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Damian J. Mole - One of the best experts on this subject based on the ideXlab platform.
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Kynurenine 3-Monooxygenase is a critical regulator of renal ischemia-reperfusion injury.
Experimental & molecular medicine, 2019Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:Acute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.
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Kynurenine 3-Monooxygenase is a critical regulator of renal ischemia–reperfusion injury
Experimental & Molecular Medicine, 2019Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:Acute kidney injury (AKI) following ischemia–reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity ( Kmo ^null mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmo ^null mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type ( Kmo ^wt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness. Inhibition of a metabolic enzyme linked to inflammation could be a novel treatment approach for sudden kidney failure following a “reperfusion” injury caused by blood flow returning to the organ after a period of insufficient blood supply. Damian Mole and colleagues from the University of Edinburgh, UK, temporarily blocked blood vessels leading to the kidneys of mice to induce organ damage. Mice that lacked a working copy of Kynurenine 3-Monooxygenase ( KMO ), a gene that encodes an enzyme involved in metabolizing an essential amino acid linked to immune activation, were protected from injury. These KMO -mutant mice experienced less damage to the kidney’s tubular cells and had fewer pro-inflammatory cells than genetically normal animals. The findings support the idea that blocking KMO and its associated metabolic pathway could help mitigate kidney damage following reperfusion injury in humans.
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Kynurenine 3-Monooxygenase (KMO) is a critical regulator of renal ischemia-reperfusion injury
2018Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:SUMMARYAcute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. This advances our previous work showing that KMO blockade protects against acute lung injury and AKI in experimental multiple organ failure caused by acute pancreatitis. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically-active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid and downstream metabolites. In experimental AKI induced by unilateral kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared to wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.
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Diclofenac Identified as a Kynurenine 3-Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques.
ACS omega, 2018Co-Authors: Steven Shave, Damian J. Mole, Scott P. Webster, Kris Mcguire, Nhan T. Pham, Manfred AuerAbstract:In this study, we apply a battery of molecular similarity techniques to known inhibitors of Kynurenine 3-Monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar KD and IC50, respectively, and low millimolar cellular IC50. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing.
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Diclofenac Identified as a Kynurenine 3‑Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques
2018Co-Authors: Steven Shave, Damian J. Mole, Scott P. Webster, Kris Mcguire, Nhan T. Pham, Manfred AuerAbstract:In this study, we apply a battery of molecular similarity techniques to known inhibitors of Kynurenine 3-Monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar KD and IC50, respectively, and low millimolar cellular IC50. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing
Scott P. Webster - One of the best experts on this subject based on the ideXlab platform.
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Kynurenine 3-Monooxygenase is a critical regulator of renal ischemia-reperfusion injury.
Experimental & molecular medicine, 2019Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:Acute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.
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Kynurenine 3-Monooxygenase is a critical regulator of renal ischemia–reperfusion injury
Experimental & Molecular Medicine, 2019Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:Acute kidney injury (AKI) following ischemia–reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity ( Kmo ^null mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmo ^null mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type ( Kmo ^wt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness. Inhibition of a metabolic enzyme linked to inflammation could be a novel treatment approach for sudden kidney failure following a “reperfusion” injury caused by blood flow returning to the organ after a period of insufficient blood supply. Damian Mole and colleagues from the University of Edinburgh, UK, temporarily blocked blood vessels leading to the kidneys of mice to induce organ damage. Mice that lacked a working copy of Kynurenine 3-Monooxygenase ( KMO ), a gene that encodes an enzyme involved in metabolizing an essential amino acid linked to immune activation, were protected from injury. These KMO -mutant mice experienced less damage to the kidney’s tubular cells and had fewer pro-inflammatory cells than genetically normal animals. The findings support the idea that blocking KMO and its associated metabolic pathway could help mitigate kidney damage following reperfusion injury in humans.
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Kynurenine 3-Monooxygenase (KMO) is a critical regulator of renal ischemia-reperfusion injury
2018Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:SUMMARYAcute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. This advances our previous work showing that KMO blockade protects against acute lung injury and AKI in experimental multiple organ failure caused by acute pancreatitis. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically-active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid and downstream metabolites. In experimental AKI induced by unilateral kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared to wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.
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Diclofenac Identified as a Kynurenine 3-Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques.
ACS omega, 2018Co-Authors: Steven Shave, Damian J. Mole, Scott P. Webster, Kris Mcguire, Nhan T. Pham, Manfred AuerAbstract:In this study, we apply a battery of molecular similarity techniques to known inhibitors of Kynurenine 3-Monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar KD and IC50, respectively, and low millimolar cellular IC50. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing.
