- Pneumocandin biosynthesis: Involvement of a trans-selective proline hydroxylase
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Echinocandins are cyclic nonribosomal hexapeptides based mostly on nonproteinogenic amino acids and displaying strong antifungal activity. Despite previous studies on their biosynthesis by fungi, the origin of three amino acids, trans-4-and trans-3-hydroxyproline, as well as trans-3-hydroxy-4-meth-ylproline, is still unknown. Here we describe the identification, overexpression, and characterization of GloF, the first eukaryot-ic a-ketoglutarate/FeII-dependent proline hydroxylase from the pneumocandin biosynthesis cluster of the fungus Glarea loz-oyensis ATCC 74030. In in vitro transformations with L-proline, GloF generates trans-4- and trans-3-hydroxyproline simultaneously in a ratio of 8:1; the latter reaction was previously unknown for proline hydroxylase catalysis. trans-4-Methyl-L-proline is converted into the corresponding trans-3-hydroxypro-line. All three hydroxyprolines required for the biosynthesis of the echinocandins pneumocandins A0 and B0 in G. lozoyensis are thus provided by GloF. Sequence analyses revealed that GloF is not related to bacterial proline hydroxylases, and none of the putative proteins with high sequence similarity in the databases has been characterized so far.
- Houwaart, Stefanie,Youssar, Loubna,Hüttel, Wolfgang
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Read Online
- Enzymatic production of trans-4-hydroxy-L-proline by regio- and stereospecific hydroxylation of L-proline.
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A proline 4-hydroxylase gene, which was cloned from Dactylosporangium sp. RH1, was overexpressed in Escherichia coli W1485 on a plasmid under a tryptophan tandem promoter after the codon usage of the 5' end of the gene was optimized. The proline 4-hydroxylase activity was l600-fold higher than that in Dactylosporangium sp. RH1. trans-4-Hydroxy-L-proline(Hyp) was produced and accumulated to 41 g/L (87% yield from L-proline) in 100 h when the recombinant E. coli was cultivated in a medium containing L-proline and glucose. 2-Oxoglutarate, which is necessary for the hydroxylation of L-proline by proline 4-hydroxylase, was apparently supplied from glucose through the cellular metabolic pathway. The putA mutant of W1485, which is not able to degrade L-proline, has allowed the quantitative conversion of L-proline to Hyp. The formation of other isomers of hydroxyproline was not observed. Productivity of Hyp was almost the same in a larger-scale culture. The method of manufacturing Hyp from L-proline was established.
- Shibasaki,Mori,Ozaki
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Read Online
- A carbohydrate based straightforward approach to trans-4-hydroxy-D-proline and trans-4-hydroxy-D-prolinol
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Synthesis of trans-4-hydroxy-D-proline and the corresponding prolinol has been accomplished starting from 4,6-di-O-benzyl-3-deoxy-D-glucal, an enol-ether derived from D-glucose, through oxidative cleavage of a vicinal diol intermediate as the key step. This work represents a practical approach to an unnatural, yet synthetically and biologically very significant, amino acid.
- Kumar Mishra, Umesh,Ramesh, Namakkal G.
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- Recharacterization of the mammalian cytosolic type 2 (R)-β-hydroxybutyrate dehydrogenase as 4-oxo-L-proline reductase (EC 1.1.1.104)
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Early studies revealed that chicken embryos incubated with a rare analog of L-proline, 4-oxo-L-proline, showed increased levels of the metabolite 4-hydroxy-L-proline. In 1962, 4-oxo-L-proline reductase, an enzyme responsible for the reduction of 4-oxo-L-proline, was partially purified from rabbit kidneys and characterized biochemically. However, only recently was the molecular identity of this enzyme solved. Here, we report the purification from rat kidneys, identification, and biochemical characterization of 4-oxo-L-proline reductase. Following mass spectrometry analysis of the purified protein preparation, the previously annotated mammalian cytosolic type 2 (R)-βhydroxybutyrate dehydrogenase (BDH2) emerged as the only candidate for the reductase. We subsequently expressed rat and human BDH2 in Escherichia coli, then purified it, and showed that it catalyzed the reversible reduction of 4-oxo-L-proline to cis-4-hydroxy-L-proline via chromatographic and tandem mass spectrometry analysis. Specificity studies with an array of compounds carried out on both enzymes showed that 4-oxo-L-proline was the best substrate, and the human enzyme acted with 12,500-fold higher catalytic efficiency on 4-oxo-L-proline than on (R)-β-hydroxybutyrate. In addition, human embryonic kidney 293T (HEK293T) cells efficiently metabolized 4-oxo-L-proline to cis-4-hydroxy-L-proline, whereas HEK293T BDH2 KO cells were incapable of producing cis-4-hydroxy-L-proline. Both WT and KO HEK293T cells also produced trans-4-hydroxy-L-proline in the presence of 4-oxo-L-proline, suggesting that the latter compound might interfere with the trans-4-hydroxy-L-proline breakdown in human cells. We conclude that BDH2 is a mammalian 4-oxo-L-proline reductase that converts 4-oxo-L-proline to cis-4-hydroxy-L-proline and not to trans-4-hydroxy-L-proline, as originally thought. We also hypothesize that this enzyme may be a potential source of cis-4-hydroxy-L-proline in mammalian tissues.
