- Pyruvate Aldolases Catalyze Cross-Aldol Reactions between Ketones: Highly Selective Access to Multi-Functionalized Tertiary Alcohols
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Tertiary alcohols are widely represented in nature and among bioactive molecules. Their importance is attested by the continuous efforts to meet the challenge of their stereoselective synthesis. In this context, we propose an enzymatic approach, involving class II pyruvate aldolases. These enzymes are shown to catalyze selective cross-aldol reactions between pyruvic acid or derivatives as nucleophiles and a series of ketones as electrophiles. This catalytic activity is exemplified by the highly stereoselective preparation of seven branched ketols with good yields. One of them was readily converted into a constrained 4-hydroxyproline analogue in a multienzymatic one-pot one-step process.
- De Berardinis, Véronique,Gefflaut, Thierry,Gourbeyre, Léa,Guérard-Hélaine, Christine,Hélaine, Virgil,Laurent, Victor,Lemaire, Marielle,Nauton, Lionel,Salanoubat, Marcel,Tra?kia, Mounir,Uzel, Alexandre
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- Stereochemistry of the methyl group in (R)-3-methylitaconate derived by rearrangement of 2-methylideneglutarate catalysed by a coenzyme B12-dependent mutase
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2-Methylideneglutarate mutase is an adenosylcobalamin (coenzyme B12)-dependent enzyme that catalyses the equilibration of 2-methylideneglutarate with (R)-3-methylitaconate. This reaction is believed to occur via protein-bound free radicals derived from substrate and product. The stereochemistry of the formation of the methyl group of 3-methylitaconate has been probed using a 'chiral methyl group'. The methyl group in 3-([2H1,3H]methyl)itaconate derived from either (R)- or (S)-2-methylidene[3-2H1,3-3H1]glutarate was a 50 : 50 mixture of (R)- and (S)-forms. It is concluded that the barrier to rotation about the C-C bond between the methylene radical centre and adjacent C-atom in the product-related radical [CH2CH(-O2CC=CH2)CO2-] is relatively low, and that the interaction of the radical with cob(1I)alamin is minimal. Hence, cob(I1)alamin is a spectator of the molecular rearrangement of the substrate radical to product radical.
- Ciceri, Daniele,Pierik, Antonio J.,Hartrampf, Guenter,Broeker, Gerd,Speranza, Giovanna,Buckel, Wolfgang,Cornforth, Sir John,Golding, Bernard T.
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- FLAVIN-MEDIATED PHOTOLYSIS OF MYCOSPORINES
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Under aerobic conditions and in the presence of flavins, light causes the photolysis of mycosporine glutamine into aminocyclohexenone and 2-hydroxy glutaric acid.This photolysis, which is temperature dependent, is also observed when other photosensitizers which are carriers of singlet oxygen replace flavins.This photodestruction also occurs with mycosporine amino alcohols but at reduced rate and probably by another mechanism.
- Bernillon, Jacques,Parussini, Ermis,Letoublon, Robert,Favre-Bonvin, Jean,Arpin, Noel
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- CONVERSION OF 1,2,5,6-HEXANETETROL (HTO) TO TETRAHYDROFURAN DICARBOXYLIC ACID (THFDCA)
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Disclosed herein are methods for synthesizing useful intermediates and/or products from 1,2,5,6-hexanetetrol (HTO), which itself can be derived from a sugar. In an aspect, a process is provided for production of THFDCA from 1,2,5,6-hexanetetrol (HTO). The process comprises the steps of (a) ring closing to form a ring compound and (b) oxidizing using a catalyst comprising platinum and bismuth to form an acid mixture. Step (a) may be performed before or after step (b).
