5- Hydroxykynurenine

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). 

Figure 30-16. Formation of xanthurenate in vitamin Bg deficienqr. Conversion of the tryptophan metabolite 3-hydroxykynurenine to 3-hydroxyanthranilate is impaired (see Figure 30-15). A large portion is therefore converted to xanthurenate.

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. " "... 

FIGURE 10.5 Pathways for degradation of L-tryptophan (a) via 4-hydroxyquinoline-2-carboxylate and (b) 3-hydroxykynurenine. 

The analysis of amino acids involves chromatographic issues similar to those encountered in analysis of simple amines. Underivatized amino acids have, with a few exceptions, weak UV absorbance and a strong tendency to interact with stationary phases in undesirable ways. Underivatized amino acids are normally separated with ion exchange chromatography, then visualized post-column by reaction with ninhydrin, o-phthaladehyde (OPA), or other agents. Underivatized tryptophan and the metabolites kynurenine, 3-hydroxykynurenine, kynurenic acid, and 3-hydroxyanthranilic acid, were separated on a Partisphere 5-p ODS column with fluorescent detection.121... 

This pyridoxal-phosphate-dependent enzyme [EC 3.7.1.3] catalyzes the hydrolysis of kynurenine to produce anthranilate and alanine. 3 -Hydroxykynurenine and some other (3-arylcarbonyl)alanines can also be acted upon by this enzyme. 

This FAD-dependent enzyme [EC 1.14.13.9], also called kynurenine 3-monooxygenase, catalyzes the reaction of kynurenine with NADPH and dioxygen to produce 3-hydroxykynurenine, NADP, and water. 

Alkaloids derived from nicotinic acid contain a pyridine nucleus. Nicotinic acid itself is synthesized from L-tryptophan via A-formylkynurenine, L-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid. 

Although the oxidation of indoles by air and light has been studied extensively, e.g., the photooxidation of tryptophan to kynurenine and 3-hydroxykynurenine in the presence of methylene blue as sensitizer,311 313 little is known about the course of pyrrole photooxidation.173180 184 Under very mild conditions, irradiation of 2,3,4,5-tetra-phenylpyrrole in methanol and in the presence of air and methylene blue effected its oxidation to 5-methoxy-3,4-epoxy-2,3,4,5-tetraphenyl-A -pyrroline (CXVI) and a-A-benzoylamino-a -benzoyl stilbene(CXVII).303 Photooxidation in the presence of potassium hydroxide gave the lactam (CXVIII). 

Cleavage of 3-hydroxykynurenine by kynureninase (step g, Fig. 25-11) forms 3-hydroxyanthranilate, which is opened under the action of another dioxygenase (step h) with eventual degradation to acetyl-CoA, as indicated. In insects the reactive 3-hydroxyanthranilate is utilized in "tanning" reactions, e.g., coupling to tyrosine residues to toughen insect cuticles and walls of cocoons.214... 

Neurotoxins produced by the body. Some normal body constituents are neurotoxic in excess. These incluse quinolinic acid (Fig. 25-11),889 3-hydroxykynurenine (Fig. 25-11 p. 1444),890 and homocysteine.891 Elevated levels of homocysteine are also associated with vascular disease and stroke (Chapter 24). 3-Hydroxykynurenine is a precursor to ommochrome pigments of insects and an intermediate in conversion of tryptophan into the nicotinamide ring of NAD in humans (Fig. 25-11). 6-Hydroxydopamine (Fig. 30-26), which may be formed in the body, is severely toxic to catecholaminergic neurons.892... 

Actinomycin.—Kynurenine and 3-hydroxykynurenine are actinomycin precursors in Streptomyces antibioticus (cf. Vol. 6, p. 42). Recently, kynureninase and hydroxykynureninase activity has been identified in S. parvulus cultures and the latter activity was found to show correlation with actinomycin formation.57... 

L-Kynurenine was separated from 3-hydroxykynurenine (observed in some assays) by chromatography on a Beckman Ultrasphere ODS column (4.6 mm x 150 mm). The mobile phase (1.5 m/min) was a 5 235 mixture of acetonitrile and 0.1 M ammonium acetate buffer (pH 4.65). The column effluent was monitored at 365 nm. 

Kynurenine was separated from L-3-hydroxykynurenine by chromatography on a Waters /uBondapak Qg column (8 mm X 100 mm, 10-/i,m), using a flow rate of 3 mL/min. The mobile phase was 0.02 M sodium acetate (pH 5.5) containing 2% methanol. Radioactivity was quantitated with a flow-through detector, using scintillation fluid at 3 mL/min. 

Figure 8.4. Pathways of tryptophan metaholism. Tryptophan dioxygenase, EC 1.13.11.11 formylkynurenine formamidase, EC 3.5.1.9 kynurenine hydroxylase, EC 1.14.13.9 kynureninase, EC 3.7.1.3 3-hydroxyanthranilate oxidase, EC 1.10.3.5 picolinate carboxylase, EC 4.1.1.45 kynurenine oxoglutarate aminotransferase, EC 2.6.1.7 kynurenine glyoxylate aminotransferase, 2.6.1.63 tryptophan hydroxylase, EC 1.14.16.4 and 5-hydroxytryptophan decarboxylase, EC 4.1.1.26. Relative molecular masses (Mr) tryptophan, 204.2 serotonin, 176.2 kynurenine, 208.2 3-hydroxykynurenine, 223.2 kynurenic acid, 189.2 xanthurenic acid, 205.2 and quinolinic acid 167.1. CoA, coenzyme A.

Kynureninase Kynureninase is apyridoxalphosphate (vitamin Be)-dependent enzyme that catalyzes the hydrolysis of 3-hydroxykynurenine to 3-hydroxyanthranilic acid, releasing the side chain as alanine. Impairment... 

Guilarte TR and Wagner HN Jr (1987) Increased concentrations of 3-hydroxykynurenine in vitamin Be deficient neonatal rat brain. Journal of Neurochemistry 49, 1918-26. 

Excess xanthurenate in the urine. Xanthure-nate levels in the urine increase with vitamin B6 deficiency because B (as pyridoxal phosphate) is necessary for the further chemical transformation of 3-hydroxykynurenine. Pyridoxine deficiency may be detected by giving the patient a loading dose of tryptophan. If pyridoxine deficiency is present, there will be a detectable excess of xanthurinate in the urine. Oral contraceptives may increase urinary xanthurenate levels, possibly... 

An increase of quinolinic acid is strongly associated with several prominent features of depression decrease in reaction time (Martin et al., 1992, 1993 Heyes et al., 1991) and cognitive deficits, in particular difficulties in learning (Heyes et al., 1998). In an animal model, an increase of quinolinic acid and 3-hydroxykynurenine was associated with anxiety (Lapin, 2003). 

HK 5-ASA 5-fflAA 5-HT 5- HT 6- OHDA 8-OHdG yc 3-hydroxykynurenine 5-aminosalicychc acid 5-hydroxyindole acetic acid 5- hydroxy hyptophan 5 -hydroxy hyp t amine 6- hydoxydopamine 8-hydroxy-2 -deoxyguanosine common y-chain ... 

It was furthermore reported (K20) that nicotinic acid-deficient animals would grow only if given tryptophan, thus suggesting the conversion of tryptophan to nicotinic acid. Not only is tryptophan converted to nicotinic acid but also kynurenine and 3-hydroxyanthranilic acid. The peculiar degradation of the latter to pyridine derivatives gave rise to many interesting investigations. 3-Hydroxyanthranilic acid is derived from 3-hydroxykynurenine, another important tryptophan metabolite, the his-... 

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