Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy

Herein we report the first proof for the application of type II 2′-deoxyribosyltransferase from Lactobacillus delbrueckii (LdNDT) in suicide gene therapy for cancer treatment. To this end, we first confirm the hydrolytic ability of LdNDT over the nucleoside-based prodrugs 2′-deoxy-5-fluorouridine (d...

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Autores:
Acosta, Javier
Pérez, Elena
Sánchez-Murcia, Pedro Alejandro
Fillat, Cristina
Fernández-Lucas, Jesús
Rosas, Ennis
Tipo de recurso:
Article of journal
Fecha de publicación:
2021
Institución:
Corporación Universidad de la Costa
Repositorio:
REDICUC - Repositorio CUC
Idioma:
eng
OAI Identifier:
oai:repositorio.cuc.edu.co:11323/7937
Acceso en línea:
https://hdl.handle.net/11323/7937
https://doi.org/10.3390/biom11010120
https://repositorio.cuc.edu.co/
Palabra clave:
Chemotherapy
Suicide gene therapy
Nucleoside analogues
2′-deoxyribosyltransferase
Structural bioinformatics
Molecular dynamics
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openAccess
License
CC0 1.0 Universal
id RCUC2_be2b86152777b2cbf1dc77c94b48535a
oai_identifier_str oai:repositorio.cuc.edu.co:11323/7937
network_acronym_str RCUC2
network_name_str REDICUC - Repositorio CUC
repository_id_str
dc.title.spa.fl_str_mv Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy
title Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy
spellingShingle Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy
Chemotherapy
Suicide gene therapy
Nucleoside analogues
2′-deoxyribosyltransferase
Structural bioinformatics
Molecular dynamics
title_short Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy
title_full Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy
title_fullStr Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy
title_full_unstemmed Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy
title_sort Molecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy
dc.creator.fl_str_mv Acosta, Javier
Pérez, Elena
Sánchez-Murcia, Pedro Alejandro
Fillat, Cristina
Fernández-Lucas, Jesús
Rosas, Ennis
dc.contributor.author.spa.fl_str_mv Acosta, Javier
Pérez, Elena
Sánchez-Murcia, Pedro Alejandro
Fillat, Cristina
Fernández-Lucas, Jesús
dc.contributor.author.none.fl_str_mv Rosas, Ennis
dc.subject.spa.fl_str_mv Chemotherapy
Suicide gene therapy
Nucleoside analogues
2′-deoxyribosyltransferase
Structural bioinformatics
Molecular dynamics
topic Chemotherapy
Suicide gene therapy
Nucleoside analogues
2′-deoxyribosyltransferase
Structural bioinformatics
Molecular dynamics
description Herein we report the first proof for the application of type II 2′-deoxyribosyltransferase from Lactobacillus delbrueckii (LdNDT) in suicide gene therapy for cancer treatment. To this end, we first confirm the hydrolytic ability of LdNDT over the nucleoside-based prodrugs 2′-deoxy-5-fluorouridine (dFUrd), 2′-deoxy-2-fluoroadenosine (dFAdo), and 2′-deoxy-6-methylpurine riboside (d6MetPRib). Such activity was significantly increased (up to 30-fold) in the presence of an acceptor nucleobase. To shed light on the strong nucleobase dependence for enzymatic activity, different molecular dynamics simulations were carried out. Finally, as a proof of concept, we tested the LdNDT/dFAdo system in human cervical cancer (HeLa) cells. Interestingly, LdNDT/dFAdo showed a pronounced reduction in cellular viability with inhibitory concentrations in the low micromolar range. These results open up future opportunities for the clinical implementation of nucleoside 2′-deoxyribosyltransferases (NDTs) in cancer treatment.