- Bozko, Maria,Drozak, Jakub,Jagielski, Adam K.,Kocdemir, Kubra,Kwiatkowski, Sebastian,Witecka, Apolonia,Zarod, Michal
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- Discovery of New Fe(II)/α-Ketoglutarate-Dependent Dioxygenases for Oxidation of l-Proline
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Genome mining for novel Fe(II)/α-ketoglutarate-dependent dioxygenases (αKGDs) to expand the enzymatic repertoire in the oxidation of l-proline is reported. Through clustering of proteins, we predicted regio- and stereoselectivity in the hydroxylation reaction and validated this hypothesis experimentally. Two novel byproducts in the reactions with enzymes from Bacillus cereus and Streptomyces sp. were isolated, and the structures were determined to be a 3,4-epoxide and a 3,4-diol, respectively. The mechanism for the formation of the epoxide was investigated by performing an 18O-labeling experiment. We propose that the mechanism proceeds via initial cis-3-hydroxylation followed by ring closure. A biocatalytic step was run on subgram quantities of starting material without any significant optimization of the conditions. However, the substrate concentration was 40-fold higher than the usual reported titers for recombinant P450-mediated hydroxylations, showing the synthetic potential of αKGDs on a preparative scale.
- Dussauge, Solene,Moore, Charles,Snajdrova, Radka,Tassano, Erika,Vargas, Alexandra
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supporting information
(2022/02/09)
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- Modular Chemoenzymatic Synthesis of GE81112 B1 and Related Analogues Enables Elucidation of Its Key Pharmacophores
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The GE81112 complex has garnered much interest due to its broad antimicrobial properties and unique ability to inhibit bacterial translation initiation. Herein we report the use of a chemoenzymatic strategy to complete the first total synthesis of GE81112 B1. By pairing iron and α-ketoglutarate dependent hydroxylases found in GE81112 biosynthesis with traditional synthetic methodology, we were able to access the natural product in 11 steps (longest linear sequence). Following this strategy, 10 GE81112 B1 analogues were synthesized, allowing for identification of its key pharmacophores. A key feature of our medicinal chemistry effort is the incorporation of additional biocatalytic hydroxylations in modular analogue synthesis to rapidly enable exploration of relevant chemical space.
- Zwick, Christian R.,Sosa, Max B.,Renata, Hans
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supporting information
p. 1673 - 1679
(2021/01/25)
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- Studies on the selectivity of proline hydroxylases reveal new substrates including bicycles
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Studies on the substrate selectivity of recombinant ferrous-iron- and 2-oxoglutarate-dependent proline hydroxylases (PHs) reveal that they can catalyse the production of dihydroxylated 5-, 6-, and 7-membered ring products, and can accept bicyclic substrates. Ring-substituted substrate analogues (such hydroxylated and fluorinated prolines) are accepted in some cases. The results highlight the considerable, as yet largely untapped, potential for amino acid hydroxylases and other 2OG oxygenases in biocatalysis.
- Smart, Tristan J.,Hamed, Refaat B.,Claridge, Timothy D.W.,Schofield, Christopher J.
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supporting information
(2019/11/26)
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- Spiegelmeric 4R/S-hydroxy/amino-L/D-prolyl collagen peptides: conformation and morphology of self-assembled structures
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The primary structure of collagen, the major protein in connective tissue of mammals, comprises of repeating triads [(LPro-LHyp-Gly)n, P1, LHyp being 4R-hydroxy-lProline)] in a single strand that adopts left-handed polyproline II type helix. Three such single stranded helices wind around each another and held together by interchain H-bonds to form right-handed triple helix. This manuscript reports on collagen derived from its mirror image triad [(DPro-DHyp-Gly)n, P2, DHyp being 4S-hydroxy-DProline) and its 4-amino analogue (DPro-DAmp-Gly)n P4, DAmp being 4S-amino-DProline that form corresponding spiegelmeric triplexes. The amino L-collagen peptide (LPro-LAmp-Gly)n P3 and its D-analogue P4 show higher thermal stabilities compared to 4-hydroxy-lProline collagen peptides P1 and P2. The enantiomeric peptide pairs show mirror image CD profiles and identical thermal stability, with ionizable 4-amino group in P3 and P4 imparting pH dependent triplex stability. Upon cold mixing of the L- and D-collagen peptides, different morphological nanostructures arise from inter triplex peptide association. When the peptides are hot mixed (annealed), the inter peptide association occurs via interaction of single stranded peptide chains of opposite handedness leading to networked gel formation in P1 and P2, while the charged peptides P3 and P4 show more ordered nanofibers, different from the enantiomerically pure peptides. The nanocomposites of such chiral hybrid peptides may have not only interesting physicomorphology, but also biological properties that need exploration.
- Ganesh, Krishna N,More, Shahaji H
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- INHIBITORS OF CYCLIN DEPENDNT KINASE 7 (CDK7)
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The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.
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Paragraph 339
(2018/02/28)
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- Discovery of new A- and B-type laxaphycins with synergistic anticancer activity
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Two new cyclic lipopeptides termed laxaphycins B4 (1) and A2 (2) were discovered from a collection of the marine cyanobacterium Hormothamnion enteromorphoides, along with the known compound laxaphycin A. The planar structures were solved based on a combined interpretation of 1D and 2D NMR data and mass spectral data. The absolute configurations of the subunits were determined by chiral LC-MS analysis of the hydrolysates, advanced Marfey's analysis and 1D and 2D ROESY experiments. Consistent with similar findings on other laxaphycin A- and B-type peptides, laxaphycin B4 (1) showed antiproliferative effects against human colon cancer HCT116 cells with IC50 of 1.7 μM, while laxaphycins A and A2 (2) exhibited weak activities. The two major compounds isolated from the sample, laxaphycins A and B4, were shown to act synergistically to inhibit the growth of HCT116 colorectal cancer cells.