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Diclofenac Identified as a Kynurenine 3‑Monooxygenase Binder and Inhibitor by Molecular Similarity Techniques
2018Co-Authors: Steven Shave, Damian J. Mole, Scott P. Webster, Kris Mcguire, Nhan T. Pham, Manfred AuerAbstract:In this study, we apply a battery of molecular similarity techniques to known inhibitors of Kynurenine 3-Monooxygenase (KMO), querying each against a repository of approved, experimental, nutraceutical, and illicit drugs. Four compounds are assayed against KMO. Subsequently, diclofenac (also known by the trade names Voltaren, Voltarol, Aclonac, and Cataflam) has been confirmed as a human KMO protein binder and inhibitor in cell lysate with low micromolar KD and IC50, respectively, and low millimolar cellular IC50. Hit to drug hopping, as exemplified here for one of the most successful anti-inflammatory medicines ever invented, holds great promise for expansion into new disease areas and highlights the not-yet-fully-exploited potential of drug repurposing
Xiaozhong Zheng - One of the best experts on this subject based on the ideXlab platform.
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Kynurenine 3-Monooxygenase is a critical regulator of renal ischemia-reperfusion injury.
Experimental & molecular medicine, 2019Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:Acute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.
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Kynurenine 3-Monooxygenase is a critical regulator of renal ischemia–reperfusion injury
Experimental & Molecular Medicine, 2019Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:Acute kidney injury (AKI) following ischemia–reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity ( Kmo ^null mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmo ^null mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type ( Kmo ^wt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness. Inhibition of a metabolic enzyme linked to inflammation could be a novel treatment approach for sudden kidney failure following a “reperfusion” injury caused by blood flow returning to the organ after a period of insufficient blood supply. Damian Mole and colleagues from the University of Edinburgh, UK, temporarily blocked blood vessels leading to the kidneys of mice to induce organ damage. Mice that lacked a working copy of Kynurenine 3-Monooxygenase ( KMO ), a gene that encodes an enzyme involved in metabolizing an essential amino acid linked to immune activation, were protected from injury. These KMO -mutant mice experienced less damage to the kidney’s tubular cells and had fewer pro-inflammatory cells than genetically normal animals. The findings support the idea that blocking KMO and its associated metabolic pathway could help mitigate kidney damage following reperfusion injury in humans.
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Kynurenine 3-Monooxygenase (KMO) is a critical regulator of renal ischemia-reperfusion injury
2018Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:SUMMARYAcute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. This advances our previous work showing that KMO blockade protects against acute lung injury and AKI in experimental multiple organ failure caused by acute pancreatitis. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically-active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid and downstream metabolites. In experimental AKI induced by unilateral kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared to wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.
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Overexpression of human Kynurenine-3-Monooxygenase protects against 3-hydroxyKynurenine-mediated apoptosis through bidirectional nonlinear feedback.
Cell death & disease, 2016Co-Authors: Kris Wilson, Xiaozhong Zheng, John P. Iredale, Manfred Auer, Scott P. Webster, Margaret Binnie, Nhan T. Pham, Damian J. MoleAbstract:Kynurenine 3-Monooxygenase (KMO) is a critical regulator of inflammation. The preferred KMO substrate, Kynurenine, is converted to 3-hydroxyKynurenine (3HK), and this product exhibits cytotoxicity through mechanisms that culminate in apoptosis. Here, we report that overexpression of human KMO with orthotopic localisation to mitochondria creates a metabolic environment during which the cell exhibits increased tolerance for exogenous 3HK-mediated cellular injury. Using the selective KMO inhibitor Ro61-8048, we show that KMO enzyme function is essential for cellular protection. Pan-caspase inhibition with Z-VAD-FMK confirmed apoptosis as the mode of cell death. By defining expression of pathway components upstream and downstream of KMO, we observed alterations in other key Kynurenine pathway components, particularly tryptophan-2,3-dioxygenase upregulation, through bidirectional nonlinear feedback. KMO overexpression also increased expression of inducible nitric oxide synthase (iNOS). These changes in gene expression are functionally relevant, because siRNA knockdown of the pathway components kynureninase and quinolinate phosphoribosyl transferase caused cells to revert to a state of susceptibility to 3HK-mediated apoptosis. In summary, KMO overexpression, and importantly KMO activity, have metabolic repercussions that fundamentally affect resistance to cell stress.
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Kynurenine-3-Monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis
Nature medicine, 2016Co-Authors: Damian J. Mole, Kris Wilson, Xiaozhong Zheng, Scott P. Webster, Margaret Binnie, Jonathan P. Hutchinson, Ann Louise Walker, Iain Uings, Olivier Mirguet, Benjamin BeaufilsAbstract:Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that Kynurenine-3-Monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the Kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 A resolution. Treatment with GSK180 resulted in rapid changes in the levels of Kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.