publishDate 2021
dc.date.accessioned.none.fl_str_mv 2021-02-26T20:07:44Z
dc.date.available.none.fl_str_mv 2021-02-26T20:07:44Z
dc.date.issued.none.fl_str_mv 2021
dc.type.spa.fl_str_mv Artículo de revista
dc.type.coar.fl_str_mv http://purl.org/coar/resource_type/c_2df8fbb1
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dc.type.content.spa.fl_str_mv Text
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/article
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dc.type.version.spa.fl_str_mv info:eu-repo/semantics/acceptedVersion
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dc.identifier.issn.spa.fl_str_mv 2218-273X
dc.identifier.uri.spa.fl_str_mv https://hdl.handle.net/11323/7937
dc.identifier.doi.spa.fl_str_mv https://doi.org/10.3390/biom11010120
dc.identifier.instname.spa.fl_str_mv Corporación Universidad de la Costa
dc.identifier.reponame.spa.fl_str_mv REDICUC - Repositorio CUC
dc.identifier.repourl.spa.fl_str_mv https://repositorio.cuc.edu.co/
identifier_str_mv 2218-273X
Corporación Universidad de la Costa
REDICUC - Repositorio CUC
url https://hdl.handle.net/11323/7937
https://doi.org/10.3390/biom11010120
https://repositorio.cuc.edu.co/
dc.language.iso.none.fl_str_mv eng
language eng
dc.relation.references.spa.fl_str_mv 1. WHO. Who Report on Cancer: Setting Priorities, Investing Wisely and Providing Care for All. Available online: https://www.who.int/publications/i/item/who-report-on-cancer-setting-priorities-investing-wisely-and-providing-care-for-all (accessed on 14 January 2021).
2. Jordheim, L.P.; Durantel, D.; Zoulim, F.; Dumontet, C. Advances in the Development of Nucleoside and Nucleotide Analogues for Cancer and Viral Diseases. Nat. Rev. Drug Discov. 2013, 12, 447–464. [CrossRef] [PubMed]
3. Galmarini, C.M.; Mackey, J.R.; Dumontet, C. Nucleoside Analogues and Nucleobases in Cancer Treatment. Lancet Oncol. 2002, 3, 415–424. [CrossRef]
4. Parker, W.B. Enzymology of Purine and Pyrimidine Antimetabolites Used in the Treatment of Cancer. Chem. Rev. 2009, 109, 2880–2893. [CrossRef] [PubMed]
5. Zhang, J.; Kale, V.; Chen, M. Gene-Directed Enzyme Prodrug Therapy. AAPS J. 2015, 17, 102–110. [CrossRef] [PubMed]
6. Parker, W.B.; Sorscher, E.J. Use of E. Coli Purine Nucleoside Phosphorylase in the Treatment of Solid Tumors. Curr. Pharm. Des. 2018, 23, 7003–7024. [CrossRef]
7. Sharma, S.K.; Bagshawe, K.D. Antibody Directed Enzyme Prodrug Therapy (ADEPT): Trials and Tribulations. Adv. Drug Deliv. Rev. 2017, 118, 2–7. [CrossRef]
8. Nemani, K.V.; Ennis, R.C.; Griswold, K.E.; Gimi, B. Magnetic Nanoparticle Hyperthermia Induced Cytosine Deaminase Expression in Microencapsulated, E. Coli for Enzyme-Prodrug Therapy. J. Biotechnol. 2015, 203, 32–40. [CrossRef]
9. Ardiani, A.J.; Johnson, A.; Ruan, H.; Sanchez-Bonilla, M.; Serve, K.E.; Black, M. Enzymes to Die For: Exploiting Nucleotide Metabolizing Enzymes for Cancer Gene Therapy. Curr. Gene Ther. 2012, 12, 77–91. [CrossRef]
10. López-Estévez, S.; Ferrer, G.; Torres-Torronteras, J.; Mansilla, M.J.; Casacuberta-Serra, S.; Martorell, L.; Hirano, M.; Martí, R.; Barquinero, J. Thymidine Phosphorylase Is Both a Therapeutic and a Suicide Gene in a Murine Model of Mitochondrial Neurogastrointestinal Encephalomyopathy. Gene Ther. 2014, 21, 673–681. [CrossRef]
11. Fresco-Taboada, A.; De La Mata, I.; Arroyo, M.; Fernández-Lucas, J. New Insights on Nucleoside 20 -Deoxyribosyltransferases: A Versatile Biocatalyst for One-Pot One-Step Synthesis of Nucleoside Analogs. Appl. Microbiol. Biotechnol. 2013, 97, 3773–3785. [CrossRef]