- Cai, Weijing,Matthew, Susan,Chen, Qi-Yin,Paul, Valerie J.,Luesch, Hendrik
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p. 2310 - 2319
(2018/04/02)
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- 2-Keto-3-Deoxy-l-Rhamnonate Aldolase (YfaU) as Catalyst in Aldol Additions of Pyruvate to Amino Aldehyde Derivatives
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4-Hydroxy-2-keto acid derivatives are versatile building blocks for the synthesis of amino acids, hydroxy carboxylic acids and chiral aldehydes. Pyruvate aldolases are privileged catalysts for a straightforward access to this class of keto acid compounds. In this work, a Class II pyruvate aldolase from Escherichia coli K-12, 2-keto-3-deoxy-l-rhamnonate aldolase (YfaU), was evaluated for the synthesis of amino acid derivatives of proline, pipecolic acid, and pyrrolizidine-3-carboxylic acid. The aldol addition of pyruvate to N-protected amino aldehydes was the key enzymatic aldol addition step followed by catalytic intramolecular reductive amination. The corresponding N-Cbz-amino-4-hydroxy-2-keto acid (Cbz=benzyloxycarbonyl) precursors were obtained in 51–95% isolated yields and enantioselectivity ratios from 26:74 to 95:5, with chiral α-substituted N-Cbz-amino aldehydes. (S)-N-Cbz-amino aldehydes gave aldol adducts with preferentially (R)-configuration at the newly formed stereocenter, whereas the contrary is true for (R)-N-Cbz-amino aldehydes. Addition reactions to achiral amino aldehydes rendered racemic aldol adducts. Molecular models of the pre-reaction ternary complexes YfaU-pyruvate enolate-acceptor aldehyde were constructed to explain the observed stereochemical outcome of the reactions. Catalytic reductive amination of the aldol adducts yielded 4-hydroxy-2-pipecolic acid, and unprecedented C-5 substituted 4-hydroxyproline and pyrrolizidine-3-carboxylic acid derivatives. (Figure presented.).
- Hernández, Karel,Gómez, Ariadna,Joglar, Jesús,Bujons, Jordi,Parella, Teodor,Clapés, Pere
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p. 2090 - 2100
(2017/06/23)
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- An improved, scalable synthesis of bis-amino acids
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trans-4-Hydroxy-L-proline derived bis-amino acids are chiral, cyclic building blocks that display two alpha-amino acids that are differentiated from each other with protecting groups. They are assembled into spiroligomers—rigid, shape-programmable spirocyclic oligomers that are both stereochemically and functionally diverse. The synthesis presented here focuses on recent improvements that allow for a convenient, large-scale synthesis of twelve stereochemically pure bis-amino acids from inexpensive trans-4-hydroxy-L-proline. The bis-amino acids differ in stereochemistry as well as the amine protecting group, one of which (para-nitrobenzyl carbamate) has not been previously incorporated into bis-amino acids.
- Cheong, Jae Eun,Pfeiffer, Conrad T.,Northrup, Justin D.,Parker, Matthew F.L.,Schafmeister, Christian E.
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supporting information
p. 4882 - 4884
(2016/10/24)
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- A short diastereoselective synthesis of cis-(2S,4S) and cis-(2R,4R)-4-hydroxyprolines
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A concise synthesis of (2R,4R)-4-hydroxyproline (1) and (2S,4S)-4-hydroxyproline (2) has been developed in enantiomerically pure form from commercially available starting materials with excellent diastereoselectivity. The tightly bound chelation controlled transition state formed during the 5-exo-tet ring closure reaction is assumed to be the origin of high diastereoselectivity.
- Gajare, Vikas S.,Khobare, Sandip R.,Malavika,Rajana, Nagaraju,Venkateswara Rao,Syam Kumar
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supporting information
p. 3743 - 3746
(2015/06/08)
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- Production of cis-4-hydroxyproline
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PROBLEM TO BE SOLVED: To produce cis-4-hydroxyproline useful as a raw material of medicines and agrochemicals by an industrially suitable method.SOLUTION: The method for producing cis-4-hydroxyproline includes: hydrolyzing a hydroxyproline derivative represented by formula (1), wherein Rdenotes a 1-6C alkylcarbonyl group, an arylcarbonyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group, in the presence of a hydrochloric acid catalyst; neutralizing the resultant with an organic base; and thereafter diluting the resultant with an alcohol.
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Paragraph 00056-0062; 0065; 0066
(2018/11/24)
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- Peptide Tyrosinase Activators
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Peptides that increase melanin synthesis are provided. These peptides include pentapeptides YSSWY, YRSRK, and their variants. The peptides may activate the enzymatic activity of tyrosinase to increase melanin synthesis. The pharmaceutical, cosmetic, and other compositions including the peptides are also provided. The methods of increasing melanin production in epidermis of a subject are provided where the methods include administering compositions comprising an amount of one or more peptides effective to increase the melanin production. The methods also include treating vitiligo or other hypopigmentation disorders with compositions including one or more peptides.
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- Regio- and stereoselective oxygenation of proline derivatives by using microbial 2-oxoglutarate-dependent dioxygenases
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We evaluated the substrate specificities of four proline cis-selective hydroxylases toward the efficient synthesis of proline derivatives. In an initial evaluation, 15 proline-related compounds were investigated as substrates. In addition to L-proline and L-pipecolinic acid, we found that 3,4-dehydro-L-proline, L-azetidine-2-carboxylic acid, cis-3-hydroxy-L-proline, and L-thioproline were also oxygenated. Subsequently, the product structures were determined, revealing cis-3,4-epoxy-L-proline, cis-3-hydroxy-L-azetidine-2-carboxylic acid, and 2,3-cis-3,4-cis-3,4-dihydroxy-L-proline.
