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Trends in the biosynthesis and production of the immunosuppressant tacrolimus (FK506)

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Abstract

The current off-patent state of tacrolimus (FK506) has opened the hunting season for new generic pharmaceutical formulations of this immunosuppressant. This fact has boosted the scientific and industrial research on tacrolimus for the last 5 years in order to improve its production. The fast discovery of tacrolimus producer strains has generated a huge number of producers, which presents the biosynthetic cluster of FK506 as a high promiscuous genetic region. For the first time, the current state-of-the-art on the tacrolimus biosynthesis, production improvements and drug purification is reviewed. On one hand, all the genes involved in the tacrolimus biosynthesis, in addition to the traditional PKS/NRPS, as well as their regulation are analysed. On the other hand, tacrolimus direct and indirect precursors are reviewed as a straight manner to improve the final yield, which is a current trend in the field. Twenty years of industrial and scientific improvements on tacrolimus production are summarised, whereas future trends are also drafted.

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Acknowledgments

We acknowledge Juan F. Martín for his kind introduction to the tacrolimus study by Streptomyces species; H. Petkovic for his advice about immunosuppressant-producing species and C. Prieto, S. Albillos and A. Sola-Landa for their support on scientific concerns. We thank A. Mulero-Fernández for her excellent technical assistance. Special thanks to the anonymous reader that day by day improves our work.

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  1. Instituto de Biotecnología de León (INBIOTEC), Parque Científico de León, Avda. Real, no 1, León, 24006, Spain

    Carlos Barreiro

  2. Gadea Biopharma SL, Parque Tecnológico de León, C/ Nicostrato Vela s/n, León, 24009, Spain

    Miriam Martínez-Castro

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  1. Carlos Barreiro
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Correspondence to Carlos Barreiro.

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Barreiro, C., Martínez-Castro, M. Trends in the biosynthesis and production of the immunosuppressant tacrolimus (FK506). Appl Microbiol Biotechnol 98, 497–507 (2014). https://doi.org/10.1007/s00253-013-5362-3

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