Details for: KMO

Gene ID: 8564

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: KMO

Ensembl ID: ENSG00000117009

Description: kynurenine 3-monooxygenase

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • myeloid leukocyte CL0000766
    CSI 28.33
    rCSI 26.14%
    PRS 77.58
  • VIP GABAergic cortical interneuron CL4023016
    CSI 11.61
    rCSI 13.86%
    PRS 57.33
  • sncg GABAergic cortical interneuron CL4023015
    CSI 9.23
    rCSI 14.84%
    PRS 59.1
  • Kupffer cell CL0000091
    CSI 7.29
    rCSI 16.67%
    PRS 76.79
  • alternatively activated macrophage CL0000890
    CSI 6.07
    rCSI 7.63%
    PRS 85.99
  • mature B cell CL0000785
    CSI 5.76
    rCSI 5%
    PRS 85.69
  • mononuclear phagocyte CL0000113
    CSI 5.26
    rCSI 11.58%
    PRS 80.04
  • hepatocyte CL0000182
    CSI 4.59
    rCSI 8.21%
    PRS 75.22
  • naive B cell CL0000788
    CSI 4.57
    rCSI 3.92%
    PRS 82.97
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 4.52
    rCSI 7.58%
    PRS 57.37
  • immature B cell CL0000816
    CSI 4.41
    rCSI 3.28%
    PRS 87.32
  • midzonal region hepatocyte CL0019028
    CSI 3.47
    rCSI 8.14%
    PRS 77
  • lung macrophage CL1001603
    CSI 3.22
    rCSI 7.18%
    PRS 83.54
  • class switched memory B cell CL0000972
    CSI 3.07
    rCSI 2.29%
    PRS 88.81
  • lung interstitial macrophage CL4033043
    CSI 3.02
    rCSI 6.78%
    PRS 88.96
  • dendritic cell, human CL0001056
    CSI 3.01
    rCSI 4.62%
    PRS 84.98
  • elicited macrophage CL0000861
    CSI 2.93
    rCSI 2.69%
    PRS 84.32
  • epithelial cell of proximal tubule CL0002306
    CSI 2.55
    rCSI 6.23%
    PRS 68.63
  • alveolar macrophage CL0000583
    CSI 2.41
    rCSI 3.97%
    PRS 80.56
  • small pre-B-II cell CL0000954
    CSI 2.34
    rCSI 2.25%
    PRS 90.94
  • periportal region hepatocyte CL0019026
    CSI 2.17
    rCSI 8.43%
    PRS 76.74
  • parietal epithelial cell CL1000452
    CSI 2.08
    rCSI 5.55%
    PRS 67.06
  • centrilobular region hepatocyte CL0019029
    CSI 1.96
    rCSI 5.12%
    PRS 75.66
  • placental villous trophoblast CL2000060
    CSI 1.95
    rCSI 3.01%
    PRS 75.11
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 1.83
    rCSI 4.73%
    PRS 71.03
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 1.78
    rCSI 2.15%
    PRS 84.05
  • syncytiotrophoblast cell CL0000525
    CSI 1.67
    rCSI 4.81%
    PRS 83.71
  • conjunctival epithelial cell CL1000432
    CSI 1.62
    rCSI 2.47%
    PRS 76.31
  • intermediate monocyte CL0002393
    CSI 1.57
    rCSI 2.37%
    PRS 81.48
  • corneal epithelial cell CL0000575
    CSI 1.56
    rCSI 4.45%
    PRS 83.93
  • CD14-low, CD16-positive monocyte CL0002396
    CSI 1.33
    rCSI 1.02%
    PRS 78.18
  • tissue-resident macrophage CL0000864
    CSI 1.14
    rCSI 5.34%
    PRS 87.9
  • large pre-B-II cell CL0000957
    CSI 1.1
    rCSI 3.13%
    PRS 82.82

