- Structural insight into the inhibition of human kynurenine aminotransferase I/Glutamine transaminase K
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Human kynurenine aminotransferase I (hKAT I) catalyzes the formation of kynurenic acid, a neuroactive compound. Here, we report three high-resolution crystal structures (1.50-1.55 ?) of hKAT I that are in complex with glycerol and each of two inhibitors of hKAT I: indole-3-acetic acid (IAC) and Tris. Because Tris is able to occupy the substrate binding position, we speculate that this may be the basis for hKAT I inhibition. Furthermore, the hKAT/IAC complex structure reveals that the binding moieties of the inhibitor are its indole ring and a carboxyl group. Six chemicals with both binding moieties were tested for their ability to inhibit hKAT I activity; 3-indolepropionic acid and DL-indole-3-lactic acid demonstrated the highest level of inhibition, and as they cannot be considered as substrates of the enzyme, these two inhibitors are promising candidates for future study. Perhaps even more significantly, we report the discovery of two different ligands located simultaneously in the hKAT I active center for the first time.
- Han, Qian,Robinson, Howard,Cai, Tao,Tagle, Danilo A.,Li, Jianyong
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- Synthesis and Photocleavage of Quinoline Methyl Ethers: A Mild and Efficient Method for the Selective Protection and Deprotection of the Alcohol Functionality
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The synthesis and photocleavage of quinolinyl methyl ether-protected alcohols is reported in this study. A variety of quinoline methyl chlorides were synthesized, and protection of the various alcohols was performed via a substitution reaction in the presence of a strong base. Photocleavage of the quinolinyl methyl ether moiety proceeded under visible light with the formation of the charged quinolinyl radical intermediate through a single-electron transfer in the presence of a photosensitizer dye leading to the deprotected alcohol in excellent yields. The utility of triethylamine as a sacrificial reductant and d-sorbitol as a radical scavenger were also investigated in this study.
- Provatas, Anthony A.,Epling, Gary A.,Stuart, James D.
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p. 763 - 769
(2016/08/09)
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- Involvement of common intermediate 3-hydroxy-L-kynurenine in chromophore biosynthesis of quinomycin family antibiotics
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Quinomycin antibiotics, represented by echinomycin, are an important class of antitumor antibiotics. We have recently succeeded in identification of biosynthetic gene clusters of echinomycin and SW-163D, and have achieved heterologous production of echinomycin in Escherichia coli. In addition, we have engineered echinomycin non-ribosomal peptide synthetase to generate echinomycin derivatives. However, the biosynthetic pathways of intercalative chromophores quinoxaline-2-carboxylic acid (QXC) and 3-hydroxyquinaldic acid (HQA), which are important for biological activity, were not fully elucidated. Here, we report experiments involving incorporation of a putative advanced precursor, (2S, 3R)-6′- 2 H-3-hydroxy-L-kynurenine, and functional analysis of the enzymes Swb1 and Swb2 responsible for late-stage biosynthesis of HQA. On the basis of these experimental results, we propose biosynthetic pathways for both QXC and HQA through the common intermediate 3-hydroxy-L-kynurenine.
- Hirose, Yuki,Watanabe, Kenji,Minami, Atsushi,Nakamura, Takemichi,Oguri, Hiroki,Oikawa, Hideaki
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experimental part
p. 117 - 122
(2012/01/31)
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- 3-indolepyruvic acid derivatives and pharmaceutical use thereof
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The present invention is directed to 3-indolepyruvic acid derivatives, compositions and methods of treating central nervous system disturbances due to the presence of an excessive amount of excitatory amino acids.
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