- Hara, Ryotaro,Uchiumi, Naoko,Okamoto, Naoko,Kino, Kuniki
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p. 1384 - 1388
(2015/07/20)
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- Epoxy amino acids produced from allylglycines intramolecularly cyclised to yield four stereoisomers of 4-hydroxyproline derivatives
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Derivatives of 2-amino-4-pentenoic acid (allylglycine) were efficiently resolved using Subtilisin or acylase. The side-chain unsaturated bond of the enantiomerically pure amino acid with tert-butoxycarbonyl (Boc) protection was smoothly epoxidized with m-chloroperbenzoic acid. When the Boc protection of the amino group was removed, the amino group intramolecularly attacked the side-chain epoxide, generating compounds with five-membered rings: the 4-hydroxyproline derivatives. Two diastereomeric products were formed through the cyclisation reaction, for example, (2S,4S)-4-hydroxyproline benzyl ester (cis-8) and (2S,4R)-4-hydroxyproline benzyl ester (trans-8) were formed from (2S)-amino acid with a side-chain epoxide. Compound (2S,4S)-4-hydroxyproline benzyl ester (cis-8) was transformed to a lactone (cis-hydroxyproline lactone, 10) with the removal of benzyl alcohol. The cis-conformation was essential for the intramolecular ester exchange reaction; in fact, no lactone formation was observed for the trans isomer (trans-8). The separation of cis-hydroxyproline lactone and the trans-isomeric hydroxyproline benzyl ester was facile and clear, in contrast to the difficult separation of cis- and trans-hydroxyproline derivatives. Thus, two diastereomers of hydroxyproline derivatives for l-hydroxyproline and also for d-hydroxyproline were obtained, i.e., four diastereomers of hydroxyproline derivatives.
- Krishnamurthy, Suvratha,Arai, Toru,Nakanishi, Kanae,Nishino, Norikazu
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p. 2482 - 2490
(2014/01/06)
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- Substrate specificity and stereoselectivity of two Sulfolobus 2-keto-3-deoxygluconate aldolases towards azido-substituted aldehydes
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The 2-keto-3-deoxygluconate aldolases (KDGAs) isolated from Sulfolobus species convert pyruvate and glyceraldehyde reversibly into 2-keto-3-deoxygluconate and -galactonate. As a result of their high thermostability and activity on nonphosphorylated substrates, KDGA enzymes have potential as biocatalysts for the production of building blocks for fine chemical and pharmaceutical applications. Up to now, wild-type enzymes have only shown moderate stereocontrol for their natural reaction. However, if a set of azido-functionalized aldehydes were applied as alternative acceptors in the reaction with pyruvate, the stereoselectivity was strongly increased to give enantiomeric or diastereomeric excess values up to 97 %. The Sulfolobus acidocaldarius KDGA displayed a higher stereoselectivity than Sulfolobus solfataricus KDGA for all tested reactions. The azido-containing products are useful chiral intermediates in the synthesis of nitrogen heterocycles. Taming the wild-type: Two 2-keto-3-deoxygluconate aldolases from Sulfolobus species readily couple azido-substituted aldehydes to pyruvate in a stereoselective manner. The resulting compounds yield chiral nitrogen heterocycles upon reduction.
- Schurink, Marloes,Wolterink-Van Loo, Suzanne,Van Der Oost, John,Sonke, Theo,Franssen, Maurice C. R.
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p. 1073 - 1081
(2014/05/06)
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- PROCESS FOR PRODUCING SOLID AMINO ACID
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The problem to be solved by the present invention is to ea lily and efficiently produce an amino acid having 2 to 7 carbon atoms as a high-purity solid without complicated operation, which is useful as a synthetic intermediate for medicines or agrochemicals. The present invention is characterized in comprising a step of precipitating solid amino acid with high purity. In the present invention, the by-produced salt composed of the sulfonic acid and the amine was removed to the mother liquor by reacting an amine with a sulfonic acid salt of amino acid in an aprotic polar solvent, or by reacting a sulfonic acid with an amine salt of amino acid in an aprotic polar solvent. The sulfonic acid salt of amino acid, for example, may be produced by reacting a N-(tert-butoxycarbonyl) amino acid with a sulfonic acid, or by reacting an amino acid tert-butyl ester with a sulfonic acid.
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Paragraph 0055
(2014/12/09)
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- Biochemical characterisation and assessment of fibril-forming ability of collagens extracted from Bester sturgeon Huso huso × Acipenser ruthenus
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Collagens purified from Bester sturgeon organs were characterised biochemically, and their fibril-forming abilities and fibril morphologies formed in vitro clarified. Yields of collagens were 2.1%, 11.9%, 0.4%, 18.1%, 0.4%, 0.8% and 0.03% (collagen dry weight/tissue wet weight) from scales, skin, muscle, swim bladder, digestive tract, notochord and snout cartilage, respectively. Using SDS-PAGE and amino acid composition analyses, collagens from scales, skin, muscle, the swim bladder and digestive tract were characterised as type I, and collagens from the notochord and snout cartilage as type II. Denaturation temperatures of the collagens, measured using circular dichroism, were 29.6, 26.8, 29.0, 32.9, 31.6 and 36.3 °C in scales, skin, muscle, swim bladder, digestive tract, and notochord, respectively. For fibril formation, swim bladder and skin collagen showed a more rapid rate of increase in turbidity, a shorter time to attain the maximum turbidity, and formed thicker fibrils compared with porcine tendon type I collagen.
- Zhang, Xi,Ookawa, Mika,Tan, Yongkai,Ura, Kazuhiro,Adachi, Shinji,Takagi, Yasuaki
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p. 305 - 312
(2014/05/06)
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- Meteorites as catalysts for prebiotic chemistry
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From outer space: Twelve meteorite specimens, representative of their major classes, catalyse the synthesis of nucleobases, carboxylic acids, aminoacids and low-molecular-weight compounds from formamide (see figure). Different chemical pathways are identified, the yields are high for a prebiotic process and the products come in rich and composite panels.