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Kynurenine 3-monooxygenase, encoded by the [KMO](/details-gene/8564) gene, is a mitochondrial outer membrane enzyme that plays a critical role in the tryptophan catabolic pathway. It catalyzes the hydroxylation of L-kynurenine to 3-hydroxy-L-kynurenine, a pivotal step that directs tryptophan metabolism away from the production of the neuroprotectant kynurenic acid and towards the production of the pro-oxidant and neurotoxic quinolinic acid, a precursor for NAD+ biosynthesis. Expression data indicates that **Overall**, [KMO](/details-gene/8564) is most significantly expressed in [myeloid leukocyte](/details-cell/CL0000766) populations, including various macrophage subtypes and [Kupffer cell](/details-cell/CL0000091)s. Its expression is also notable in specific subsets of [VIP GABAergic cortical interneuron](/details-cell/CL4023016) and developing and mature [B cell](/details-cell/CL0000785)s, highlighting its importance at the interface of immunity, metabolism, and neuromodulation. ## Cellular Roles and Expression Landscape The expression profile of [KMO](/details-gene/8564) underscores its central function within the mononuclear phagocyte system. The highest significance score is observed in the broad category of [myeloid leukocyte](/details-cell/CL0000766) (CSI: 28.33), with strong enrichment in more specific populations such as liver-resident [Kupffer cell](/details-cell/CL0000091)s, [alternatively activated macrophage](/details-cell/CL0000890)s, and various lung macrophages. This pattern suggests that [KMO](/details-gene/8564) is a key enzymatic checkpoint controlling immunomodulatory and potentially cytotoxic metabolic pathways in macrophages, which are central to tissue homeostasis and inflammatory responses. Beyond myeloid cells, [KMO](/details-gene/8564) shows a distinct expression signature in other cell types. It is significantly expressed across the B-lymphocyte lineage, including [immature B cell](/details-cell/CL0000816)s, [naive B cell](/details-cell/CL0000788)s, and [mature B cell](/details-cell/CL0000785)s, suggesting a role in B cell metabolism or function. Furthermore, notable expression in specific neuronal subtypes, including [VIP GABAergic cortical interneuron](/details-cell/CL4023016) and [sncg GABAergic cortical interneuron](/details-cell/CL4023015), points towards a specialized function in regulating neuroactive metabolites derived from the kynurenine pathway within the central nervous system. Expression in [hepatocyte](/details-cell/CL0000182)s is consistent with the liver's central role in systemic amino acid metabolism. ## Pathways and Molecular Function [KMO](/details-gene/8564) functions as a flavin adenine dinucleotide (FAD)-binding monooxygenase, as annotated by its molecular function in [kynurenine 3-monooxygenase activity](/details-cell/GO:0004502) and [Fad binding](/details-cell/GO:0071949). Its enzymatic activity is a rate-limiting step within the [Tryptophan catabolism](/details-cell/R-HSA-71240) pathway, a key part of the broader [Metabolism of amino acids and derivatives](/details-cell/R-HSA-71291). Located primarily at the [mitochondrial outer membrane](/details-cell/GO:0005741), it diverts tryptophan metabolites toward the synthesis of quinolinate ([Quinolinate biosynthetic process](/details-cell/GO:0019805)), which is a precursor for the 'de novo' [NAD biosynthetic process from tryptophan](/details-cell/GO:0034354). The functional annotations align closely with its expression in immune cells. Involvement in [Cellular response to lipopolysaccharide](/details-cell/GO:0071222) and [Cellular response to interleukin-1](/details-cell/GO:0071347) directly links [KMO](/details-gene/8564) activity to the sensing of inflammatory triggers, which is a primary function of the myeloid cells where it is highly expressed. The pathway's metabolites are known to be highly bioactive, and [KMO](/details-gene/8564) activity can influence processes such as [positive regulation of glutamate secretion](/details-cell/GO:1903296), providing a molecular basis for its role in neuromodulation. ## Research Directions The expression pattern and enzymatic function of [KMO](/details-gene/8564) position it as a critical regulator of immune and neuronal cell function through metabolic control. Future research should focus on elucidating how its activity is regulated in a cell-type-specific manner and how this contributes to disease pathology. **Testable Hypotheses:** 1. Given its high expression in diverse macrophage populations, including [alternatively activated macrophage](/details-cell/CL0000890)s, the enzymatic activity of [KMO](/details-gene/8564) is a critical determinant of macrophage polarization. Inhibition of [KMO](/details-gene/8564) may shift the local metabolic milieu, favoring the production of kynurenic acid over 3-hydroxykynurenine, thereby promoting an anti-inflammatory macrophage phenotype. 2. In [VIP GABAergic cortical interneuron](/details-cell/CL4023016)s, cell-intrinsic [KMO](/details-gene/8564) activity controls the local production of the excitotoxic NMDA receptor agonist quinolinic acid. Dysregulation of [KMO](/details-gene/8564) in these neurons could contribute to network hyperexcitability and neuroinflammation seen in certain neurological disorders. **Proposed Experimental Approach:** To test the hypothesis regarding macrophage polarization, human primary monocytes could be differentiated into M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages in vitro. During differentiation, cells would be treated with a highly specific [KMO](/details-gene/8564) inhibitor, such as those characterized structurally and mechanistically in prior studies ([Link](https://doi.org/10.1038/ncomms15827)). The impact of [KMO](/details-gene/8564) inhibition would be assessed by measuring changes in key polarization surface markers (e.g., CD86, CD206) via flow cytometry, quantifying cytokine secretion profiles (e.g., TNF-α, IL-10, IL-6) using multiplex assays, and performing targeted metabolomics on cell supernatants to confirm the expected shift in kynurenine pathway metabolites. **Therapeutic Potential:** [KMO](/details-gene/8564) is a highly attractive therapeutic target. As an enzyme, it is amenable to inhibition by small molecules. Several studies have demonstrated that pharmacological inhibition of [KMO](/details-gene/8564) can be protective in preclinical models of inflammatory disease, such as acute pancreatitis, by reducing the production of damaging downstream metabolites ([Link](https://doi.org/10.1038/nm.4020)). Therefore, inhibition of [KMO](/details-gene/8564) represents a promising strategy for treating a range of immunometabolic and neuroinflammatory disorders where the kynurenine pathway is pathologically overactivated.

