- Determinants of dual substrate specificity revealed by the crystal structure of homoisocitrate dehydrogenase from Thermus thermophilus in complex with homoisocitrate·Mg2+·NADH
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HICDH (Homoisocitrate dehydrogenase) is a member of the β-decarboxylating dehydrogenase family that catalyzes the conversion of homoisocitrate to α-ketoadipate using NAD+ as a coenzyme, which is the fourth reaction involved in lysine biosynthesis through the α-aminoadipate pathway. Although typical HICDHs from fungi and yeast exhibit strict substrate specificities toward homoisocitrate (HIC), HICDH from a thermophilic bacterium Thermus thermophilus (TtHICDH) catalyzes the reactions using both HIC and isocitrate (IC) as substrates at similar efficiencies. We herein determined the crystal structure of the quaternary complex of TtHICDH with HIC, NADH, and Mg2+ ion at a resolution of 2.5??. The structure revealed that the distal carboxyl group of HIC was recognized by the side chains of Ser72 and Arg85 from one subunit, and Asn173 from another subunit of a dimer unit. Model structures were constructed for TtHICDH in complex with IC and also for HICDH from Saccharomyces cerevisiae (ScHICDH) in complex with HIC. TtHICDH recognized the distal carboxyl group of IC by Arg85 in the model. In ScHICDH, the distal carboxyl group of HIC was recognized by the side chains of Ser98 and Ser108 from one subunit and Asn208 from another subunit of a dimer unit. By contrast, in ScHICDH, which lacks an Arg residue at the position corresponding to Arg85 in TtHICDH, these residues may not interact with the distal carboxyl group of shorter IC. These results provide a molecular basis for the differences in substrate specificities between TtHICDH and ScHICDH.
- Takahashi, Kento,Tomita, Takeo,Kuzuyama, Tomohisa,Nishiyama, Makoto
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- HEXONE GLUCOKINASE INHIBITOR AND USE THEREOF
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The present invention relates to the technical field of pharmaceuticals, and in particular to a ketohexokinase inhibitor compound, a pharmaceutically acceptable salt, an ester or a stereoisomer thereof; a pharmaceutical composition and formulation containing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof; a method for preparing the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof; and use of the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof in the manufacture of a medicament for treating and/or preventing KHK-mediated diseases and related conditions.
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Paragraph 0104-0105
(2021/12/14)
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- INHIBITORS OF LYSINE BIOSYNTHESIS VIA THE DIAMINOPIMELATE PATHWAY
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The present invention relates to compounds that have the ability to inhibit lysine biosynthesis via the diaminopimelate pathway in certain organisms. As a result of this activity these compounds can be used in applications where inhibition of lysine biosynthesis is useful. Applications of this type include the use of the compound as herbicides and/or anti-bacterial agents.
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- One-pot conversion of cephalosporin C to 7-aminocephalosporanic acid in the absence of hydrogen peroxide
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The main drawback in the production of 7-aminocephalosporanic acid (7-ACA) at the industrial level is the inactivation of the enzymes implicated in the process due to the presence of hydrogen peroxide during the reaction. As an alternative, we have developed the conversion of cephalosporin C to 7-ACA in a single reactor without the presence of hydrogen peroxide during the reaction, achieving more than 80% yield. In order to develop this process, D-amino acid oxidase (DAAO) was co-immobilized with catalase (CAT), which is able to fully eliminate in situ the hydrogen peroxide formed by the neighbouring DAAO molecules. Thus, the product of the reaction is only α-ketoadipyl-7-ACA. This system prevents the inactivation of the oxidase by hydrogen peroxide, solving the main problem of the enzymatic process. Moreover, we have found that α-ketoadipyl-7-ACA is recognized as a substrate by glutaryl acylase (GAC) and hydrolyzed as long as glutaric acid is absent from the reaction medium (because it is able to inhibit the hydrolysis). The low stability of α-ketoadipyl-7-ACA justifies the use of a single reactor, in which glutaryl acylase is already present when this substrate is generated. Thus, the whole process may (and must) be performed in a single step, and in the absence of hydrogen peroxide that could affect the stabilities of the involved enzymes.
- Lopez-Gallego, Fernando,Batencor, Lorena,Hidalgo, Aurelio,Mateo, Cesar,Fernandez-Lafuente, Roberto,Guisan, Jose M.
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p. 1804 - 1810
(2007/10/03)
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- The invention of radical reactions. Part XXXIV. Homologation of carboxylic acids to α-keto carboxylic acids by Barton-ester based radical chain chemistry
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Carboxylic acids can be transformed into the homologous α-keto acids by Barton-ester based radical chemistry. The method was especially successful when ethyl α-trifluoroacetoxy acrylate was used as a radical trap.
- Barton, Derek H. R.,Chern, Ching-Yuh,Jaszberenyi, Joseph Cs.
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p. 1867 - 1886
(2007/10/02)
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- Two Carbon Homologation of Carboxylic Acids via Carbon Radicals Generated from the Acyl Derivatives of N-Hydroxy-2-thiopyridone: Synthesis of Cn+2 α-Keto-acids from Cn Acids. (The 'Three carbon' Problem).
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Reaction of olefins containing a three carbon atom chain with carbon radicals generated from carboxylic acids furnishes adducts that are precursors of the corresponding two carbon atom longer α-keto-acids.These keto-acids are furnished in high overall yield.
- Barton, Derek H. R.,Chern, Ching-Yuh,Jaszberenyi, Joseph Cs.
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p. 5017 - 5020
(2007/10/02)
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