- Saladino, Raffaele,Botta, Giorgia,Delfino, Michela,Di Mauro, Ernesto
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p. 16916 - 16922
(2014/01/06)
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- Synthesis of (2S,4S)-4-hydroxyproline from D-glucose
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Diacetone-D-glucose 1 gives 3-O-methylxanthate 2 on reaction with NaH=Me I. Reductive deoxygenation of compound 2 by Bu3SnH gives the corresponding 3-deoxy glucose derivative 3 and on acid-catalyzed regioselective deprotection of C-5,6-acetonide gives the diol 4. The diol on oxidative cleavage with NaIO4 gives the aldehyde 5, which on further condensation with benzylamine followed by reduction with NaBH4 gives the amine 7. Z-Protection of the amine followed by methanolysis gives methyl furanoside 9. Reaction of 9 with methanesulfonyl chloride=Et3N gives the corresponding C-3-O-mesylate derivative 10. Catalytic hydrogenation of compound 10 (Pd=C=H2=MeOH 3 kg) gives bicyclic oxaazo compound 11, due to deprotection of the N-benzyl- and Z-protecting groups and intramolecular nucleophilic displacement of the C-2-O-mesylate by the C-5 amine in a one-pot reaction. Z-Protection of the amine 11 followed by acid-catalyzed hydrolysis gives acetal 13. Reduction of acetal by use of NaBH4 gives Z-prolinol 14. Selective oxidation of diol 14 by (2,2,6,6-tetramethylpiperidin-1-yl)-oxyl (TEMPO)=[(bis)(acetoxy)iodo]-benzene (BAIB) and NaClO2=NaH 2PO4, followed by Z-deprotection, gives the title compound I in 3.5% overall yield from D-glucose. Copyright Taylor & Francis Group, LLC.
- Mereyala, Hari Babu,Pathuri, Gopal,Nagarapu, Lingaiah
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experimental part
p. 1278 - 1287
(2012/04/17)
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- Chiral imprinting with amino acids of ordered mesoporous silica exhibiting enantioselectivity after calcination
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Chiral ordered mesoporous silica (COMS) was synthesized in basic media by combining tetraethyl orthosilicate and quaternized aminosilane (with a templating role) silica sources together with four different standard amino acids (arginine, histidine, isoleucine, and proline). Besides the hexagonal MCM-41-type structure, narrow pore size distribution, and high specific surface area, it was found that these solids have potential for enantiomeric separation because of the transference of chirality from the amino acid to the silica. This is illustrated by the resolution of several racemic mixtures (those of proline, isoleucine, trans-4-hydroxyproline, pipecolic acid, valine, leucine, and phenylglycine) with the calcined COMS prepared with l-proline. The opposite behavior observed in induced circular dichroism experiments with calcined COMS, obtained using both enantiomers of proline, confirmed their chiral nature. The high number and variety of existing amino acids, and chiral organic compounds in general, makes these ordered silicas attractive for the production of enantiopure substances.(Figure Presented)
- Lacasta, Susana,Sebastian, Victor,Casado, Clara,Mayoral, Alvaro,Romero, Pilar,Larrea, Angel,Vispe, Eugenio,Lopez-Ram-De-Viu, Pilar,Uriel, Santiago,Coronas, Joaquin
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scheme or table
p. 1280 - 1287
(2012/02/15)
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- A simple procedure for selective hydroxylation of L -proline and l -pipecolic acid with recombinantly expressed proline hydroxylases
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Due to their diverse regio- and stereoselectivities, proline hydroxylases provide a straightforward access to hydroxprolines and other hydroxylated cylic amino acids, valuable chiral building blocks for chemical synthesis, which are often not available at reasonable expense by classical chemical synthesis. As yet, the application of proline hydroxylases is limited to a sophisticated industrial process for the production of two hydroxyproline isomers. This is mainly due to difficulties in their heterologues expression, their limited in vitro stability and complex product purification procedures. Here we describe a facile method for the production of cis-3-, cis-4- and trans-4-proline hydroxylase, and their application for the regio- and stereoselective hydroxylation of L-proline and its six-membered ring homologue l-pipecolic acid. Since in vitro catalysis with these enzymes is not very efficient and conversions are restricted to the milligram scale, an in vivo procedure was established, which allowed a quantitative conversion of 6 mM l-proline in shake flask cultures. After facile product purification via ion exchange chromatography, hydroxyprolines were isolated in yields of 35-61% (175-305 mg per flask). L-Pipecolic acid was converted with the isolated enzymes to prove the selectivities of the reactions. In transformations with optimized iron(II) concentration, conversions of 17-68% to hydroxylated products were achieved. The regio- and stereochemistry of the products was determined by NMR techniques. To demonstrate the applicability of the preparative in vivo approach for non-physiological substrates, L-pipecolic acid was converted with an E. coli strain producing trans-4-proline hydroxylase to trans-5-hydroxy-L-pipecolic acid in 61% yield. Thus, a synthetically valuable group of biocatalysts was made readily accessible for application in the laboratory without a need for special equipment or considerable development effort.
- Klein, Christian,Huettel, Wolfgang
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experimental part
p. 1375 - 1383
(2011/06/26)
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- Tertiary alcohol preferred: Hydroxylation of trans-3-methyl-L-proline with proline hydroxylases
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The enzymatic synthesis of tertiary alcohols by the stereospecific oxidation of tertiary alkyl centers is a most-straightforward but challenging approach, since these positions are sterically hindered. In contrast to P450-monooxygenases, there is little known about the potential of non-heme iron(II) oxygenases to catalyze such reactions. We have studied the hydroxylation of trans-3-methyl-Lproline with the a-ketoglutarate (α-KG) dependent oxygenases, cis-3-proline hydroxylase type II and cis-4-proline hydroxylase (cis-P3H-II and cis-P4H). With cis-P3H-II, the tertiary alcohol product (3R)-3-hydroxy-3-methyl-L-proline was obtained exclusively but in reduced yield (~7%) compared to the native substrate L-proline. For cis-P4H, a complete shift in regioselectivity from C-4 to C-3 was observed so that the same product as with cis-P3H-II was obtained. Moreover, the yields were at least as good as in control reactions with L-proline (~110% relative yield). This result demonstrates a remarkable potential of non-heme iron(II) oxygenases to oxidize substrates selectively at sterically hindered positions. 10.3762/bjoc.7.193.
