The Experts below are selected from a list of 1131 Experts worldwide ranked by ideXlab platform
Roger J W Truscott - One of the best experts on this subject based on the ideXlab platform.
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detection quantification and total synthesis of novel 3 Hydroxykynurenine glucoside derived metabolites present in human lenses
Investigative Ophthalmology & Visual Science, 2014Co-Authors: Nicholas Gad, Roger J W Truscott, Jasminka Mizdrak, David I Pattison, Michael J Davies, Joanne F JamieAbstract:Purpose 3-Hydroxykynurenine O-β-D-glucoside (3OHKG) protects the lens from UV damage, and novel related species may act analogously. The aim of this study was to detect, quantify, and elucidate the structures of novel 3-Hydroxykynurenine glucoside-derived metabolites present in the human lens. Methods Compounds were detected and quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS) in 24 human lenses of different ages, of which 22 were normal and two had cataract. Structures of these were confirmed through total synthesis. Results 3OHKG concentrations decreased with age in the lens nuclei, whereas the levels of three novel species, 4-(2-amino-3-hydroxyphenyl)-2-hydroxy-4-oxobutanoic acid O-β-D-glucoside (3OHKG-W), 3-Hydroxykynurenine O-β-D-glucoside yellow (3OHKG-Y), and 2-amino-3-hydroxyacetophenone O-β-D-glucoside (AHAG), increased, though to different extents. In contrast, the concentrations present in the cortex of the lens remained constant with age. Conclusions Three novel 3OHKG-derived metabolites have been detected in extracts from human lenses.
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identification of the new uv filter compound cysteine l 3 Hydroxykynurenine o β d glucoside in human lenses
FEBS Letters, 2006Co-Authors: Roger J W Truscott, Peter G Hains, Jasminka Mizdrak, Joanne F Jamie, Isla StreeteAbstract:UV filters protect the human lens and retina from UV light-induced damage. Here, we report the identification of a new UV filter, cysteine-l-3-Hydroxykynurenine O-β-d-glucoside, which is present in older normal human lenses. Its structure was confirmed by independent synthesis. It is likely this novel UV filter is formed in the lens by nucleophilic attack of cysteine on the unsaturated ketone derived from deamination of 3-Hydroxykynurenine O-β-d-glucoside. Quantitation studies revealed considerable variation in normal lens levels that may be traced to the marked instability of the cysteine adduct. The novel UV filter was not detected in advanced nuclear cataract lenses.
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3 Hydroxykynurenine oxidizes alpha crystallin potential role in cataractogenesis
Biochemistry, 2006Co-Authors: Anastasia Korlimbinis, Roger J W Truscott, Peter G Hains, Andrew J AquilinaAbstract:The alpha-, beta-, and gamma-crystallins are the major structural proteins of mammalian lenses. The human lens also contains tryptophan-derived UV filters, which are known to spontaneously deaminate at physiological pH and covalently attach to lens proteins. 3-Hydroxykynurenine (3OHKyn) is the third most abundant of the kynurenine UV filters in the lens, and previous studies have shown this compound to be unstable and to be oxidized under physiological conditions, producing H2O2. In this study, we show that methionine and tryptophan amino acid residues are oxidized when bovine alpha-crystallin is incubated with 3-Hydroxykynurenine. We observed almost complete oxidation of methionines 1 and 138 in alphaA-crystallin and a similar extent of oxidation of methionines 1 and 68 in alphaB-crystallin after 48 h. Tryptophans 9 and 60 in alphaB-crystallin were oxidized to a lesser extent. AlphaA-crystallin was also found to have 3OHKyn bound to its single cysteine residue. Examination of normal aged human lenses revealed no evidence of oxidation of alpha-crystallin; however, oxidation was detected at methionine 1 in both alphaA- and alphaB-crystallin from human cataractous lenses. Age-related nuclear cataract is associated with coloration and insolubilization of lens proteins and extensive oxidation of cysteine and methionine residues. Our findings demonstrate that 3-Hydroxykynurenine can readily catalyze the oxidation of methionine residues in both alphaB- and alphaA-crystallin, and it has been reported that alpha-crystallin modified in this way is a poorer chaperone. Thus, 3-Hydroxykynurenine promotes the oxidation and modification of crystallins and may contribute to oxidative stress in the human lens.