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Paragraph 46
(2019/11/04)
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- Metal-catalyzed reductive deamination of glutamic acid to bio-based dimethyl glutarate and methylamines
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Glutamic acid is a promising renewable platform molecule which is abundantly available in biomass waste streams; it is also efficiently manufactured by fermentation. Here we report the reductive deamination of glutamic acid to bio-based dimethyl glutarate and methylamines. In order to recycle nitrogen in an industrially relevant co-product, glutamic acid was modified to N,N-dimethylglutamic acid by a mild reductive alkylation with Pd/C. Subsequently, selective C-N hydrogenolysis in methanol resulted in dimethyl glutarate and trimethylamine. A wide screening of transition metals (Pt, Pd, Rh and Ru) immobilized on various supports showed that the highest yields of dimethyl glutarate were obtained with Pt/TiO2. An FTIR study and kinetic experiments on metal-loaded and unloaded supports demonstrate that the interplay between the metal and the moderate acidity of the support results in the excellent C-N hydrogenolysis activity and selectivity. Finally, reaction parameter optimization resulted in 81% yield of dimethyl glutarate with 1 wt% Pt/TiO2 at 225 °C, 30 bar H2 after 8 h.
- De Schouwer, Free,Cuypers, Thomas,Claes, Laurens,De Vos, Dirk E.
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p. 1866 - 1876
(2017/06/09)
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- Hydrothermal conversion of macroalgae-derived alginate to lactic acid catalyzed by metal oxides
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Alginate derived from macroalgae was evaluated as a biomass feedstock for the production of lactic acid using metal oxides as solid base catalysts under hydrothermal conditions. The CaO catalyst exhibited the highest catalytic performance, yielding about 13% lactic acid at 200°C for 1 h, while other metal oxide catalysts exhibited little activity. The hydration of CaO to Ca(OH)2 provides Br?nsted bases (OH-) in an aqueous medium. The lactic acid yields were proportional to the number of Br?nsted bases. The CaO catalyst demonstrated nearly similar activity when it was used for the second time and the spent catalyst was successfully regenerated by calcination. The deactivation of the CaO catalyst during subsequent repeated uses arises from the loss of the available basic sites. Plausible reaction pathways for the catalytic conversion of alginate to lactic acid over CaO are also discussed.
- Jeon, Wonjin,Ban, Chunghyeon,Park, Geonu,Woo, Hee Chul,Kim, Do Heui
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p. 1146 - 1156
(2016/02/27)
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- Acidic pH is a metabolic switch for 2-Hydroxyglutarate generation and signaling
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2-Hydroxyglutarate (2-HG) is an important epigenetic regulator, with potential roles in cancer and stem cell biology. The D-(R)-enantiomer (D-2-HG) is an oncometabolite generated from α-ketoglutarate (α-KG) by mutant isocitrate dehydrogenase, whereas L-(S)-2-HG is generated by lactate dehydrogenase and malate dehydrogenase in response to hypoxia. Because acidic pH is a common feature of hypoxia, as well as tumor and stem cell microenvironments, we hypothesized that pH may regulate cellular 2-HG levels. Herein we report that cytosolic acidification under normoxia moderately elevated 2-HG in cells, and boosting endogenous substrate α-KG levels further stimulated this elevation. Studies with isolated lactate dehydrogenase-1 and malate dehydrogenase-2 revealed that generation of 2-HG by both enzymes was stimulated severalfold at acidic pH, relative to normal physiologic pH. In addition, acidic pH was found to inhibit the activity of the mitochondrial L-2-HG removal enzyme L-2-HG dehydrogenase and to stimulate the reverse reaction of isocitrate dehydrogenase (carboxylation of α-KG to isocitrate). Furthermore, because acidic pH is known to stabilize hypoxia-inducible factor (HIF) and 2-HG is a known inhibitor of HIF prolyl hydroxylases, we hypothesized that 2-HG may be required for acid-induced HIF stabilization. Accordingly, cells stably overexpressing L-2-HG dehydrogenase exhibited a blunted HIF response to acid. Together, these results suggest that acidosis is an important and previously overlooked regulator of 2-HG accumulation and other oncometabolic events, with implications for HIF signaling.
- Sergiy, M. Nadtochiy,Xenia, Schafer,Dragony, Fu,Keith, Nehrke,Joshua, Munger,Brookes, Paul S.
