Robust fermentation production of tacrolimus and related immunosuppressors: Molecular genetics and metabolic engineering to construct a by-product free superproducer.

acronym: IMMUNOTEC

Results of IMMUNOTEC
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Project coordinator
- Prof. Juan-Francisco Martín - INBIOTEC Instituto de Biotecnología
  de León - Spain
Project leaders
- Prof. Wolfgang Wohlleben - Eberhard Karls Universität Tübingen -
- Dr. Marta Vas Mendes - IBMC Instituto de Biología Molecular
  e Celular - Portugal
- Prof. Lutz Heide - Eberhard Karls Universität Tübingen - Germany
- Prof. José Luis Barredo - Antibióticos S.A. - Spain

Tacrolimus (FK506) and ascomycin (FK520) are closely related polyketide compounds with potent immunosuppressor activity that are widely used to avoid transplant rejection. They are produced by Streptomyces tsukubaensis and other Streptomyces species. These compounds bind the human FKBP protein causing a reaction cascade that gives rise to a reduction in the T-cell mediated human immune response thus avoiding transplant rejection. In addition, novel derivatives of these molecules (rapamycin analogues) have potential as antitumor compounds.
The biosynthesis of tacrolimus is controlled by complex networks involving phosphate and nitrogen limitation and strong aeration that causes oxidative stress. The aim of this project is to develop a robust fermentation process based on the use of genetically improved strains.
The project integrates the complementary efforts of five outstanding research groups from three different countries, very active in research at the international level in subjects that include molecular genetics of Streptomyces, physiology and metabolic regulation studies, oxidative stress and process optimization. The involvement of the medium-size biotechnology company, ANTIBIOTICOS S.A., guaranties the industrial usefulness of this study. Other European companies are also interested in this field.
The project is divided in six work packages that will be developed in close cooperation between the five partners. Close coordination will be supervised by Prof. Martin, who has a broad experience on coordination of EU projects.