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3 Hydroxykynurenine oxidizes alpha crystallin potential role in cataractogenesis
Biochemistry, 2006Co-Authors: Roger J W Truscott, Andrew Aquilina, Peter G Hains, Anastasia KorlimbinisAbstract:The α-, β-, and γ-crystallins are the major structural proteins of mammalian lenses. The human lens also contains tryptophan-derived UV filters, which are known to spontaneously deaminate at physiological pH and covalently attach to lens proteins. 3-Hydroxykynurenine (3OHKyn) is the third most abundant of the kynurenine UV filters in the lens, and previous studies have shown this compound to be unstable and to be oxidized under physiological conditions, producing H2O2. In this study, we show that methionine and tryptophan amino acid residues are oxidized when bovine α-crystallin is incubated with 3-Hydroxykynurenine. We observed almost complete oxidation of methionines 1 and 138 in αA-crystallin and a similar extent of oxidation of methionines 1 and 68 in αB-crystallin after 48 h. Tryptophans 9 and 60 in αB-crystallin were oxidized to a lesser extent. αA-Crystallin was also found to have 3OHKyn bound to its single cysteine residue. Examination of normal aged human lenses revealed no evidence of oxidation ...
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identification of 3 Hydroxykynurenine bound to proteins in the human lens a possible role in age related nuclear cataract
Biochemistry, 2006Co-Authors: Anastasia Korlimbinis, Roger J W TruscottAbstract:Age-related nuclear (ARN) cataract is a major cause of world blindness. With the onset of ARN cataract, the normally transparent and colorless lens becomes opaque and can take on colors ranging from orange, brown, and even black. The molecular basis for this remarkable transformation is unknown. ARN cataract is also characterized by extensive oxidation, insolubilization, and cross-linking of polypeptides, particularly in the nucleus of the lens. It has been postulated that 3-Hydroxykynurenine (3OHKyn) may be involved in these changes. This endogenous tryptophan metabolite is readily oxidized and is involved in the tanning of moth cocoons and the formation of pigments in the eyes of butterflies. 3OHKyn is a component of our primate-specific UV-filter pathway, and the brownish hue of ARN cataract lenses is also unique to humans. Because numerous colored compounds can be produced by autoxidation of 3OHKyn, this process could provide an explanation for the variety of lens colors and other changes seen in ARN ...
Thereza A Soares - One of the best experts on this subject based on the ideXlab platform.
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a second generation of 1 2 4 oxadiazole derivatives with enhanced solubility for inhibition of 3 Hydroxykynurenine transaminase hkt from aedes aegypti
RSC Medicinal Chemistry, 2021Co-Authors: Larissa G Maciel, Thereza A Soares, Andrey Da S Barbosa, Edilson B Alencarfilho, Janaina Dos V AnjosAbstract:The most widely used method for the control of the Aedes aegypti mosquito population is the chemical control method. It represents a time- and cost-effective way to curb several diseases (e.g. dengue, Zika, chikungunya, yellow fever) through vector control. For this reason, the discovery of new compounds with a distinct mode of action from the available ones is essential in order to minimize the rise of insecticide resistance. Detoxification enzymes are an attractive target for the discovery of new insecticides. The kynurenine pathway is an important metabolic pathway, and it leads to the chemically stable xanthurenic acid, biosynthesized from 3-Hydroxykynurenine, a precursor of reactive oxygen and nitrogen species, by the enzyme 3-Hydroxykynurenine transaminase (HKT). Previously, we have reported the effectiveness of 1,2,4-oxadiazole derivatives acting as larvicides for A. aegypti and AeHKT inhibitors from in vitro and in silico studies. Here, we report the synthesis of new sodium 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] propanoates and the cognate HKT-inhibitory activity. These new derivatives act as competitive inhibitors with IC50 values in the range of 42 to 339 μM. We further performed molecular docking simulations and QSAR analysis for the previously synthesized sodium 4-[3-(aryl)-1,2,4-oxadiazol-5-yl] butanoates reported earlier by our group and the data produced herein. Most of the 1,2,4-oxadiazole derivatives, including the canonical compounds for both series, showed a similar binding mode with HKT. The binding occurs similarly to the co-crystallized inhibitor via anchoring to Arg356 and positioning of the aromatic ring and its substituents outwards at the entry of the active site. QSAR analysis was performed in search of more than 770 molecular descriptors to establish a relationship between the lowest energy conformations and the IC50 values. The five best descriptors were selected to create and validate the model, which exhibited parameters that attested to its robustness and predictability. In summary, we observed that compounds with a para substitution and heavier groups (i.e. CF3 and NO2 substituents) had an enhanced HKT-inhibition profile. These compounds comprise a series described as AeHKT inhibitors via enzymatic inhibition experiments, opening the way to further the development of new substances with higher potency against HKT from Aedes aegypti.