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p. 20188 - 20197
(2016/11/03)
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- Single arginine mutation in two yeast isocitrate dehydrogenases: Biochemical characterization and functional implication
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Isocitrate dehydrogenase (IDH), a housekeeping gene, has drawn the attention of cancer experts. Mutation of the catalytic Arg132 residue of human IDH1 (HcIDH) eliminates the enzyme's wild-type isocitrate oxidation activity, but confer the mutant an ability of reducing α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). To examine whether an analogous mutation in IDHs of other eukaryotes could cause similar effects, two yeast mitochondrial IDHs, Saccharomyces cerevisiae NADP+- IDH1 (ScIDH1) and Yarrowia lipolytica NADP+-IDH (YlIDH), were studied. The analogous Arg residues (Arg148 of ScIDH1 and Arg141 of YlIDH) were mutated to His. The Km values of ScIDH1 R148H and YlIDH R141H for isocitrate were determined to be 2.4-fold and 2.2-fold higher, respectively, than those of the corresponding wild-type enzymes. The catalytic efficiencies (kcat/Km) of ScIDH1 R148H and YlIDH R141H for isocitrate oxidation were drastically reduced by 227- fold and 460-fold, respectively, of those of the wild-type enzymes. As expected, both ScIDH1 R148H and YlIDH R141H acquired the neomorphic activity of catalyzing a-KG to 2-HG, and the generation of 2-HG was confirmed using gas chromatography/time of flight-mass spectrometry (GC/TOF-MS). Kinetic analysis showed that ScIDH1 R148H and YlIDH R141H displayed 5.2-fold and 3.3-fold higher affinities, respectively, for α-KG than the HcIDH R132H mutant. The catalytic efficiencies of ScIDH1 R148H and YlIDH R141H for α-KG were 5.5-fold and 4.5- fold, respectively, of that of the HcIDH R132H mutant. Since the HcIDH Arg132 mutation is associated with the tumorigenesis, this study provides fundamental information for further research on the physiological role of this IDH mutation in vivo using yeast.
- Song, Ping,Wei, Huanhuan,Cao, Zhengyu,Wang, Peng,Zhu, Guoping
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- Investigations into the phenolic constituents of Dog's mercury (Mercurialis perennis L.) by LC-MS/MS and GC-MS analyses
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Introduction Dog's mercury (Mercurialis perennis L.) is a traditional European medicinal plant considered as a rich source of bioactive natural products. Yet phytochemical data of the plant are scant. Objective This study aimed to identify the hydrophilic phenolic constituents from M. perennis by aqueous and hydroalcoholic extraction. Methodology Extracts of herbal parts were investigated in-depth by HPLC(DAD)-MS/MS and GC/MS analyses. In addition, a novel compound was isolated and fully characterised by 1- and 2D-NMR experiments. Results Several conjugates of caffeic, p-coumaric and ferulic acids together with glucaric or 2-hydroxyglutaric acids (depsides) were detected in the aqueous extracts from aerial plant parts by use of LC-MS/MS techniques as well UV-spectral data. By implementation of preparative chromatography on polyamide pretreated with formic acid followed by vacuum liquid chromatography on reversed-phase C18-silica, one of the predominant depsides was isolated as a pure compound. The NMR spectra (1H and 13C NMR) together with 2D-hetereonuclear multiple bond correlation NMR experiments (gHMBC and gHSQC) and chiral GC investigation, allowed identification of this compound as (-)-(E)-caffeoyl-2-(R)-oxoglutarate. This structure was additionally supported by GC/MS data after silylation and methylation reactions. The hydroalcoholic extract from aerial parts was separated by solvent partition between ethyl acetate and n-butanol. The latter fraction (n-butanol) yielded a mixture of mono- and oligo-glycosides of kaempferol and quercetin, all of them being assigned by LC-MS/MS. Conclusions The present investigation constitutes the first comprehensive report on the hydrophilic constituents of the rarely studied plant Mercurialis and thus completes the phytochemical knowledge on M. perennis.
- Lorenz, Peter,Conrad, Juergen,Bertrams, Julia,Berger, Melanie,Duckstein, Sarina,Meyer, Ulrich,Stintzing, Florian C.
