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Enzymatic Synthesis of Therapeutic Nucleosides using a Highly Versatile Purine Nucleoside 2’‐DeoxyribosylTransferase from Trypanosoma brucei

Published on Oct 9, 2018in Chemcatchem4.495
· DOI :10.1002/cctc.201800775
Elena Pérez2
Estimated H-index: 2
(UEM: European University of Madrid),
Pedro A. Sánchez-Murcia8
Estimated H-index: 8
(University of Vienna)
+ 4 AuthorsJesús Fernández-Lucas12
Estimated H-index: 12
(Grupo México)
Abstract
  • References (49)
  • Citations (5)
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References49
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#1Jon Del ArcoH-Index: 4
Last. Jesús Fernández-LucasH-Index: 12
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The enzymatic synthesis of nucleotides offers several advantages over traditional multistep chemical methods, such as stereoselectivity, regioselectivity, enantioselectivity, simple downstream processing, and the use of mild reaction conditions. However, in order to scale up these bioprocesses, several drawbacks, such as the low enzyme stability and recycling, must be considered. Enzyme immobilization may overcome these cost-related problems by enhancing protein stability and facilitating the se...
5 CitationsSource
#1Javier AcostaH-Index: 2
#2Jon Del ArcoH-Index: 4
Last. Jesús Fernández-LucasH-Index: 12
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Biocatalysis reproduce nature’s synthetic strategies in order to synthesize different organic compounds. Natural metabolic pathways usually involve complex networks to support cellular growth and survival. In this regard, multi-enzymatic systems are valuable tools for the production of a wide variety of organic compounds. Methods: The production of different purine nucleosides and nucleoside-5′-monophosphates has been performed for first time, catalyzed by the sequential action of 2′-deoxyribosy...
6 CitationsSource
#1Pedro A. Sánchez-Murcia (University of Vienna)H-Index: 8
#2Álvaro Cortés-Cabrera (University of Alcalá)H-Index: 6
Last. Federico Gago (University of Alcalá)H-Index: 36
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At least four classes of structurally distinct natural products with potent antiproliferative activities target the translation elongation factor eEF1A1, which is best known as the G-protein that delivers amino acyl transfer RNAs (aa-tRNAs) to ribosomes during mRNA translation. We present molecular models in atomic detail that provide a common structural basis for the high-affinity binding of didemnin B, ternatin, ansatrienin B and nannocystin A to eEF1A1, as well as a rationale based on molecul...
7 CitationsSource
#1Gesa Hollermann (University of Bremen)H-Index: 2
#2Radhika Dhekane (University of Bremen)H-Index: 1
Last. Kurosch Rezwan (University of Bremen)H-Index: 26
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Abstract Porous Al 2 O 3 /SiO 2 microbeads (MBs) are propped as carriers for enzymes used in flow reactor setups for tandem enzymatic reactions. Glucose oxidase (GOx) and catalase (CAT) perform sequential reactions. GOx catalyzes the conversion of glucose and O 2 to gluconic acid and H 2 O 2 . CAT decomposes H 2 O 2 to H 2 O and O 2 . Spherical MBs were fabricated via ionotropic gelation followed by rapid-sintering (1200 °C/5 min), featuring reasonably high open porosity (∼50%), appropriate spec...
5 CitationsSource
#1N. Crespo (CSIC: Spanish National Research Council)H-Index: 1
#2Pedro A. Sánchez-Murcia (University of Vienna)H-Index: 8
Last. José M. Mancheño (CSIC: Spanish National Research Council)H-Index: 29
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Processes catalyzed by enzymes offer numerous advantages over chemical methods although in many occasions the stability of the biocatalysts becomes a serious concern. Traditionally, synthesis of nucleosides using poorly water-soluble purine bases, such as guanine, xanthine, or hypoxanthine, requires alkaline pH and/or high temperatures in order to solubilize the substrate. In this work, we demonstrate that the 2′-deoxyribosyltransferase from Leishmania mexicana (LmPDT) exhibits an unusually high...
9 CitationsSource
#1María J. Lapponi (CONICET: National Scientific and Technical Research Council)H-Index: 3
#2Cintia W. Rivero (CONICET: National Scientific and Technical Research Council)H-Index: 9
Last. Jorge A. Trelles (CONICET: National Scientific and Technical Research Council)H-Index: 10
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Abstract The present review deals with current advances in the chemoenzymatic synthesis of biologically important nucleoside analogues (NA), either by the use of microorganisms or enzymes as biocatalysts. The interest in exploiting these biocatalysts is constantly increasing nowadays because of the advantages they have with respect to classic organic chemistry synthesis, such as a fewer number of synthesis steps, an improved chemo-, regio- and stereoselectivity, high catalytic efficiency, and si...
19 CitationsSource
#1Evelin A. Manoel (UFRJ: Federal University of Rio de Janeiro)H-Index: 9
#2Martina Pinto (UFRJ: Federal University of Rio de Janeiro)H-Index: 5
Last. Roberto Fernandez-LaFuente (UFRJ: Federal University of Rio de Janeiro)H-Index: 1
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Different core–shell polymeric supports, exhibiting different morphologies and composition, were produced through simultaneous suspension and emulsion polymerization, using styrene (S) and divinylbenzene (DVB) as co-monomers. Supports composed of polystyrene in both the core and the shell (PS/PS) and the new poly(styrene-co-divinylbenzene) support (PS-co-DVB/PS-co-DVB) were used for the immobilization of three different lipases (from Rhizomucor miehie (RML), from Themomyces lanuginosus (TLL) and...