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discovery of 1 2 4 oxadiazole derivatives as a novel class of noncompetitive inhibitors of 3 Hydroxykynurenine transaminase hkt from aedes aegypti
Bioorganic & Medicinal Chemistry, 2020Co-Authors: Larissa G Maciel, A A Oliveira, Tatiany Patricia Romao, Laylla L L Leal, Rafael Victorio Carvalho Guido, Maria Helena Neves Lobo Silvafilha, Janaina Dos V Anjos, Thereza A SoaresAbstract:The mosquito Aedes aegypti is the vector of arboviruses such as Zika, Chikungunya, dengue and yellow fever. These infectious diseases have a major impact on public health. The unavailability of effective vaccines or drugs to prevent or treat most of these diseases makes vector control the main form of prevention. One strategy to promote mosquito population control is the use of synthetic insecticides to inhibit key enzymes in the metabolic pathway of these insects, particularly during larval stages. One of the main targets of the kynurenine detoxification pathway in mosquitoes is the enzyme 3-Hydroxykynurenine transaminase (HKT), which catalyzes the conversion of 3-Hydroxykynurenine (3-HK) into xanthurenic acid (XA). In this work, we report eleven newly synthesized oxadiazole derivatives and demonstrate that these compounds are potent noncompetitive inhibitors of HKT from Ae. aegypti. The present data provide direct evidence that HKT can be explored as a molecular target for the discovery of novel larvicides against Ae. aegypti. More importantly, it ensures that structural information derived from the HKT 3D-structure can be used to guide the development of more potent inhibitors.
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the enzyme 3 Hydroxykynurenine transaminase as potential target for 1 2 4 oxadiazoles with larvicide activity against the dengue vector aedes aegypti
Bioorganic & Medicinal Chemistry, 2013Co-Authors: Vanessa S Oliveira, Laylla L L Leal, Janaina Dos V Anjos, Cecilia Pimenteira, Diana C B Da Silvaalves, Ricardo A W Nevesfilho, Daniela Maria Do Amaral Ferraz Navarro, Geanne K N Santos, Kamilla A Dutra, Thereza A SoaresAbstract:The mosquito Aedes aegypti is the vector agent responsible for the transmission of yellow fever and dengue fever viruses to over 80 million people in tropical and subtropical regions of the world. Exhaustive efforts have lead to a vaccine candidate with only 30% effectiveness against the dengue virus and failure to protect patients against the serotype 2. Hence, vector control remains the most viable route to dengue fever control programs. We have synthesized a class of 1,2,4-oxadiazole derivatives whose most biologically active compounds exhibit potent activity against Aedes aegypti larvae (ca. of 15 ppm) and low toxicity in mammals. Exposure to these larvicides results in larvae pigmentation in a manner correlated with the LC50 measurements. Structural comparisons of the 1,2,4-oxadiazole nucleus against known inhibitors of insect enzymes allowed the identification of 3-Hydroxykynurenine transaminase as a potential target for these synthetic larvicides. Molecular docking calculations indicate that 1,2,4-oxadiazole compounds can bind to 3-Hydroxykynurenine transaminase with similar conformation and binding energies as its crystallographic inhibitor 4-(2-aminophenyl)-4-oxobutanoic acid.
Anastasia Korlimbinis - One of the best experts on this subject based on the ideXlab platform.
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3 Hydroxykynurenine oxidizes alpha crystallin potential role in cataractogenesis
Biochemistry, 2006Co-Authors: Anastasia Korlimbinis, Roger J W Truscott, Peter G Hains, Andrew J AquilinaAbstract:The alpha-, beta-, and gamma-crystallins are the major structural proteins of mammalian lenses. The human lens also contains tryptophan-derived UV filters, which are known to spontaneously deaminate at physiological pH and covalently attach to lens proteins. 3-Hydroxykynurenine (3OHKyn) is the third most abundant of the kynurenine UV filters in the lens, and previous studies have shown this compound to be unstable and to be oxidized under physiological conditions, producing H2O2. In this study, we show that methionine and tryptophan amino acid residues are oxidized when bovine alpha-crystallin is incubated with 3-Hydroxykynurenine. We observed almost complete oxidation of methionines 1 and 138 in alphaA-crystallin and a similar extent of oxidation of methionines 1 and 68 in alphaB-crystallin after 48 h. Tryptophans 9 and 60 in alphaB-crystallin were oxidized to a lesser extent. AlphaA-crystallin was also found to have 3OHKyn bound to its single cysteine residue. Examination of normal aged human lenses revealed no evidence of oxidation of alpha-crystallin; however, oxidation was detected at methionine 1 in both alphaA- and alphaB-crystallin from human cataractous lenses. Age-related nuclear cataract is associated with coloration and insolubilization of lens proteins and extensive oxidation of cysteine and methionine residues. Our findings demonstrate that 3-Hydroxykynurenine can readily catalyze the oxidation of methionine residues in both alphaB- and alphaA-crystallin, and it has been reported that alpha-crystallin modified in this way is a poorer chaperone. Thus, 3-Hydroxykynurenine promotes the oxidation and modification of crystallins and may contribute to oxidative stress in the human lens.