12. Crespo, N.; Sánchez-Murcia, P.A.; Gago, F.; Cejudo-Sanches, J.; Galmes, M.A.; Fernández-Lucas, J.; Mancheño, J.M. 20 - Deoxyribosyltransferase from Leishmania Mexicana, an Efficient Biocatalyst for One-Pot, One-Step Synthesis of Nucleosides from Poorly Soluble Purine Bases. Appl. Microbiol. Biotechnol. 2017, 101, 7187–7200. [CrossRef]
13. Pérez, E.; Sánchez-Murcia, P.A.; Jordaan, J.; Blanco, M.D.; Mancheño, J.M.; Gago, F.; Fernández-Lucas, J. Enzymatic Synthesis of Therapeutic Nucleosides Using a Highly Versatile Purine Nucleoside 20 -Deoxyribosyl Transferase from Trypanosoma Brucei. ChemCatChem 2018, 10, 4406–4416. [CrossRef]
14. Del Arco, J.; Perona, A.; González, L.; Fernández-Lucas, J.; Gago, F.; Sánchez-Murcia, P.A. Reaction Mechanism of Nucleoside 20 -Deoxyribosyltransferases: Free-Energy Landscape Supports an Oxocarbenium Ion as the Reaction Intermediate. Org. Biomol. Chem. 2019, 17, 7891–7899. [CrossRef]
15. Smar, M.; Short, S.A.; Wolfenden, R. Lyase Activity of Nucleoside 2-Deoxyribosyltransferase: Transient Generation of Ribal and Its Use in the Synthesis of 20 -Deoxynucleosides. Biochemistry 1991, 30, 7908–7912. [CrossRef]
16. Del Arco, J.; Mills, A.; Gago, F.; Fernández-Lucas, J. Structure-Guided Tuning of a Selectivity Switch towards Ribonucleosides in Trypanosoma Brucei Purine Nucleoside 20 -Deoxyribosyltransferase. ChemBioChem 2019, 20, 2996–3000. [CrossRef]
17. Kaminski, P.A.; Dacher, P.; Dugué, L.; Pochet, S. In Vivo Reshaping the Catalytic Site of Nucleoside 20 -Deoxyribosyltransferase for Dideoxy- and Didehydronucleosides via a Single Amino Acid Substitution. J. Biol. Chem. 2008, 283, 20053–20059. [CrossRef]
18. Fernández-Lucas, J.; Acebal, C.; Sinisterra, J.V.; Arroyo, M.; De La Mata, I. Lactobacillus Reuteri 20 -Deoxyribosyltransferase, a Novel Biocatalyst for Tailoring of Nucleosides. Appl. Environ. Microbiol. 2010, 76, 1462–1470. [CrossRef]
19. Fresco-Taboada, A.; Fernández-Lucas, J.; Acebal, C.; Arroyo, M.; Ramón, F.; De La Mata, I.; Mancheño, J.M. 20 -Deoxyribosyltransferase from Bacillus Psychrosaccharolyticus: A Mesophilic-like Biocatalyst for the Synthesis of Modified Nucleosides from a Psychrotolerant Bacterium. Catalysts 2018, 8, 8. [CrossRef]
20. Vichier-Guerre, S.; Dugué, L.; Bonhomme, F.; Pochet, S. Expedient and Generic Synthesis of Imidazole Nucleosides by Enzymatic Transglycosylation. Org. Biomol. Chem. 2016, 14, 3638–3653. [CrossRef]
21. Lapponi, M.J.; Rivero, C.W.; Zinni, M.A.; Britos, C.N.; Trelles, J.A. New Developments in Nucleoside Analogues Biosynthesis: A Review. J. Mol. Catal B Enzym. 2016, 133, 218–233. [CrossRef]
22. Acosta, J.; Del Arco, J.; Martinez-Pascual, S.; Clemente-Suárez, V.J.; Fernández-Lucas, J. One-Pot Multi-Enzymatic Production of Purine Derivatives with Application in Pharmaceutical and Food Industry. Catalysts 2018, 8, 9. [CrossRef]
23. Lawrence, K.A.; Jewett, M.W.; Rosa, P.A.; Gherardini, F.C. Borrelia Burgdorferi Bb0426 Encodes a 20 -Deoxyribosyltransferase That Plays a Central Role in Purine Salvage. Mol. Microbiol. 2009, 72, 1517–1529. [CrossRef]
24. Bosch, J.; Robien, M.A.; Mehlin, C.; Boni, E.; Riechers, A.; Buckner, F.S.; Van Voorhis, W.C.; Myler, P.J.; Worthey, E.A.; DeTitta, G.; et al. Using Fragment Cocktail Crystallography to Assist Inhibitor Design of Trypanosoma Brucei Nucleoside 2-Deoxyribosyltransferase. J. Med. Chem. 2006, 49, 5939–5946. [CrossRef]