- Klein, Christian,Huettel, Wolfgang
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scheme or table
p. 1643 - 1647
(2012/01/19)
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- Rh(II) catalysts with 4-hydroxyproline-derived ligands
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Three new chiral Rh(II) catalysts with 4-hydroxyproline-derived ligands have been synthesised through a short and efficient synthetic route. The catalysts give good yields and ees in C-H insertion and cyclopropanation reactions, and their properties indicate an all-up reactive conformation of proline- and 4-hydroxyproline-derived Rh(II) catalysts.
- Bonge, Hanne Therese,Kaboli, Massoud,Hansen, Tore
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scheme or table
p. 5375 - 5377
(2010/11/02)
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- Prolinol-based nucleoside phosphonic acids: new isosteric conformationally flexible nucleotide analogues
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trans-4-Hydroxy-l-proline has been used as a starting material for the synthesis of prolinol-based nucleotide analogues with an N-phosphonomethyl moiety attached to the prolinol ring nitrogen atom. The synthetic methodology based on the inversion of configuration at both 1- and 4-position led to all diastereoisomeric O-protected 4-mesyloxyprolinol-N-phosphonates. Alkylation of nucleobases using the synthons in the l-series afforded the nucleotide analogues corresponding to α-l- and β-l-nucleotide. The NMR-based conformational study of these compounds in aqueous solution performed at two different pH values, showing either N-fully protonated or deprotonated forms, revealed the occurrence of the same mostly populated conformer in both cases. All final l-prolinol-based nucleoside phosphonic acids were tested for cytotoxic and antiviral properties, but no significant activity was found.
- Vaněk, Václav,Budě?ínsky, Milo?,Rinnová, Markéta,Rosenberg, Ivan
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experimental part
p. 862 - 876
(2009/05/09)
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- Synthesis of fmoc-pro-hyp(TBDPS)-gly-OH and its application as a versatile building block for the preparation of collagen model peptides
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The efficient synthesis of the tripeptidic building block Fmoc-Pro-Hyp(TBDPS)-Gly-OH and its application for the preparation of collagen model peptides (CMPs) has been achieved. The silyl ether protecting group prevents undesired side reactions during the
- Erdmann, Roman S.,Wennemers, Helma
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experimental part
p. 143 - 147
(2009/06/19)
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- Practical syntheses of 4-fluoroprolines
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4-Fluoroprolines are among the most useful nonnatural amino acids in chemical biology. Here, practical routes are reported for the synthesis of the 2S,4R, 2S,4S, and 2R,4S diastereomers of 4-fluoroproline. Each route starts with (2S,4R)-4-hydroxyproline, which is a prevalent component of collagen and hence readily available, and uses a fluoride salt to install the fluoro group. Hence, the routes provide process-scale access to these useful nonnatural amino acids.
- Chorghade, Mukund S.,Mohapatra, Debendra K.,Sahoo, Gokarneswar,Gurjar, Mukund K.,Mandlecha, Manish V.,Bhoite, Nitin,Moghe, Santosh,Raines, Ronald T.
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experimental part
p. 781 - 784
(2009/04/04)
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- 4-Substituted-α,α-diaryl-prolinols improve the enantioselective catalytic epoxidation of α,β-enones
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To seek novel metal-free organic catalysts for epoxidation with high stereoselectivity, a series of 4-substituted-α,α-diaryl-prolinols were synthesized in four steps from trans-4-hydroxyl-L-proline. These prolinol derivatives catalyzed the asymmetric epoxidation of α,β-enones to give the corresponding chiral epoxides in good yields and high enantioselectivities under mild reaction conditions. Studies of substituent effects on enantioselectivity revealed that steric bulk and electronic effect promoted higher enantioselectivity, and prolinol 8a was found to be the best catalyst until now.
- Li, Yawen,Liu, Xinyuan,Yang, Yingquan,Zhao, Gang
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p. 288 - 291
(2007/10/03)
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- Compounds and compositions for use in the prevention and treatment of obesity and related syndromes
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The invention relates to 4-hydroxyisoleucine, isomers, analogs, lactones, salts, and prodrugs thereof, to processes for their preparation, and to pharmaceutical compositions comprising the same. More particularly, the invention relates to the use of those compounds in the prevention and treatment of obesity and related syndromes.
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Page/Page column 60
(2010/11/24)
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- Enzymatic synthesis of cyclic amino acids by N-methyl-l-amino acid dehydrogenase from Pseudomonas putida
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A new enzymatic system for the synthesis of enantiomerically pure cyclic amino acids (CAA) from the corresponding diamino acids or racemic CAA is described. α,ω-Diamino acids were oxidized to α-keto acids with amino acid oxidases (AAO). The α-keto acids were spontaneously transformed into cyclic imino acids in the reaction medium. The resulting imines were reduced to the l-form CAA with N-methyl-l-amino acid dehydrogenase (NMAADH) from Pseudomonas putida ATCC12633 using NADPH as a cofactor. l-Form CAA were also obtained from racemic CAA using d-amino-acid oxidase and NMAADH. Using this method, a new compound [1,4]-thiazepane-3-carboxylic acid (Fig. 1) was synthesized from aminopropylcystein.
- Yasuda, Mari,Ueda, Makoto,Muramatsu, Hisashi,Mihara, Hisaaki,Esaki, Nobuyoshi
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p. 1775 - 1779
(2007/10/03)
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- Process for producing alpha 2,3/ alpha 2,8-sialyltransferase and sialic acid-containing complex sugar
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The present invention can provide a process for producing a protein having α2,3/α2,8-sialyltransferase activity using a transformant comprising a DNA encoding a protein having α2,3/α2,8-sialyltransferase activity derived from a microorganism belonging to the genus Pasteurella and a process for producing a sialic acid-containing complex carbohydrate using a transformant capable of producing a protein having α2,3/α2,8-sialyltransferase activity derived from a microorganism.