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3 Hydroxykynurenine oxidizes alpha crystallin potential role in cataractogenesis
Biochemistry, 2006Co-Authors: Roger J W Truscott, Andrew Aquilina, Peter G Hains, Anastasia KorlimbinisAbstract:The α-, β-, and γ-crystallins are the major structural proteins of mammalian lenses. The human lens also contains tryptophan-derived UV filters, which are known to spontaneously deaminate at physiological pH and covalently attach to lens proteins. 3-Hydroxykynurenine (3OHKyn) is the third most abundant of the kynurenine UV filters in the lens, and previous studies have shown this compound to be unstable and to be oxidized under physiological conditions, producing H2O2. In this study, we show that methionine and tryptophan amino acid residues are oxidized when bovine α-crystallin is incubated with 3-Hydroxykynurenine. We observed almost complete oxidation of methionines 1 and 138 in αA-crystallin and a similar extent of oxidation of methionines 1 and 68 in αB-crystallin after 48 h. Tryptophans 9 and 60 in αB-crystallin were oxidized to a lesser extent. αA-Crystallin was also found to have 3OHKyn bound to its single cysteine residue. Examination of normal aged human lenses revealed no evidence of oxidation ...
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identification of 3 Hydroxykynurenine bound to proteins in the human lens a possible role in age related nuclear cataract
Biochemistry, 2006Co-Authors: Anastasia Korlimbinis, Roger J W TruscottAbstract:Age-related nuclear (ARN) cataract is a major cause of world blindness. With the onset of ARN cataract, the normally transparent and colorless lens becomes opaque and can take on colors ranging from orange, brown, and even black. The molecular basis for this remarkable transformation is unknown. ARN cataract is also characterized by extensive oxidation, insolubilization, and cross-linking of polypeptides, particularly in the nucleus of the lens. It has been postulated that 3-Hydroxykynurenine (3OHKyn) may be involved in these changes. This endogenous tryptophan metabolite is readily oxidized and is involved in the tanning of moth cocoons and the formation of pigments in the eyes of butterflies. 3OHKyn is a component of our primate-specific UV-filter pathway, and the brownish hue of ARN cataract lenses is also unique to humans. Because numerous colored compounds can be produced by autoxidation of 3OHKyn, this process could provide an explanation for the variety of lens colors and other changes seen in ARN ...
Richard C Scarpa - One of the best experts on this subject based on the ideXlab platform.
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3 Hydroxykynurenine and 3 hydroxyanthranilic acid generate hydrogen peroxide and promote α crystallin cross linking by metal ion reduction
Biochemistry, 2000Co-Authors: Lee E Goldstein, Michael C Leopold, Xudong Huang, Craig S Atwood, Aleister J Saunders, Mariana A Hartshorn, James Lim, Kyle Y Faget, Julien Muffat, Richard C ScarpaAbstract:The kynurenine pathway catabolite 3-Hydroxykynurenine (3HK) and redox-active metals such as copper and iron are implicated in cataractogenesis. Here we investigate the reaction of kynurenine pathwa...
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3 Hydroxykynurenine and 3 hydroxyanthranilic acid generate hydrogen peroxide and promote α crystallin cross linking by metal ion reduction
Biochemistry, 2000Co-Authors: Lee E Goldstein, Michael C Leopold, Xudong Huang, Craig S Atwood, Aleister J Saunders, Mariana A Hartshorn, James Lim, Kyle Y Faget, Julien Muffat, Richard C ScarpaAbstract:The kynurenine pathway catabolite 3-Hydroxykynurenine (3HK) and redox-active metals such as copper and iron are implicated in cataractogenesis. Here we investigate the reaction of kynurenine pathway catabolites with copper and iron, as well as interactions with the major lenticular structural proteins, the alpha-crystallins. The o-aminophenol kynurenine catabolites 3HK and 3-hydroxyanthranilic acid (3HAA) reduced Cu(II)>Fe(III) to Cu(I) and Fe(II), respectively, whereas quinolinic acid and the nonphenolic kynurenine catabolites kynurenine and anthranilic acid did not reduce either metal. Both 3HK and 3HAA generated superoxide and hydrogen peroxide in a copper-dependent manner. In addition, 3HK and 3HAA fostered copper-dependent alpha-crystallin cross-linking. 3HK- or 3HAA-modifed alpha-crystallin showed enhanced redox activity in comparison to unmodified alpha-crystallin or ascorbate-modified alpha-crystallin. These data support the possibility that 3HK and 3HAA may be cofactors in the oxidative damage of proteins, such as alpha-crystallin, through interactions with redox-active metals and especially copper. These findings may have relevance for understanding cataractogenesis and other degenerative conditions in which the kynurenine pathway is activated.
