurenine pathway. 

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