25. Armstrong, S.R.; Cook, W.J.; Short, S.A.; Ealick, S.E. Crystal Structures of Nucleoside 2-Deoxyribosyltransferase in Native and Ligand-Bound Forms Reveal Architecture of the Active Site. Structure 1996, 4, 97–107. [CrossRef]
26. Anandakrishnan, R.; Aguilar, B.; Onufriev, A.V. H++ 3.0: Automating PK Prediction and the Preparation of Biomolecular Structures for Atomistic Molecular Modeling and Simulations. Nucleic Acids Res. 2012, 40, w537–w541. [CrossRef]
27. Jorgensen, W.L.; Chandrasekhar, J.; Madura, J.D.; Impey, R.W.; Klein, M.L. Comparison of Simple Potential Functions for Simulating Liquid Water. J. Chem. Phys. 1983, 79, 926–935. [CrossRef]
28. Berendsen, H.J.C.; Postma, J.P.M.; Van Gunsteren, W.F.; Dinola, A.; Haak, J.R. Molecular Dynamics with Coupling to an External Bath. J. Chem. Phys. 1984, 81, 3684–3690. [CrossRef]
29. Darden, T.; York, D.; Pedersen, L. Particle Mesh Ewald: An N·log(N) Method for Ewald Sums in Large Systems. J. Chem. Phys. 1993, 98, 10089–10092. [CrossRef]
30. Ausubel, F.M.; Brent, R.; Kingston, R.E.; Moore, D.D.; Seidman, J.G.; Smith, J.A.; Struhl, K. Current Protocols in Molecular Biology; John Wiley: New York, NY, USA, 1988; pp. 431–433. [CrossRef]
31. Graham, F.L.; Van der Eb, A.J. A New Technique for the Assay of Infectivity of Human Adenovirus 5 DNA. Virology 1973, 52, 456–469. [CrossRef]
32. Mosmann, T. Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays. J. Immunol. Methods 1983, 65, 55–63. [CrossRef]
33. Bennett, E.M.; Anand, R.; Allan, P.W.; Hassan, A.E.A.; Hong, J.S.; Levasseur, D.N.; McPherson, D.T.; Parker, W.B.; Secrist III, J.A.; Sorscher, E.J.; et al. Designer Gene Therapy Using an Escherichia Coli Purine Nucleoside Phosphorylase/Prodrug System. Chem. Biol. 2003, 10, 1173–1181. [CrossRef] [PubMed]
34. Cook, W.J.; Short, S.A.; Ealick, S.E. Crystallization and Preliminary X-Ray Investigations of Recombinant Lactobacillus Leichmannii Nucleoside Deoxyribosyltransferase. J. Biol. Chem. 1990, 265, 2682–2683. [CrossRef]
35. Short, S.A.; Armstrong, S.R.; Ealick, S.E.; Porter, D.J.T. Active Site Amino Acids That Participate in the Catalytic Mechanism of Nucleoside 20 -Deoxyribosyltransferase. J. Biol. Chem. 1996, 271, 4978–4987. [CrossRef]
36. Parker, W.B.; Allan, P.W.; Hassan, A.E.A.; Secrist, J.A.; Sorscher, E.J.; Waud, W.R. Antitumor Activity of 2-Fluoro-20 -Deoxyadenosine against Tumors That Express Escherichia Coli Purine Nucleoside Phosphorylase. Cancer Gene Ther. 2003, 10, 23–29. [CrossRef]
37. Silamkoti, A.V.; Allan, P.W.; Hassan, A.E.A.; Fowler, A.T.; Sorscher, E.J.; Parker, W.B.; Secrist, J.A. Synthesis and Biological Activity of 2-Fluoro Adenine and 6-Methyl Purine Nucleoside Analogs as Prodrugs for Suicide Gene Therapy of Cancer. Nucleosides Nucleotides Nucleic Acids. 2005, 24, 881–885. [CrossRef]
38. Behbahani, T.E.; Rosenthal, E.L.; Parker, W.B.; Sorscher, E.J. Intratumoral Generation of 2-Fluoroadenine to Treat Solid Malignancies of the Head and Neck. Head Neck 2019, 41, 1979–1983. [CrossRef]
39. Rosenthal, E.L.; Chung, T.K.; Parker, W.B.; Allan, P.W.; Clemons, L.; Lowman, D.; Hong, J.; Hunt, F.R.; Richman, J.; Conry, R.M.; et al. Phase I Dose-Escalating Trial of Escherichia Coli Purine Nucleoside Phosphorylase and Fludarabine Gene Therapy for Advanced Solid Tumors. Ann. Oncol. 2015, 26, 1481–1487. [CrossRef]