Peter G Hains - One of the best experts on this subject based on the ideXlab platform.
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identification of the new uv filter compound cysteine l 3 Hydroxykynurenine o β d glucoside in human lenses
FEBS Letters, 2006Co-Authors: Roger J W Truscott, Peter G Hains, Jasminka Mizdrak, Joanne F Jamie, Isla StreeteAbstract:UV filters protect the human lens and retina from UV light-induced damage. Here, we report the identification of a new UV filter, cysteine-l-3-Hydroxykynurenine O-β-d-glucoside, which is present in older normal human lenses. Its structure was confirmed by independent synthesis. It is likely this novel UV filter is formed in the lens by nucleophilic attack of cysteine on the unsaturated ketone derived from deamination of 3-Hydroxykynurenine O-β-d-glucoside. Quantitation studies revealed considerable variation in normal lens levels that may be traced to the marked instability of the cysteine adduct. The novel UV filter was not detected in advanced nuclear cataract lenses.
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3 Hydroxykynurenine oxidizes alpha crystallin potential role in cataractogenesis
Biochemistry, 2006Co-Authors: Anastasia Korlimbinis, Roger J W Truscott, Peter G Hains, Andrew J AquilinaAbstract:The alpha-, beta-, and gamma-crystallins are the major structural proteins of mammalian lenses. The human lens also contains tryptophan-derived UV filters, which are known to spontaneously deaminate at physiological pH and covalently attach to lens proteins. 3-Hydroxykynurenine (3OHKyn) is the third most abundant of the kynurenine UV filters in the lens, and previous studies have shown this compound to be unstable and to be oxidized under physiological conditions, producing H2O2. In this study, we show that methionine and tryptophan amino acid residues are oxidized when bovine alpha-crystallin is incubated with 3-Hydroxykynurenine. We observed almost complete oxidation of methionines 1 and 138 in alphaA-crystallin and a similar extent of oxidation of methionines 1 and 68 in alphaB-crystallin after 48 h. Tryptophans 9 and 60 in alphaB-crystallin were oxidized to a lesser extent. AlphaA-crystallin was also found to have 3OHKyn bound to its single cysteine residue. Examination of normal aged human lenses revealed no evidence of oxidation of alpha-crystallin; however, oxidation was detected at methionine 1 in both alphaA- and alphaB-crystallin from human cataractous lenses. Age-related nuclear cataract is associated with coloration and insolubilization of lens proteins and extensive oxidation of cysteine and methionine residues. Our findings demonstrate that 3-Hydroxykynurenine can readily catalyze the oxidation of methionine residues in both alphaB- and alphaA-crystallin, and it has been reported that alpha-crystallin modified in this way is a poorer chaperone. Thus, 3-Hydroxykynurenine promotes the oxidation and modification of crystallins and may contribute to oxidative stress in the human lens.
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3 Hydroxykynurenine oxidizes alpha crystallin potential role in cataractogenesis
Biochemistry, 2006Co-Authors: Roger J W Truscott, Andrew Aquilina, Peter G Hains, Anastasia KorlimbinisAbstract:The α-, β-, and γ-crystallins are the major structural proteins of mammalian lenses. The human lens also contains tryptophan-derived UV filters, which are known to spontaneously deaminate at physiological pH and covalently attach to lens proteins. 3-Hydroxykynurenine (3OHKyn) is the third most abundant of the kynurenine UV filters in the lens, and previous studies have shown this compound to be unstable and to be oxidized under physiological conditions, producing H2O2. In this study, we show that methionine and tryptophan amino acid residues are oxidized when bovine α-crystallin is incubated with 3-Hydroxykynurenine. We observed almost complete oxidation of methionines 1 and 138 in αA-crystallin and a similar extent of oxidation of methionines 1 and 68 in αB-crystallin after 48 h. Tryptophans 9 and 60 in αB-crystallin were oxidized to a lesser extent. αA-Crystallin was also found to have 3OHKyn bound to its single cysteine residue. Examination of normal aged human lenses revealed no evidence of oxidation ...