Flaviano Giorgini - One of the best experts on this subject based on the ideXlab platform.
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ablation of Kynurenine 3 Monooxygenase rescues plasma inflammatory cytokine levels in the r6 2 mouse model of huntington s disease
Scientific Reports, 2021Co-Authors: Marie Katrin Bondulich, Flaviano Giorgini, Yilan Fan, Yeojin Song, Gillian P BatesAbstract:Kynurenine 3-Monooxygenase (KMO) regulates the levels of neuroactive metabolites in the Kynurenine pathway (KP), dysregulation of which is associated with Huntington’s disease (HD) pathogenesis. KMO inhibition leads to increased levels of neuroprotective relative to neurotoxic metabolites, and has been found to ameliorate disease-relevant phenotypes in several HD models. Here, we crossed KMO knockout mice to R6/2 HD mice to examine the effect of KMO depletion in the brain and periphery. KP genes were dysregulated in peripheral tissues from R6/2 mice and KMO ablation normalised levels of a subset of these. KP metabolites were also assessed, and KMO depletion led to increased levels of neuroprotective kynurenic acid in brain and periphery, and dramatically reduced neurotoxic 3-hydroxykunurenine levels in striatum and cortex. Notably, the increased levels of pro-inflammatory cytokines TNFa, IL1β, IL4 and IL6 found in R6/2 plasma were normalised upon KMO deletion. Despite these improvements in KP dysregulation and peripheral inflammation, KMO ablation had no effect upon several behavioural phenotypes. Therefore, although genetic inhibition of KMO in R6/2 mice modulates several metabolic and inflammatory parameters, these do not translate to improvements in primary disease indicators—observations which will likely be relevant for other interventions targeted at peripheral inflammation in HD.
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Advantages of brain penetrating inhibitors of Kynurenine-3-Monooxygenase for treatment of neurodegenerative diseases.
Archives of biochemistry and biophysics, 2020Co-Authors: Shaowei Zhang, Flaviano Giorgini, Derren J. Heyes, Mary E.w. Collier, Nigel S. ScruttonAbstract:Abstract Kynurenine-3-Monooxygenase (KMO) is an important therapeutic target for several brain disorders that has been extensively studied in recent years. Potent inhibitors towards KMO have been developed and tested within different disease models, showing great therapeutic potential, especially in models of neurodegenerative disease. The inhibition of KMO reduces the production of downstream toxic Kynurenine pathway metabolites and shifts the flux to the formation of the neuroprotectant kynurenic acid. However, the efficacy of KMO inhibitors in neurodegenerative disease has been limited by their poor brain permeability. Combined with virtual screening and prodrug strategies, a novel brain penetrating KMO inhibitor has been developed which dramatically decreases neurotoxic metabolites. This review highlights the importance of KMO as a drug target in neurological disease and the benefits of brain permeable inhibitors in modulating Kynurenine pathway metabolites in the central nervous system.
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A novel role for Kynurenine 3-Monooxygenase in mitochondrial dynamics.
PLoS genetics, 2020Co-Authors: Daniel C. Maddison, Carlo Breda, Aisha M Swaih, Mónica Alfonso-núñez, Susanna Campesan, Natalie Allcock, Anna Straatman-iwanowska, Charalambos P. Kyriacou, Flaviano GiorginiAbstract:The enzyme Kynurenine 3-Monooxygenase (KMO) operates at a critical branch-point in the Kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson's disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the Kynurenine pathway.
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Assessing and Modulating Kynurenine Pathway Dynamics in Huntington's Disease: Focus on Kynurenine 3-Monooxygenase.
Methods in molecular biology (Clifton N.J.), 2018Co-Authors: Korrapati V. Sathyasaikumar, Carlo Breda, Robert Schwarcz, Flaviano GiorginiAbstract:The link between disturbances in Kynurenine pathway (KP) metabolism and Huntington's disease (HD) pathogenesis has been explored for a number of years. Several novel genetic and pharmacological tools have recently been developed to modulate key regulatory steps in the KP such as the reaction catalyzed by the enzyme Kynurenine 3-Monooxygenase (KMO). This insight has offered new options for exploring the mechanistic link between this metabolic pathway and HD, and provided novel opportunities for the development of candidate drug-like compounds. Here, we present an overview of the field, focusing on some novel approaches for interrogating the pathway experimentally.