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spelling Acosta, JavierPérez, ElenaSánchez-Murcia, Pedro AlejandroFillat, CristinaFernández-Lucas, JesúsRosas, Ennisvirtual::987-12021-02-26T20:07:44Z2021-02-26T20:07:44Z20212218-273Xhttps://hdl.handle.net/11323/7937https://doi.org/10.3390/biom11010120Corporación Universidad de la CostaREDICUC - Repositorio CUChttps://repositorio.cuc.edu.co/Herein we report the first proof for the application of type II 2′-deoxyribosyltransferase from Lactobacillus delbrueckii (LdNDT) in suicide gene therapy for cancer treatment. To this end, we first confirm the hydrolytic ability of LdNDT over the nucleoside-based prodrugs 2′-deoxy-5-fluorouridine (dFUrd), 2′-deoxy-2-fluoroadenosine (dFAdo), and 2′-deoxy-6-methylpurine riboside (d6MetPRib). Such activity was significantly increased (up to 30-fold) in the presence of an acceptor nucleobase. To shed light on the strong nucleobase dependence for enzymatic activity, different molecular dynamics simulations were carried out. Finally, as a proof of concept, we tested the LdNDT/dFAdo system in human cervical cancer (HeLa) cells. Interestingly, LdNDT/dFAdo showed a pronounced reduction in cellular viability with inhibitory concentrations in the low micromolar range. These results open up future opportunities for the clinical implementation of nucleoside 2′-deoxyribosyltransferases (NDTs) in cancer treatment.Acosta, JavierPérez, ElenaSánchez-Murcia, Pedro A-will be generated-orcid-0000-0001-8415-870X-600Fillat, Cristina-will be generated-orcid-0000-0002-0801-3338-600Fernández-Lucas, Jesús-will be generated-orcid-0000-0001-7045-8306-600application/pdfengCorporación Universidad de la CostaCC0 1.0 Universalhttp://creativecommons.org/publicdomain/zero/1.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Biomoleculeshttps://www.mdpi.com/2218-273X/11/1/120ChemotherapySuicide gene therapyNucleoside analogues2′-deoxyribosyltransferaseStructural bioinformaticsMolecular dynamicsMolecular basis of Ndt-mediated activation of nucleoside-based prodrugs and application in suicide gene therapyArtículo de revistahttp://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1Textinfo:eu-repo/semantics/articlehttp://purl.org/redcol/resource_type/ARTinfo:eu-repo/semantics/acceptedVersion1. WHO. Who Report on Cancer: Setting Priorities, Investing Wisely and Providing Care for All. Available online: https://www.who.int/publications/i/item/who-report-on-cancer-setting-priorities-investing-wisely-and-providing-care-for-all (accessed on 14 January 2021).2. Jordheim, L.P.; Durantel, D.; Zoulim, F.; Dumontet, C. Advances in the Development of Nucleoside and Nucleotide Analogues for Cancer and Viral Diseases. Nat. Rev. Drug Discov. 2013, 12, 447–464. [CrossRef] [PubMed]3. Galmarini, C.M.; Mackey, J.R.; Dumontet, C. Nucleoside Analogues and Nucleobases in Cancer Treatment. Lancet Oncol. 2002, 3, 415–424. [CrossRef]4. Parker, W.B. Enzymology of Purine and Pyrimidine Antimetabolites Used in the Treatment of Cancer. Chem. Rev. 2009, 109, 2880–2893. [CrossRef] [PubMed]5. Zhang, J.; Kale, V.; Chen, M. Gene-Directed Enzyme Prodrug Therapy. AAPS J. 2015, 17, 102–110. [CrossRef] [PubMed]6. Parker, W.B.; Sorscher, E.J. Use of E. Coli Purine Nucleoside Phosphorylase in the Treatment of Solid Tumors. Curr. Pharm. Des. 2018, 23, 7003–7024. [CrossRef]7. Sharma, S.K.; Bagshawe, K.D. Antibody Directed Enzyme Prodrug Therapy (ADEPT): Trials and Tribulations. Adv. Drug Deliv. Rev. 2017, 118, 2–7. [CrossRef]8. Nemani, K.V.; Ennis, R.C.; Griswold, K.E.; Gimi, B. Magnetic Nanoparticle Hyperthermia Induced Cytosine Deaminase Expression in Microencapsulated, E. Coli for Enzyme-Prodrug Therapy. J. Biotechnol. 