Biosynthesis Engineering of Immunosuppressant Compounds

Immunosuppressant compounds such as tacrolimus, rapamycin and ascomycin derive from complex polyketide pathways in actinomycete bacteria and play a pivotal role in organ transplantation and the treatment of autoimmune disorders. Traditional fermentation processes yield low titres of these macrolides, prompting the development of biosynthetic engineering strategies to enhance production and enable structural diversification. Approaches include the manipulation of global transcriptional regulators to upregulate entire gene clusters, the application of genome-scale metabolic models to identify metabolic bottlenecks, and the refactoring of biosynthetic operons through promoter replacement and gene cluster rearrangement. Complementary methods such as precursor-directed biosynthesis, mutasynthesis and combinatorial pathway assembly have permitted the introduction of non-natural substituents, yielding analogue libraries with improved pharmacological properties. Advances in systems biology and synthetic biology have further facilitated real-time monitoring of pathway fluxes and the dynamic control of enzyme expression. Collectively, these techniques are transforming the manufacture of immunosuppressants, reducing costs and expanding the chemical diversity available for clinical development.

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Biosynthesis Engineering of Immunosuppressant Compounds publication trend

The graph below shows the total number of articles in biosynthesis engineering of immunosuppressant compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Polyketide synthase: A modular enzyme complex that assembles polyketide chains by sequential condensation of simple acyl-CoA building blocks.

Global regulator: A transcription factor that coordinates the expression of multiple genes or entire gene clusters, often in response to small-molecule signals.

Genome-scale metabolic model: A computational reconstruction of an organism’s metabolic network used to predict flux distributions and identify bottlenecks.

Promoter refactoring: The systematic replacement or fine-tuning of native promoters to modulate gene expression levels within a biosynthetic operon.

Ethylmalonyl-CoA: An uncommon extender unit in polyketide biosynthesis derived from the ethylmalonyl pathway, critical for introducing specific alkyl side chains.

References

1. Optimization of FK-506 production in Streptomyces tsukubaensis by modulation of Crp-mediated regulation. Applied Microbiology and Biotechnology (2023).
2. Metabolic network model guided engineering ethylmalonyl-CoA pathway to improve ascomycin production in Streptomyces hygroscopicus var. ascomyceticus. Microbial Cell Factories (2017).
3. Improvement of FK506 production via metabolic engineering-guided combinational strategies in Streptomyces tsukubaensis. Microbial Cell Factories (2021).