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A29 Kynurenine 3-Monooxygenase interacts with huntingtin at the outer mitochondrial membrane
Pathogenic mechanisms, 2018Co-Authors: Carlo Breda, Aisha M Swaih, Mariaelena Repici, Flaviano GiorginiAbstract:Background Kynurenine 3-Monooxygenase (KMO), an outer mitochondrial membrane protein, catalyses the conversion of l-Kynurenine to the neurotoxin 3-hydroxyKynurenine (3-HK) – thereby playing a critical role in the Kynurenine pathway (KP). Increased KMO activity likely contributes to the toxicity observed in neurodegenerative disorders by enhancing levels of 3-HK and the excitotoxin quinolinic acid (QUIN). Notably, genetic and pharmacological inhibition of KMO ameliorates disease-relevant phenotypes in models of Huntington’s disease (HD). Aims This study interrogates the subcellular localisation of human KMO and explores its interaction with the huntingtin (HTT) protein. Methods Confocal analysis was employed to explore KMO localisation and bimolecular fluorescence complementation (BiFC) and transmission electron microscopy was used to investigate KMO and HTT interactions in HEK293T cells. Results We found that KMO exclusively localises to mitochondria when expressed in HEK293T cells. A deletion of a C-terminal portion of KMO (tKMO) which contains a putative transmembrane domain causes the mislocalisation of the enzyme from mitochondria to other cellular compartments, suggesting a critical function for this region in mitochondrial targeting. We also found an interaction between KMO and both WT and mutant HTT fragments at the outer mitochondrial membrane. Notably, the strength of this interaction was inversely correlated to the length of the HTT polyglutamine expansion. No interaction between tKMO and HTT was observed indicating that mitochondrial localization of KMO is likely critical for HTT/KMO interactions. Conclusions This study suggests that KMO and HTT may interact at the outer mitochondria membrane. The biological significance of this interaction will be explored in future experiments.
Margaret Binnie - One of the best experts on this subject based on the ideXlab platform.
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Kynurenine 3-Monooxygenase is a critical regulator of renal ischemia-reperfusion injury.
Experimental & molecular medicine, 2019Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:Acute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.
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Kynurenine 3-Monooxygenase is a critical regulator of renal ischemia–reperfusion injury
Experimental & Molecular Medicine, 2019Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:Acute kidney injury (AKI) following ischemia–reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity ( Kmo ^null mice) are protected against AKI after renal IRI. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid, and downstream metabolites. In experimental AKI induced by kidney IRI, Kmo ^null mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type ( Kmo ^wt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness. Inhibition of a metabolic enzyme linked to inflammation could be a novel treatment approach for sudden kidney failure following a “reperfusion” injury caused by blood flow returning to the organ after a period of insufficient blood supply. Damian Mole and colleagues from the University of Edinburgh, UK, temporarily blocked blood vessels leading to the kidneys of mice to induce organ damage. Mice that lacked a working copy of Kynurenine 3-Monooxygenase ( KMO ), a gene that encodes an enzyme involved in metabolizing an essential amino acid linked to immune activation, were protected from injury. These KMO -mutant mice experienced less damage to the kidney’s tubular cells and had fewer pro-inflammatory cells than genetically normal animals. The findings support the idea that blocking KMO and its associated metabolic pathway could help mitigate kidney damage following reperfusion injury in humans.
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Kynurenine 3-Monooxygenase (KMO) is a critical regulator of renal ischemia-reperfusion injury
2018Co-Authors: Xiaozhong Zheng, Scott P. Webster, Ailiang Zhang, Margaret Binnie, Kris Mcguire, Jeremy Hughes, Sarah E. M. Howie, Damian J. MoleAbstract:SUMMARYAcute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking Kynurenine 3-Monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. This advances our previous work showing that KMO blockade protects against acute lung injury and AKI in experimental multiple organ failure caused by acute pancreatitis. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically-active Kynurenine metabolites 3-hydroxyKynurenine, kynurenic acid and downstream metabolites. In experimental AKI induced by unilateral kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared to wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.
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Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis
Journal of medicinal chemistry, 2017Co-Authors: Ann Louise Walker, Margaret Binnie, Carl Haslam, Nicolas Ancellin, Benjamin Beaufils, Marylise Bergeal, Anne Marie Jeanne Bouillot, David E. Clapham, Alexis Denis, Duncan S. HolmesAbstract:Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of Kynurenine 3-Monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington’s disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development.
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Development of a Series of Kynurenine 3‑Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis
2017Co-Authors: Ann Louise Walker, Margaret Binnie, Nicolas Ancellin, Benjamin Beaufils, Marylise Bergeal, Anne Marie Jeanne Bouillot, Alexis Denis, David Clapham, Carl P. Haslam, Duncan S. HolmesAbstract:Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of Kynurenine 3-Monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington’s disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development