Genular Protein ID: 1744412875

Symbol: KMO_HUMAN

Name: N/A

UniProtKB Accession Codes:

O15229 A2A2U8 A2A2U9 A2A2V0 Q5SY07 Q5SY08 Q5SY09

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CTD 1 ChEBI 20 ChEMBL 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EC 1 EMBL 4 Ensembl 3 ExpressionAtlas 1 GO 19 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HAMAP 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRINTS 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 Reactome 1 RefSeq 1 Rhea 1 SABIO-RK 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9237672

Title: Cloning and functional expression of human kynurenine 3-monooxygenase.

PubMed ID: 9237672

DOI: 10.1016/s0014-5793(97)00627-3

PubMed ID: 10672018

Title: Functional characterization and mechanism of action of recombinant human kynurenine 3-hydroxylase.

PubMed ID: 10672018

DOI: 10.1046/j.1432-1327.2000.01104.x

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 12402501

Title: Endogenous kynurenines as targets for drug discovery and development.

PubMed ID: 12402501

DOI: 10.1038/nrd870

PubMed ID: 23575632

Title: Structural basis of kynurenine 3-monooxygenase inhibition.

PubMed ID: 23575632

DOI: 10.1038/nature12039

PubMed ID: 26752518

Title: Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.

PubMed ID: 26752518

DOI: 10.1038/nm.4020

PubMed ID: 28604669

Title: Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase.

