Magnetic Multi-Enzymatic System for Cladribine Manufacturing
- Cruz, Guillermo
- Saiz, Laura Pilar
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Bilal, Muhammad
- Eltoukhy, Lobna
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Loderer, Christoph
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Fernández-Lucas, Jesús
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1
Universidad Europea de Madrid
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2
Poznań University of Technology
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3
Dresden University of Technology
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ISSN: 1422-0067
Año de publicación: 2022
Volumen: 23
Número: 21
Páginas: 13634
Tipo: Artículo
Otras publicaciones en: International Journal of Molecular Sciences
Resumen
Enzyme-mediated processes have proven to be a valuable and sustainable alternative to traditional chemical methods. In this regard, the use of multi-enzymatic systems enables the realization of complex synthetic schemes, while also introducing a number of additional advantages, including the conversion of reversible reactions into irreversible processes, the partial or complete elimination of product inhibition problems, and the minimization of undesirable by-products. In addition, the immobilization of biocatalysts on magnetic supports allows for easy reusability and streamlines the downstream process. Herein we have developed a cascade system for cladribine synthesis based on the sequential action of two magnetic biocatalysts. For that purpose, purine 2′-deoxyribosyltransferase from Leishmania mexicana (LmPDT) and Escherichia coli hypoxanthine phosphoribosyltransferase (EcHPRT) were immobilized onto Ni2+-prechelated magnetic microspheres (MagReSyn®NTA). Among the resulting derivatives, MLmPDT3 (activity: 11,935 IU/gsupport, 63% retained activity, operational conditions: 40 °C and pH 5–7) and MEcHPRT3 (12,840 IU/gsupport, 45% retained activity, operational conditions: pH 5–8 and 40–60 °C) emerge as optimal catalysts for further synthetic application. Moreover, the MLmPDT3/MEcHPRT3 system was biochemically characterized and successfully applied to the one-pot synthesis of cladribine under various conditions. This methodology not only displayed a 1.67-fold improvement in cladribine synthesis (compared to MLmPDT3), but it also implied a practically complete transformation of the undesired by-product into a high-added-value product (90% conversion of Hyp into IMP). Finally, MLmPDT3/MEcHPRT3 was reused for 16 cycles, which displayed a 75% retained activity.
Información de financiación
Financiadores
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Spanish Ministry of Science and Innovation
- PID2020-117025RB-I00
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National Science Centre, Poland
- 2020/37/K/ST8/03805
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Deutsche Forschungsgemeinschaft
- LO 2678/2-1
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