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- Ring opening reactions of 1,2-didehydroprolines. Part II. Synthesis of 5-amino-2,4-dihydroxypentanoic acids, their 2-piperidones and pentanolides [1]
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NMR spectroscopic investigations on 1,2-didehydroproline in alkaline deuterium oxide revealed incorporation of deuterium at position C-3, presumably due to the presence of acyclic 5-amino-2-oxopentanoate in solution. Reduction of this equilibrium mixture
- Haeusler, Johannes,Kaehlig, Hanspeter
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p. 719 - 726
(2007/10/03)
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- Bis (amino acid) molecular scaffolds
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The present invention provides molecular building blocks of rigid bis(amino acids). The molecular building blocks can be linked together through the formation of rigid diketopiperazine rings, to provide the desired three dimensional structure. Also provided is method of synthesizing macromolecules from the bis (amino acid) building blocks.
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- Anti-heparin peptides
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The invention concerns a compound exhibiting an anti-heparin activity, of formula Z Bm ! (AXA)x Bn ! (AXA)y Bo (AXA)z Bp, the diagnostic reagents comprising it and the use of said compound in an in vitro diagnostic test of a medicine for anti-heparin activity.
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- Ex-chiral pool synthesis and receptor binding studies of 4-substituted prolinol derivatives
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Starting from natural 4-hydroxyproline, preparation of the four possible stereoisomers of 4-amino- and 4-aminomethyl-substituted prolinol derivatives, respectively, was accomplished by chemo- and regioselective functional group transformations at the 2- and 4-positions of the pyrrolidine moiety. These building blocks were used as valuable precursors for the preparation of new methoxybenzamide derivatives. Dopamine and serotonin binding studies involving the subtypes D1, D2long, D2short, D3 and D4 as well as 5-HT1A and 5-HT2, respectively, displayed interesting structure activity relationships, especially with respect to the absolute and relative configuration of the test compounds. As a complement to the D3 receptor preferring aminomethylpyrrolidine FAUC 21, the (2R,4R)-aminoprolinol derivative ent-24 (FAUC 65) preferentially recognizing the D4 subtype was developed.
- Heindl, Cornelia,Huebner, Harald,Gmeiner, Peter
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p. 3141 - 3152
(2007/10/03)
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- A new synthetic method for the preparation of α,β-didehydroamino acid derivatives by means of a wittig-type reaction. Syntheses of (2S, 4S)- and (2R, 4R)-4-hydroxyprolines
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Ethyl N-Boc- and N-Z-α-tosylglycinates were reacted with a variety of aldehydes in the presence of tributylphosphine and a base to afford the corresponding α,β-didehydroamino acid derivatives with high (Z)-selectivity in good yields. Moreover, ethyl (4S)- and (4R)-2-(N-Boc-amino)-4,5-isopropylidenedioxy-2-pentenoates prepared by the present method were converted to (2S, 4S)- and (2R, 4R)-4-hydroxyprolines, respectively.
- Kimura, Rumi,Nagano, Tanemasa,Kinoshita, Hideki
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p. 2517 - 2525
(2007/10/03)
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- Gene recombinant antibody and antibody fragment thereof
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A recombinant antibody or the antibody fragment thereof which specifically reacts with an extracellular domain of human CCR4; a DNA which encodes the recombinant antibody or the antibody fragment thereof; a method for producing the recombinant antibody or the antibody fragment thereof; a method for immunologically detecting CCR4, a method for immunologically detecting a cell which expressed CCR4 on the cell surface, a method for depleting a cell which expresses CCR4 on the cell surface, and a method for inhibiting production of Th2 cytokine, which comprise using the recombinant antibody according or antibody fragment thereof; a therapeutic or diagnostic agent for Th2-mediated immune diseases; and a therapeutic or diagnostic agent for a blood cancer.
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- Stereoselective synthesis of (1R,4R)-N-acyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-ones via mesoionic compounds. An improved synthesis of cis-4-hydroxy-D-proline
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We report an asymmetric synthesis of (1R,4R)-N-acyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-ones, starting from the inexpensive and commercially available trans-4-hydroxy-L-proline and achieved by treating N-acyl-trans-4-hydroxy-L-prolines with acetic anhydride. The formation of intermediate mesoionic compounds may explain the formation of N-acyl-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-ones with (R)-absolute configuration at C(4). Acidic cleavage of these lactones readily affords N-acyl-cis-4-hydroxy-D-prolines or cis-4-hydroxy-D-proline in good yields.
- Dalla Croce, Piero,La Rosa, Concetta
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p. 197 - 201
(2007/10/03)
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- Regio- and diastereoselective synthesis of 5-trans-substituted and 5,5-disubstituted 2-pyrrolidinones derived from (S)-malic acid
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5-trans-Substituted 2-pyrrolidinones 6a, 6c and 6d and 5,5-disubstituted 2-pyrrolidinones 6e-k were regio- and diastereoselectively formed through the addition of organolithium species to imides 1a,b derived from malic acid, followed by addition of triethylsilane, allyltributyltin or TMSCN to the N-acyliminium ions formed in situ from the corresponding 5-hydroxy lactams. A short and diastereoselective synthesis of non-natural amino acid trans-4-hydroxy-D-proline is reported.
- Schuch, Cristina M.,Pilli, Ronaldo A.
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p. 1973 - 1980
(2007/10/03)
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- Biphenyl derivatives and drug composition
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A biphenyl derivative represented by the following general formula (1) and a pharmaceutically acceptable salt thereof: [In the formula (1), A represents a single bond, —CH2—, —CO—, —CS— or —SO2—; B represents a single bond or —CH2—; R1represents a hydrogen atom, —OH, —NR11R12(wherein R11and R12each independently represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), —OCOCH3, or a halogen atom; R2represents a hydrogen atom or R1and R2form a group ═O together; R3represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; provided that in the formula, the absolute configuration of the position a may be either R or S]. The compound of the present invention has considerably high safety and efficacy and is useful as, in particular, a vasopressin receptor antagonist.
