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- 1. メトヘモグロビン血症の遺伝学および病因 genetics and pathogenesis of methemoglobinemia
English Journal
- Bacterial expression of human kynurenine 3-monooxygenase: Solubility, activity, purification.
- Wilson K1, Mole DJ2, Binnie M3, Homer NZ4, Zheng X5, Yard BA6, Iredale JP7, Auer M8, Webster SP9.Author information 1Drug Discovery Core, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: Kris.Wilson@ed.ac.uk.2MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: Damian.Mole@ed.ac.uk.3Drug Discovery Core, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: m.binnie@ed.ac.uk.4Mass Spectrometry Core, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: nhomer@staffmail.ed.ac.uk.5MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: xzheng@staffmail.ed.ac.uk.6Drug Discovery Core, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: byard1@staffmail.ed.ac.uk.7MRC Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: John.Iredale@ed.ac.uk.8School of Biological Sciences and School of Biomedical Sciences, University of Edinburgh, CH Waddington Building, The University of Edinburgh Kings Buildings, Mayfield Road, Edinburgh EH9 3JD, United Kingdom. Electronic address: Manfred.Auer@ed.ac.uk.9Drug Discovery Core, University/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom. Electronic address: scott.webster@ed.ac.uk.AbstractKynurenine 3-monooxygenase (KMO) is an enzyme central to the kynurenine pathway of tryptophan metabolism. KMO has been implicated as a therapeutic target in several disease states, including Huntington's disease. Recombinant human KMO protein production is challenging due to the presence of transmembrane domains, which localise KMO to the outer mitochondrial membrane and render KMO insoluble in many in vitro expression systems. Efficient bacterial expression of human KMO would accelerate drug development of KMO inhibitors but until now this has not been achieved. Here we report the first successful bacterial (Escherichia coli) expression of active FLAG™-tagged human KMO enzyme expressed in the soluble fraction and progress towards its purification.
- Protein expression and purification.Protein Expr Purif.2014 Mar;95:96-103. doi: 10.1016/j.pep.2013.11.015. Epub 2013 Dec 4.
- Kynurenine 3-monooxygenase (KMO) is an enzyme central to the kynurenine pathway of tryptophan metabolism. KMO has been implicated as a therapeutic target in several disease states, including Huntington's disease. Recombinant human KMO protein production is challenging due to the presence of transmem
- PMID 24316190
- Structure and mechanism of kynureninase.
- Phillips RS.Author information Department of Chemistry, University of Georgia, Athens, GA 30602, United States; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, United States. Electronic address: plp@uga.edu.AbstractThe kynurenine pathway is the major pathway of l-tryptophan catabolism in eukaryotes and some bacteria. In this pathway, kynureninase catalyzes the hydrolysis of l-kynurenine (in bacteria) or 3-hydroxy-l-kynurenine (in eukaryotes) to give anthranilic acid or 3-hydroxyanthranilic acid, respectively, and l-alanine. Kynureninase is a member of the aminotransferase superfamily and contains pyridoxal-5'-phosphate (PLP) as cofactor. The enzyme is a dimer of two identical subunits, with the active site containing residues contributed from both subunits. The reaction of kynureninase is formally a retro-Claisen reaction, and thus requires extensive acid-base catalysis. The pH dependence of the reaction of Pseudomonas fluorescens kynureninase shows two pKa's, a base with 6.5 and an acid with 8.8, on kcat/Km, and one pKa of 6.8 on kcat. The effects of mutagenesis of Tyr-226 and 31P NMR results suggest that the basic group with pKa of 6.5 is the phosphate group of the PLP, which accepts a proton from the amino acid substrate zwitterion to initiate transaldimination. The external aldimine of kynurenine and PLP is then deprotonated by the ε-amino group of Lys-227 to give a quinonoid intermediate, which is reprotonated at C-4' to give a ketimine. Addition of water to the γ-carbonyl, assisted by Lys-227, then gives a gem-diol, which undergoes Cβ-Cγ cleavage to give the first product, anthranilic acid, and an enamine intermediate. The enamine is protonated at the β-carbon, resulting in a pyruvate ketimine. Deprotonation at C-4' and reprotonation of the α-carbon gives the external aldimine of l-alanine, which releases the second product, l-alanine. The reaction specificity of kynureninases is determined in part by active site residues, Trp64, Gly281, and Thr282 in P. fluorescens, and the homologous His102, Ser332, and Asn333 in human kynureninase. Asn333 can form a hydrogen bond to the 3-OH of 3-hydroxykynurenine in the human enzyme. Halogenation of kynurenine at C-5 increases activity with both enzymes, but halogenation at C-3 only increases activity for human kynureninase. The effect of halogenation at C-5 may be due to hydrophobic or van der Waals effects, and the effect of halogenation at C-3 for the human enzyme may be due to halogen bonding.