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experimental part
p. 60 - 71
(2012/05/19)
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- pH-Dependent Chemoselective Synthesis of α-Amino Acids. Reductive Amination of α-Keto Acids with Ammonia Catalyzed by Acid-Stable Iridium Hydride Complexes in Water
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An acid-stable hydride complex [Cp*IrIII(bpy)H]+ {1, Cp* = η5-C5Me5, bpy = 2,2′-bipyridine} serves as the active catalyst for the highly chemoselective synthesis of α-amino acids by reductive aminatio
- Ogo, Seiji,Uehara, Keiji,Abura, Tsutomu,Fukuzumi, Shunichi
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p. 3020 - 3021
(2007/10/03)
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- Effects of Gln102Arg and Cys97Gly mutations on the structural specificity and stereospecificity of the L-lactate dehydrogenase from Bacillus stearothermophilus
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The L-lactate dehydrogenase of Bacillus stearothermophilus (BSLDH) is a thermostable enzyme with considerable potential for applications in asymmetric synthesis. An understanding of the factors controlling its structural specificity and stereospecificity is therefore of interest. In this paper the effects of Gln102 → Arg and Cys97 → Gly mutations have been evaluated. In a survey of thirteen 2-keto acids, the Q102R mutation was found to reduce the activity of BSLDH toward the reduction of RCOCOOH substrates with small or hydrophilic R groups without affecting its activity toward those with larger, hydrophobic R substituents. In addition, the mutants have a high affinity for C3- and C4-2-keto dicarboxylates. The extent of fructose 1,6-diphosphate activation of the mutant enzymes was similar to its effect on wild-type BSLDH. The mutants also retained the synthetically desirable thermostability. As a probe of the commitment of BSLDH to L stereospecificity, the Q102R mutation was introduced to allow the new 102R site to compete with Arg171 for binding of the COO- groups of the RCOCOOH substrates, which would reverse the normal RCOCOOH orientation at the active site and thereby open up the possibility of the formation of a D-2-hydroxy acid in place of the natural L product. However, L stereospecificity in 2-keto acid reduction was strictly retained by the Q102R mutants. This was confirmed by preparative-scale reductions of pyruvate and phenylpyruvate to give the corresponding L-hydroxy acids in enantiomerically pure form and by comparison of the kinetics of oxidation of L- and D-lactate and L- and D-phenyl lactate. No evidence for substrate activity for the D enantiomers of either of these was seen with WT or mutant enzymes. Some catalysis of D-malate oxidation by both WT and mutant BSLDH was observed, but the L enantiomer was still preferred to approximately the same degree in both cases. That the inability of BSLDH and its 102R mutants to catalyze D-2-hydroxy acid oxidations was not simply due to the failure of the D enantiomers to bind at the active site was established by a comparison of competitive inhibition constants for the above L- and D-hydroxy acids. CD spectroscopy showed that the Gln102 → Arg mutations were not benign but induced significant structural perturbations. Electrostatic potential contours suggest that the structural changes are partly due to long-range interactions of the positive charge of the guanidinium group of Arg102 with several other residues that form an area of negative potential adjacent to the active site. The Cys97 → Gly mutation, while inadvertent, was of interest because of the potential specificity effects arising from its location adjacent to the hinge of the flexible 98-110 loop. However, its effects on BSLDH specificity were minor.
- Kallwass, Helmut K. W.,Luyten, Marcel A.,Parris, Wendy,Gold, Marvin,Kay, Cyril M.,Bryan Jones
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p. 4551 - 4557
(2007/10/02)
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- Reactivite du nitrite de sodium. V. Action sur les amino-acides, peptides et proteines
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The action of sodium nitrite on various amino-acids was re-examined in conditions approximating to a biological medium. 13C-NMR provides evidence of the existence of intramolecular ring closures and the formation of 5-membered rings with ornithine, citrulline and arginine.The reaction of cystine shows the opening of the sulphur bridges, whereas cysteine leads to the formation of carboxy-thiiran and 3-sulpho-lactic acid.The hydrolysis of the amide bonds of asparagine and glutamine is complete whereas the peptides studied - carnosine and aspartam - do not undergo hydrolysis of the peptide linkage.However, the first deamination of glutathion (γ-Glu-Cys-Gly) induces the peptide link to be broken and a cyclization with the formation of lactone to occur.A second deamination takes place on the cysteinyl residue released and allows the formation of a thiiran by intramolecular cyclization with the thiol group.The formation of thiiran was also observed with oxidized glutathion which has an S-S bridge.Finally, the formation of nitrosamines was detected by 15N-NMR during the reaction of sodium nitrite with two commercial products available to the general public.
- Gouesnard, Jean-Paul
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