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- Chemoenzymatic Synthesis of cis-4-Hydroxy-D-proline
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Candida antarctica lipase fraction B (CALB) catalyzed the hydrolysis of the (S)-enantiomer of racemic 4-oxo-1,2-pyrrolidinedicarboxylic acid dimethyl ester with high enantioselectivity (> 99.5% ee at 51% conversion). Regioselective hydrogenation of the isolated (R)-4-oxo-1,2-pyrrolidinedicarboxylic acid dimethyl ester produced (2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylic acid dimethyl ester in 98% yield, and subsequent hydrolysis of the ester and N-(alkoxycarbonyl) groups produced cis-4-hydroxy-D-proline in 98% yield and 96% de. Diastereomeric mixtures of 4-hydroxy-1,2-pyrrolidinedicarboxylic acid dimethyl esters were also resolved using CALB to produce cis-4-hydroxy-D-proline or trans-4-hydroxy-L-proline in 93 to > 99.5% diastereomeric excess.
- Sigmund, Amy E.,Hong, Wonpyo,Shapiro, Rafael,DiCosimo, Robert
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p. 587 - 590
(2007/10/03)
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- FR901469, a novel antifungal antibiotic from an unidentified fungus No. 11243. III. Structure determination
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A novel antifungal antibiotic, FR901469, was isolated from an unidentified fungus No. 11243. It is a water-soluble 40-membered macrocyclic lipopeptidolactone, consisting of D-Ala, L-Tyr, L-Val, trans-4OH-L-Pro, trans-3OH-L-Pro, threo-3OH-L-Gln, Gly, L-Orn, L-Thr, three residues of D-allo Thr and a (3R)-hydroxypalmitic acid. Its structure, including absolute configurations, was unequivocally determined as 1 based on chemical and spectroscopic evidence.
- Fujie,Muramatsu,Yoshimura,Hashimoto,Shigematsu,Takase
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p. 588 - 594
(2007/10/03)
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- Process for producing trans-4-hydroxy-L-proline
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An industrially applicable process for producing trans-4-hydroxy-L-proline, which is useful as a raw material for medicines or as an additive to foods. In the process, L-proline is converted into trans-4-hydroxy-L-proline in the presence of an enzyme source which is derived from a microorganism belonging to the genus Dactylosporangium, Amycolatopsis or Streptomyces and which catalyzes the hydroxylation of L-proline into trans-4-hydroxy-L-proline, a divalent iron ion and 2-ketoglutaric acid, in an aqueous medium, and the produced trans-4-hydroxy-L-proline is collected from the aqueous medium. Also provided is a novel enzyme L-proline-4-hydroxylase which is useful for the process, a gene of L-proline-4-hydroxylase which is useful for the process, a transformant containing the gene, and a process for producing L-proline-4-hydroxylase using the transformant. In addition, provided is a process for producing L-proline-4-hydroxylase using the transformant which contains the gene and has a reinforced proline biosynthesis activity.
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- COSMETICS
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The present invention relates to skin aging inhibitors and/or skin quality-improving agents comprising hydroxyproline, its N-acyl derivatives or salts thereof, and cosmetic compositions for inhibiting skin aging and/or improving skin quality comprising said skin aging inhibitors and/or skin quality-improving agents.
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- Amine compounds and combinatorial libraries comprising same
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The present invention provides monocyclic, bicyclic and oligomeric amine compounds with at least two sites of diversity. These compounds are formed from monocyclic scaffolds which can be cyclized to form bicyclic amine scaffolds. These can then be reacted with building blocks to form the amine compounds of the invention. This invention further provides libraries or monocyclic, bicyclic and oligomeric amine compounds. Also provided are methods for preparing monocyclic, bicyclic and oligomeric amine compounds and libraries thereof. The present invention also provides pharmaceutical compositions of the monocyclic, bicyclic and oligomeric amine compounds.
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- Low molecular weight bicyclic thrombin inhibitors
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This invention relates to the discovery of heterocyclic competitive inhibitors of the enzyme thrombin, their preparation, and pharmaceutical compositions thereof. As well, this invention relates to the use of such compounds and compositions in vitro as anticoagulants and in vivo as agents for the treatment and prophylaxis of thrombotic disorders such as venous thrombosis, pulmonary embolism and arterial thrombosis resulting in acute ischemic events such as myocardial infarction or cerebral infarction. Moreover, these compounds and compositions have therapeutic utility for the prevention and treatment of coagulopathies associated with coronary bypass operations as well as restenotic events following transluminal angioplasty.
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- Substituted quinoxaline-2-ones as glutamate receptor antagonists
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A novel series of substituted quinoxaline 2-ones useful as neuroprotective agents are taught. Novel intermediates, processes of preparation, and pharmaceutical compositions containing the compounds are also taught. The compounds are glutamate receptor antagonists and are useful in the treatment of stroke, cerebral ischemia, or cerebral infarction resulting from thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia, seizure disorders, pain, Alzheimer's, Parkinson's, and Huntington's Diseases.
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- Pyrrolidine PNA: A Novel Conformationally Restricted PNA Analogue
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A new conformationally restricted PNA adenine monomer has been synthesized in 13 steps from cis-4-hydroxy-D-proline. A fully modified adenine decamer displayed improved binding affinity toward complementary DNA and RNA oligonucleotides as compared to that of the parent PNA adenine decamer.
- Pueschi, Ask,Tedeschi, Tullia,Nielsen, Peter E.
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p. 4161 - 4164
(2007/10/03)
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