2015, 203, 32–40. [CrossRef]9. Ardiani, A.J.; Johnson, A.; Ruan, H.; Sanchez-Bonilla, M.; Serve, K.E.; Black, M. Enzymes to Die For: Exploiting Nucleotide Metabolizing Enzymes for Cancer Gene Therapy. Curr. Gene Ther. 2012, 12, 77–91. [CrossRef]10. López-Estévez, S.; Ferrer, G.; Torres-Torronteras, J.; Mansilla, M.J.; Casacuberta-Serra, S.; Martorell, L.; Hirano, M.; Martí, R.; Barquinero, J. Thymidine Phosphorylase Is Both a Therapeutic and a Suicide Gene in a Murine Model of Mitochondrial Neurogastrointestinal Encephalomyopathy. Gene Ther. 2014, 21, 673–681. [CrossRef]11. Fresco-Taboada, A.; De La Mata, I.; Arroyo, M.; Fernández-Lucas, J. New Insights on Nucleoside 20 -Deoxyribosyltransferases: A Versatile Biocatalyst for One-Pot One-Step Synthesis of Nucleoside Analogs. Appl. Microbiol. Biotechnol. 2013, 97, 3773–3785. [CrossRef]12. Crespo, N.; Sánchez-Murcia, P.A.; Gago, F.; Cejudo-Sanches, J.; Galmes, M.A.; Fernández-Lucas, J.; Mancheño, J.M. 20 - Deoxyribosyltransferase from Leishmania Mexicana, an Efficient Biocatalyst for One-Pot, One-Step Synthesis of Nucleosides from Poorly Soluble Purine Bases. Appl. Microbiol. Biotechnol. 2017, 101, 7187–7200. [CrossRef]13. Pérez, E.; Sánchez-Murcia, P.A.; Jordaan, J.; Blanco, M.D.; Mancheño, J.M.; Gago, F.; Fernández-Lucas, J. Enzymatic Synthesis of Therapeutic Nucleosides Using a Highly Versatile Purine Nucleoside 20 -Deoxyribosyl Transferase from Trypanosoma Brucei. ChemCatChem 2018, 10, 4406–4416. [CrossRef]14. Del Arco, J.; Perona, A.; González, L.; Fernández-Lucas, J.; Gago, F.; Sánchez-Murcia, P.A. Reaction Mechanism of Nucleoside 20 -Deoxyribosyltransferases: Free-Energy Landscape Supports an Oxocarbenium Ion as the Reaction Intermediate. Org. Biomol. Chem. 2019, 17, 7891–7899. [CrossRef]15. Smar, M.; Short, S.A.; Wolfenden, R. Lyase Activity of Nucleoside 2-Deoxyribosyltransferase: Transient Generation of Ribal and Its Use in the Synthesis of 20 -Deoxynucleosides. Biochemistry 1991, 30, 7908–7912. [CrossRef]16. Del Arco, J.; Mills, A.; Gago, F.; Fernández-Lucas, J. Structure-Guided Tuning of a Selectivity Switch towards Ribonucleosides in Trypanosoma Brucei Purine Nucleoside 20 -Deoxyribosyltransferase. ChemBioChem 2019, 20, 2996–3000. [CrossRef]17. Kaminski, P.A.; Dacher, P.; Dugué, L.; Pochet, S. In Vivo Reshaping the Catalytic Site of Nucleoside 20 -Deoxyribosyltransferase for Dideoxy- and Didehydronucleosides via a Single Amino Acid Substitution. J. Biol. Chem. 2008, 283, 20053–20059. [CrossRef]18. Fernández-Lucas, J.; Acebal, C.; Sinisterra, J.V.; Arroyo, M.; De La Mata, I. Lactobacillus Reuteri 20 -Deoxyribosyltransferase, a Novel Biocatalyst for Tailoring of Nucleosides. Appl. Environ. Microbiol. 2010, 76, 1462–1470. [CrossRef]19. Fresco-Taboada, A.; Fernández-Lucas, J.; Acebal, C.; Arroyo, M.; Ramón, F.; De La Mata, I.; Mancheño, J.M. 20 -Deoxyribosyltransferase from Bacillus Psychrosaccharolyticus: A Mesophilic-like Biocatalyst for the Synthesis of Modified Nucleosides from a Psychrotolerant Bacterium. Catalysts 2018, 8, 8. [CrossRef]20. Vichier-Guerre, S.; Dugué, L.; Bonhomme, F.; Pochet, S. Expedient and Generic Synthesis of Imidazole Nucleosides by Enzymatic Transglycosylation. Org. Biomol. Chem. 2016, 14, 3638–3653. [CrossRef]21. 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