KMO is a flavin protease existing in the outer mitochondrial membrane, mainly distributed in tissues such as the liver and brain. This enzyme catalyzes a key step in the tryptophan metabolic pathway, converting kynuurine to 3-hydroxykynuurine, thereby influencing neurotransmitter synthesis and immune regulation processes. Patients with mental disorders often exhibit abnormal KMO activity, which makes it a potential therapeutic target. This enzyme was first identified in the 1970s. Its crystal structure was analyzed by X-ray diffraction technology in 2013, revealing its substrate binding sites and catalytic mechanism. The in-depth research of KMO has provided important clues for understanding the molecular mechanisms of neurodegenerative diseases, inflammatory responses and mental disorders, and has promoted the progress of related drug development fields.
KMO is a flavin-dependent monooxygenase with a molecular weight of approximately 50-55 kDa, and its precise molecular weight varies slightly among species.
| Species | Human | Mice | Rats |
| Molecular Weight (kDa) | 16.7 | 16.9 | 16.8 |
| Primary Structural Differences | Conservative FAD binding domain | Slightly high catalytic efficiency | Minor variations in the substrate binding region |
KMO is composed of 486 amino acids and has a typical mitochondrial outer membrane protein structure. Its tertiary structure consists of an FAD (flavin adenine dinucleotide) binding domain and an NADPH binding domain, which together form the catalytic active center. Enzyme activity depends on FAD cofactors, which give it characteristic flavoprotein properties.
Fig. 1 A schematic illustrating KMO and its enzymatic product QUIN exerted a novel broadly antiviral function.1
Key structural properties of KMO:
KMO is a key enzyme in the tryptophan metabolic pathway, whose main function is to catalyze the conversion of kynuurine to 3-hydroxykynuurine, and it also participates in multiple neural and immune regulatory processes.
| Function | Description |
| Neurometabolic regulation | Catalyze the hydroxylation reaction of kynurenine, affecting the balance of neurotransmitters and the generation of neuroprotective/neurotoxic substances. |
| Immune regulation | By regulating the ratio of quinolinic acid to canine uric acid, it participates in inflammatory responses and immune responses. |
| Oxidative stress response | Reactive oxygen species (ROS) are produced during metabolism and are closely related to the REDOX state of cells. |
| Association with mental illness | The active anomaly and the pathogenesis of depression, schizophrenia and other mental disorders. |
| Drug development targets | As a potential target for the treatment of neurodegenerative diseases and inflammatory diseases, it has received extensive attention. |
The catalytic reaction of KMO exhibits typical dual-substrate kinetic characteristics (requiring simultaneous binding of kynurenine and NADPH), and its enzymatic activity is jointly regulated by substrate concentration, mitochondrial functional status and genetic polymorphism. Unlike other enzymes in the tryptophan metabolic pathway (such as IDO and TDO), the specific inhibitors of KMO can selectively change the direction of metabolic flow and have significant therapeutic application value.
1. Liao, Fu-Jun, et al. "Identification and experimental validation of KMO as a critical immune-associated mitochondrial gene in unstable atherosclerotic plaque." Journal of Translational Medicine 22.1 (2024): 668. https://doi.org/10.1186/s12967-024-05464-5
Research has found that the mitochondrial-related gene KMO is closely related to macrophage infiltration and the stability of atherosclerotic plaques. KMO is significantly highly expressed in vulnerable plaques. Its silencing can alleviate plaque formation in mice and enhance stability, indicating that KMO can serve as a potential biomarker for diagnosing plaque instability.
2. Jin, Haojie, et al. "Prognostic significance of kynurenine 3-monooxygenase and effects on proliferation, migration and invasion of human hepatocellular carcinoma." Scientific reports 5.1 (2015): 10466. https://doi.org/10.1038/srep10466
Research has found that KMO is highly expressed in hepatocellular carcinoma (HCC) and is associated with a poor prognosis for patients. KMO promotes the proliferation, migration and invasion of HCC cells and can be used as a novel prognostic marker for HCC.
3. Danquah, Bright D., et al. "Mass Spectrometric analysis of antibody—Epitope peptide complex dissociation: Theoretical concept and practical procedure of binding strength characterization." Molecules 25.20 (2020): 4776. https://doi.org/10.1371/journal.ppat.1010366
Research has found that KMO and its metabolite quinolinic acid (QUIN) promote the production of type I interferons by activating the NMDAR-CaMKII-IRF3 pathway, exerting broad-spectrum antiviral effects on multiple viruses and providing a new strategy for antiviral treatment.
4. Wang, Yu, et al. "Circular RNA SCMH1 suppresses KMO expression to inhibit mitophagy and promote functional recovery following stroke." Theranostics 14.19 (2024): 7292. https://doi.org/10.7150/thno.99323
Research has found that brain-targeted delivery of circSCMH1 can promote mitochondrial fusion and reduce mitochondrial autophagy by inhibiting KMO expression, thereby improving neural repair after ischemic stroke and providing a new target for stroke treatment.
5. Lassiter, Randi, et al. "Protective role of kynurenine 3-monooxygenase in allograft rejection and tubular injury in kidney transplantation." Frontiers in immunology 12 (2021): 671025. https://doi.org/10.3389/fimmu.2021.671025
Studies have found that the expression of KMO is significantly reduced in renal transplant rejection. Its metabolites, 3HK/3HAA, can protect renal tubular epithelial cells by enhancing the expression of Bcl-xL and TJP1 and inhibit T cell proliferation, providing a new therapeutic strategy for improving transplant rejection.
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