- Archives of biochemistry and biophysics.Arch Biochem Biophys.2014 Feb 15;544C:69-74. doi: 10.1016/j.abb.2013.10.020. Epub 2013 Nov 4.
- The kynurenine pathway is the major pathway of l-tryptophan catabolism in eukaryotes and some bacteria. In this pathway, kynureninase catalyzes the hydrolysis of l-kynurenine (in bacteria) or 3-hydroxy-l-kynurenine (in eukaryotes) to give anthranilic acid or 3-hydroxyanthranilic acid, respectively,
- PMID 24200862
- Characterisation of a novel UV filter in the lens of the thirteen-lined ground squirrel (Ictidomys tridecemlineatus).
- Lyons B1, Karuso P2, Jamie JF2, Simpanya MF3, Giblin F3, Truscott RJ4.Author information 1Save Sight Institute, University of Sydney, Sydney Eye Hospital, 8 Macquarie St, Sydney, NSW 2001, Australia. Electronic address: brianlyons21@gmail.com.2Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW 2109, Australia.3Eye Research Institute, Oakland University, Rochester, MI 48309, USA.4Illawarra Health and Medical Research Institute, University of Wollongong, Northfields Ave, Wollongong, NSW 2522, Australia. Electronic address: rjwt@uow.edu.au.AbstractStructural analysis of a novel UV filter present in the lens of the thirteen-lined ground squirrel has shown that it is related in structure to N-acetyl-3-hydroxykynurenine. This finding is consistent with the fact that the squirrel lenses also contain high levels of this tryptophan metabolite. Analysis of both NMR and mass spectrometric data suggested that the novel UV filter compound forms by condensation of proline with N-acetyl-3-hydroxykynurenine. Its absorption maximum at 340 nm is more than 20 nm lower than that of the kynurenines and it may therefore assist in filtering the more damaging shorter wavelengths of UVA.
- Experimental eye research.Exp Eye Res.2014 Feb 12. pii: S0014-4835(14)00037-2. doi: 10.1016/j.exer.2014.01.022. [Epub ahead of print]
- Structural analysis of a novel UV filter present in the lens of the thirteen-lined ground squirrel has shown that it is related in structure to N-acetyl-3-hydroxykynurenine. This finding is consistent with the fact that the squirrel lenses also contain high levels of this tryptophan metabolite. Anal
- PMID 24530498
Japanese Journal
- 統合失調症のキヌレン酸仮説
- 日本生物学的精神医学会誌 = Japanese journal of biological psychiatry 26(4), 223-234, 2015-12
- NAID 40020734363
- The Urinary Ratio of 3-Hydroxykynurenine/3-Hydroxyanthranilic Acid Is an Index to Predicting the Adverse Effects of <small>D</small>-Tryptophan in Rats
- Journal of Nutritional Science and Vitaminology 60(4), 261-268, 2014
- NAID 130004695718
- Time-Dependent Effects of <small>L</small>-Tryptophan Administration on Urinary Excretion of <small>L</small>-Tryptophan Metabolites
- Journal of Nutritional Science and Vitaminology 60(4), 255-260, 2014
- NAID 130004695717
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