Disease relevance of KMO

• These results suggest roles for increased activities of IDO, kynurenine-3-hydroxylase and kynureninase in accelerating the synthesis of QUIN, L-KYN and KYNA in conditions of brain inflammation [1].
• The efficacy of o,o'-bismyristoyl thiamine disulfide (BMT) was examined in detail against HIV-1 laboratory isolates (HTLV-IIIB, JRFL, and MN), primary isolates (KMT and KMO), and simian immunodeficiency virus (SIVmac251) in vitro [2].
• These results suggest that elevation of KYNA levels through inhibition of kynurenine 3-hydroxylase constitutes a promising novel approach for managing LID in Parkinson's disease [3].
• The antidystonic efficacy of Ro 61-8048 at well-tolerated doses suggests that kynurenine 3-hydroxylase inhibitors should be considered as new therapeutic candidates for the treatment of dyskinesias [4].
• The kynurenine 3-hydroxylase inhibitor Ro 61-8048 improves dystonia in a genetic model of paroxysmal dyskinesia [4].

High impact information on KMO

• By means of suppression subtractive hybridization, we identified kynurenine 3-monooxygenase and subsequently indoleamine 2,3-dioxygenase (IDO) to be overexpressed in FcepsilonRI-activated monocytes [5].
• Kynurenine 3-monooxygenase, an enzyme involved in the degradation of the amino acid tryptophan, is significantly up-regulated during the late phase after 24 h of FcepsilonRI induction [6].
• Induction of spinal cord IDO (35.9-fold) accompanied smaller, but proportional increases in kynurenine-3-hydroxylase (2.4-fold) and kynureninase (2.3-fold) activities, which were correlated to CSF and tissue QUIN levels, as well as to measures of inflammatory lesions [1].
• Kynurenine-3-hydroxylase activity was increased in the duodenum, lung, and spleen, but not in the brain, kidney, or liver [7].
• In the late phase of acute PM, we found a significant transcriptional upregulation of kynurenine-3-hydroxylase and an accumulation of the neurotoxic metabolites 3-hydroxykynurenine (3-HKYN) and 3-hydroxyanthranilic acid in cortex and hippocampus [8].

Biological context of KMO

• The gene was localized to the region of chromosome 1q43 also encompassing the kynurenine monooxygenase (KMO) and choroideremia-like Rab escort protein 2 (CHML) genes [9].
• The mitochondrial outer membrane enzyme kynurenine 3-hydroxylase (K3H) is an NADPH-dependent flavin mono-oxygenase involved in the tryptophan pathway, where it catalyzes the hydroxylation of kynurenine [10].
• Single-marker and haplotype analyses for 6-tag single nucleotide polymorphisms (SNPs) of KMO were performed (cases = 465, controls = 440) [11].
• Cloning and characterization of the Tribolium castaneum eye-color genes encoding tryptophan oxygenase and kynurenine 3-monooxygenase [12].

Anatomical context of KMO

• Kynurenine aminotransferase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilic acid dioxygenase appeared to be constitutively expressed in both cell lines [13].
• K3H was transiently expressed in COS-1 cells as a glutathione S-transferase (GST) fusion protein, and the pure recombinant protein (rec-K3H) was obtained with a specific activity of about 2000 nmol.min-1.mg-1 [10].
• Marked increases in the activity of kynureninase, kynurenine 3-hydroxylase, and 3-hydroxyanthranilate-3,4-dioxygenase were also detected in hippocampus but not in cerebellum on day 4 of recirculation [14].
• Kinetic analysis of kynurenine-3-hydroxylase activity in the cerebral cortex of postischemic gerbils showed that Vmax increased, without changes in Km [15].
• High activities of kynurenine 3-hydroxylase, kynureninase or 3-hydroxyanthranilate 3,4-dioxygenase were found in interferon-gamma-stimulated macrophages, THP-1 cells and SKHEP1 cells, and these cells made large amounts of quinolinate when supplied with L-tryptophan, L-kynurenine, 3-hydroxykynurenine or 3-hydroxyanthranilate [16].

Associations of KMO with chemical compounds

• Rec-K3H was shown to have an optimum pH at 7.5, to use NADPH more efficiently than NADH, and to contain one molecule of non-covalently bound FAD per molecule of enzyme [10].
• Further kinetic studies revealed that K3H activity was inhibited by both pyridoxal phosphate and Cl-, and that NADPH-catalyzed oxidation occurred even in the absence of kynurenine if 3-hydroxykynurenine was present, suggesting an uncoupling effect of 3-hydroxykynurenine with peroxide formation [10].
• In MRC-9 cells, quinolinate was produced only from 3-hydroxykynurenine and 3-hydroxyanthranilate, consistent with their low kynurenine 3-hydroxylase activity [16].
• Quinolinate production by human fetal brain cultures and U373MG cells was restricted by the low activities of kynurenine 3-hydroxylase, kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase, and only small amounts of quinolinate were synthesized when cultures were supplied with L-tryptophan or 3-hydroxyanthranilate [16].
• To evaluate this hypothesis, we used a pharmacological tool, the kynurenine 3-hydroxylase inhibitor Ro 61-8048, which raises KYNA levels acutely [3].

Other interactions of KMO

• Furthermore, the human OPN3 gene overlaps with the neighboring KMO gene on a genomic as well as on an RNA level, whereas the corresponding genes in mouse lie close together but do not overlap [17].
• In liver, kynurenine 3-monooxygenase and kynurenine-oxoglutarate transaminase activities did not show any significant difference among the three groups of rabbits [18].

Analytical, diagnostic and therapeutic context of KMO

• A new miniature membrane oxygenator (Kuraray KMO, size, 0.3 m2, with a priming volume of 47 ml, compliance of less than 0.1 ml/100 mmHg, and pressure loss of 45 mmHg) with improved gas transfer and mechanical durability was developed and tested [19].
• The effects of the novel kynurenine 3-hydroxylase inhibitor 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide (Ro 61-8048) on severity of dystonia were examined in dt(sz) mutant hamsters, an animal model of paroxysmal dystonia, in which stress precipitates dystonic episodes [4].

References