Magnetic Multi-Enzymatic System for Cladribine Manufacturing

  1. Cruz, Guillermo
  2. Saiz, Laura Pilar
  3. Bilal, Muhammad
  4. Eltoukhy, Lobna
  5. Loderer, Christoph
  6. Fernández-Lucas, Jesús
  1. 1 Universidad Europea de Madrid
    info

    Universidad Europea de Madrid

    Madrid, España

    ROR https://ror.org/04dp46240

  2. 2 Poznań University of Technology
    info

    Poznań University of Technology

    Posnania, Polonia

    ROR https://ror.org/00p7p3302

  3. 3 Dresden University of Technology
    info

    Dresden University of Technology

    Dresde, Alemania

    ROR https://ror.org/042aqky30

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Revista:
International Journal of Molecular Sciences

ISSN: 1422-0067

Año de publicación: 2022

Volumen: 23

Número: 21

Páginas: 13634

Tipo: Artículo

DOI: 10.3390/IJMS232113634 GOOGLE SCHOLAR lock_openAcceso abierto editor

Otras publicaciones en: International Journal of Molecular Sciences

Objetivos de desarrollo sostenible

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.

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