17 CitationsSource
Abstract An immobilized biocatalyst with 2′- N -deoxyribosyltransferase (NDT) activity, Lactobacillus animalis NDT ( La NDT), was developed from cell free extracts. La NDT was purified, characterized and then immobilized by ionic interaction. Different process parameters were optimized, resulting in an active derivative (2.6 U/g) able to obtain 1.75 mg/g of 5-fluorouracil-2′-deoxyriboside, an antimetabolite known as floxuridine, used in gastrointestinal cancer treatment. Furthermore, immobilized...
11 CitationsSource
#1Alba Fresco-Taboada (Complutense University of Madrid)H-Index: 5
#2Immacolata Serra (UNIPV: University of Pavia)H-Index: 13
Last. Marco Terreni (UNIPV: University of Pavia)H-Index: 21
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Abstract The immobilization of Bacillus psychrosaccharolyticus nucleoside 2′-deoxyribosyltransferase was deeply investigated and finally optimized. The best immobilization procedure resulted to be ionic adsorption on PEI 600 Da agarose followed by crosslinking with 70% oxidized dextran (20 kDa). The percentage of recovered activity was further improved (from 21% to 33%) by the addition of 20% glycerol to the immobilization mixture. The resulting biocatalyst showed a stability profile similar to ...
12 CitationsSource
Living cells are most perfect synthetic factory. The surprising synthetic efficiency of biological systems is allowed by the combination of multiple processes catalyzed by enzymes working sequentially. In this sense, biocatalysis tries to reproduce nature’s synthetic strategies to perform the synthesis of different organic compounds using natural catalysts such as cells or enzymes. Nowadays, the use of multienzymatic systems in biocatalysis is becoming a habitual strategy for the synthesis of or...
20 CitationsSource
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#1Sophie Vichier-Guerre (Pasteur Institute)H-Index: 12
#2Therese C. Ku (UMBC: University of Maryland, Baltimore County)H-Index: 2
Last. Katherine Seley-Radtke (UMB: University of Maryland, Baltimore)H-Index: 2
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#1Jon Del Arco (UEM: European University of Madrid)H-Index: 4
#2Javier Galindo (UEM: European University of Madrid)
Last. Jesús Fernández-Lucas (Grupo México)H-Index: 12
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Abstract Nowadays enzymatic synthesis of nucleic acid derivatives is gaining momentum over traditional chemical synthetic processes. Biotransformations catalyzed by whole cells or enzymes offer an ecofriendly and efficient alternative to the traditional multistep chemical methods, avoiding the use of chemical reagents and organic solvents that are expensive and environmentally harmful. Herein we report for the first time the covalent immobilization a uracil phosphoribosyltransferase (UPRT). In t...
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#1Jon Del ArcoH-Index: 4
#2Alberto Mills (CSIC: Spanish National Research Council)
Last. Jesús Fernández-Lucas (Grupo México)H-Index: 12
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#1Jon Del Arco (UEM: European University of Madrid)H-Index: 4
#2Justin JordaanH-Index: 2
Last. Jesús Fernández-Lucas (Grupo México)H-Index: 12
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Abstract The present work aims to develop a magnetic biocatalyst for customized production of nucleoside analogues using mutant His-tagged purine 2’-deoxyribosyltransferase from Trypanosoma brucei ( Tb PDT V11S ) immobilized onto Ni 2+ chelate magnetic iron oxide porous microparticles (M Tb PDT V11S ). Biochemical characterization revealed M Tb PDT V11S 5 as optimal candidate for further studies (10,552 IU g -1 ; retained activity 54 % at 50 °C and pH 6.5). Interestingly, M Tb PDT V11S 5 display...
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#1Akihiko Hatano (Shibaura Institute of Technology)H-Index: 9
#2Hiroyuki Wakana (Shibaura Institute of Technology)
Last. Sanae Uehara (Shibaura Institute of Technology)H-Index: 1
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Unnatural nucleosides are attracting interest as potential diagnostic tools, medicines, and functional molecules. However, it is difficult to couple unnatural nucleobases to the 1′-position of ribose in high yield and with β-regioselectivity. Purine nucleoside phosphorylase (PNP, EC2.4.2.1) is a metabolic enzyme that catalyses the conversion of inosine to ribose-1α-phosphate and free hypoxanthine in phosphate buffer with 100% α-selectivity. We explored whether PNP can be used to synthesize unnat...
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#1Jon Del Arco (UEM: European University of Madrid)H-Index: 4
#2Almudena Perona (UEM: European University of Madrid)H-Index: 7
Last. Pedro A. Sánchez-Murcia (University of Vienna)H-Index: 8
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Insight into the catalytic mechanism of Lactobacillus leichmannii nucleoside 2′-deoxyribosyltransferase (LlNDT) has been gained by calculating a quantum mechanics–molecular mechanics (QM/MM) free-energy landscape of the reaction within the enzyme active site. Our results support an oxocarbenium species as the reaction intermediate and thus an SN1 reaction mechanism in this family of bacterial enzymes. Our mechanistic proposal is validated by comparing experimental kinetic data on the impact of t...
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#1Jon Del Arco (UEM: European University of Madrid)H-Index: 4
#2Elena Pérez (UEM: European University of Madrid)H-Index: 2
Last. Jesús Fernández-Lucas (Grupo México)H-Index: 12
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Abstract The present work describes the functional and structural characterization of adenine phosphoribosyltransferase 2 from Thermus thermophilus HB8 (TtAPRT2). The combination of structural and substrate specificity data provided valuable information for immobilization studies. Dimeric TtAPRT2 was immobilized onto glutaraldehyde-activated MagReSyn®Amine magnetic iron oxide porous microparticles by two different strategies: a) an enzyme immobilization at pH 8.5 to encourage the immobilization ...
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