Search Results (3)

The confluence of a large variety of factors, achievements and developments has resulted in the current long-term success in graft transplants. Some of these events are reviewed, paying special attention to immunosuppressant drugs, which are one of the most relevant milestones in the prevention of organ transplant rejection. The discovery, industrial exploitation, mechanisms of action and side effects of several drugs exhibiting immunosuppressive effects (e.g., corticosteroids, nitrogen mustards, mycophenolic acid, rapamycin) are deeply detailed. Furthermore, new trends in immunosuppressant research, improvement and reformulation are also reviewed. Nevertheless, the core of the manuscript is the immunosuppressant tacrolimus, also called FK506, which has been sought after due to the commercial success of cyclosporine and other immunosuppressant compounds, but also because of the side effects of those previous compounds. Thus, in the mid-1980s tacrolimus was described as a more potent immunosuppressive molecule, with less undesirable effects. Currently, tacrolimus is a well-stablished API that is used as a clinical treatment to avoid graft rejection, but also shows interesting properties in terms of decreasing the impact of some autoimmune diseases and acting as an enhancer of nerve regeneration treatments. Thus, in the 40th anniversary of its discovery, this paper describes the current state of the art of this drug and how it is adapting to new social needs and clinical trends. Full article

The oxidative stress response is a key mechanism that microorganisms have to adapt to changeling environmental conditions. Adaptation is achieved by a fine-tuned molecular response that extends its influence to primary and secondary metabolism. In the past, the role of the intracellular redox status in the biosynthesis of tacrolimus in Streptomyces tsukubaensis has been briefly acknowledged. Here, we investigate the impact of the oxidative stress response on tacrolimus biosynthesis in S. tsukubaensis. Physiological characterization of S. tsukubaensis showed that the onset of tacrolimus biosynthesis coincided with the induction of catalase activity. In addition, tacrolimus displays antioxidant properties and thus a controlled redox environment would be beneficial for its biosynthesis. In addition, S. tsukubaensis ∆ahpC strain, a strain defective in the H₂O₂-scavenging enzyme AhpC, showed increased production of tacrolimus. Proteomic and transcriptomic studies revealed that the tacrolimus over-production phenotype was correlated with a metabolic rewiring leading to increased availability of tacrolimus biosynthetic precursors. Altogether, our results suggest that the carbon source, mainly used for cell growth, can trigger the production of tacrolimus by modulating the oxidative metabolism to favour a low oxidizing intracellular environment and redirecting the metabolic flux towards the increase availability of biosynthetic precursors. Full article

Streptomyces tsukubaensis stands out among actinomycetes by its ability to produce the immunosuppressant tacrolimus. Discovered about 30 years ago, this macrolide is widely used as immunosuppressant in current clinics. Other potential applications for the treatment of cancer and as neuroprotective agent have been proposed in the last years. In this review we introduce the discovery of S. tsukubaensis and tacrolimus, its biosynthetic pathway and gene cluster (fkb) regulation. We have focused this work on the omic studies performed in this species in order to understand tacrolimus production. Transcriptomics, proteomics and metabolomics have improved our knowledge about the fkb transcriptional regulation and have given important clues about nutritional regulation of tacrolimus production that can be applied to improve production yields. Finally, we address some points of S. tsukubaensis biology that deserve more attention. Full article