PubMed ID: 28604669

DOI: 10.1038/ncomms15827

PubMed ID: 29208702

Title: Biochemistry and structural studies of kynurenine 3-monooxygenase reveal allosteric inhibition by Ro 61-8048.

PubMed ID: 29208702

DOI: 10.1096/fj.201700397rr

PubMed ID: 29429898

Title: Structural Basis for Inhibitor-Induced Hydrogen Peroxide Production by Kynurenine 3-Monooxygenase.

PubMed ID: 29429898

DOI: 10.1016/j.chembiol.2018.01.008

Sequence Information:

  • Length: 486
  • Mass: 55810
  • Checksum: 164870D52E62A08A
  • Sequence:
    • MDSSVIQRKK VAVIGGGLVG SLQACFLAKR NFQIDVYEAR EDTRVATFTR GRSINLALSH 
RGRQALKAVG LEDQIVSQGI PMRARMIHSL SGKKSAIPYG TKSQYILSVS RENLNKDLLT 
AAEKYPNVKM HFNHRLLKCN PEEGMITVLG SDKVPKDVTC DLIVGCDGAY STVRSHLMKK 
PRFDYSQQYI PHGYMELTIP PKNGDYAMEP NYLHIWPRNT FMMIALPNMN KSFTCTLFMP 
FEEFEKLLTS NDVVDFFQKY FPDAIPLIGE KLLVQDFFLL PAQPMISVKC SSFHFKSHCV 
LLGDAAHAIV PFFGQGMNAG FEDCLVFDEL MDKFSNDLSL CLPVFSRLRI PDDHAISDLS 
MYNYIEMRAH VNSSWFIFQK NMERFLHAIM PSTFIPLYTM VTFSRIRYHE AVQRWHWQKK 
VINKGLFFLG SLIAISSTYL LIHYMSPRSF LRLRRPWNWI AHFRNTTCFP AKAVDSLEQI 
SNLISR

Genular Protein ID: 2774041998

Symbol: A8K693_HUMAN

Name: N/A

UniProtKB Accession Codes:

A8K693

Database IDs:

ARBA 5 AlphaFoldDB 1 BioGRID-ORCS 1 CTD 1 ChEBI 8 ChiTaRS 1 DNASU 1 DisGeNET 1 EC 1 EMBL 2 GO 8 Gene3D 1 HAMAP 1 HAMAP-Rule 1 InterPro 3 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 1 PeptideAtlas 1 Pfam 2 RefSeq 1 Rhea 1 SAM 1 SUPFAM 1 UniPathway 1

Sequence Information:

  • Length: 486
  • Mass: 55717
  • Checksum: FA369554C0051E46
  • Sequence:
    • MDSSVIQRKK VAVIGGGLVG SLQACFLAKR NFQIDVYEAR EDTRVATFTR GRSINLALSH 
RGRQALKAVG LEDQIVSQGI PMRARMIHSL SGKKSAIPYG TKSQYILSVS RENLNKDLLT 
AAEKYPNVKM HFNHRLLKCN PEEGMITVLG SDKVPKDVTC DLIVGCDGAY STVRSHLMKK 
PRSDYSQQYI PHGYMELTIP PKNGDYAMEP NYLHIWPRNT FMMIALPNMN KSFTCTLFMP 
FEELEKLLTS NDVVDFFQKY FPDAIPLIGE KLLVQDFFLL PAQPMISVKC SSFHFKSHCV 
LLGDAAHAIV PFFGQGMNAG FEDCLVFDEL MDKFSNDLSL CLPVFSRLRI PDDHAISDLS 
MYDYIEMRAH VNSSWFIFQK NMERFLHAIM PSTFIPLYTM VTFSRIRYHE AVQRWHWQKK 
VINKGLFFLG SLIAISSTYL LIHYMSPRSF LRLRRPWNWI AHFRNTTCFP AKAVDSLEQI 
SNLISR