Kynurenine-3 monooxygenase

Abstract Modulation of tryptophan metabolism and in particular the kynurenine pathway is of considerable interest in the discovery of potential new treatments for neurodegenerative diseases. A number of small molecule inhibitors of the kynurenine metabolic pathway enzymes have been identified over recent years a summary of these and their utility has been reviewed in this chapter. In particular, inhibitors of kynurenine monooxygenase represent an opportunity to develop a therapy for Huntington s disease progress in the optimization of small molecule inhibitors of this enzyme is also described. 

Keywords Enzyme inhibitors, Huntington s disease, Kynurenine monooxygenase (KMO), Kynuremine pathway, Neurodegenerative disease, Tryptophan Metabolism... 

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. 

IMIDAZOLEACETATE HYDROXYLASE INDOLEAMINE 2,3-DIOXYGENASE myo-INOSITOL OXYGENASE JUGLONE MONOOXYGENASE KYNURENINE 3-HYDROXYLASE LACCASE... 

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... 

In the metabolism of the aromatic amino acid tryptophan in mammals, two pathways for the formation of pyridine nucleotide coenzyme and in-doleamines are initiated by two well-known oxygenases, tryptophan 2,3-dioxygenase and tryptophan-5-hydroxylase (monooxygenase) (Fig. 2). Kotake and Ito (5) found in 1937 that rabbits fed D-tryptophan excreted D-kynurenine in the urine. Although the tryptophan-cleaving activity in... 

Xanthommatin deficient mutants are devoid either of tryptophan 2,3-dioxygenase activity (no. 1) or of kynurenine 3-monooxygenase activity (no. 2). 

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...

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