Abstract
Production of small molecule drugs in a recombinant host is becoming an increasingly popular alternative to chemical synthesis or production in natural hosts such as plants due to the ease of growing microorganisms with higher titers and less cost. While there are a wide variety of well-developed cloning techniques to produce small molecule drugs in a heterologous host, there are still many challenges towards efficient production. Therefore, this paper reviews some of these recently developed tools for metabolic engineering and categorizes them according to a chronological series of steps for a generalized method of drug production in a heterologous host, including 1) pathway discovery from a natural host, 2) pathway assembly in the recombinant host, and 3) pathway optimization to increase titers and yield.
Highlights
Small molecules derived from natural organisms offer a wide range of useful applications
These methods include fusing new promoters to silent gene clusters such as in the discovery of the novel polyketide, asperfuranone [31]; prevention of heterochromatin formation, which activated the production of monodictyphenone in Aspergillus nidulans [32]; and co-incubation with microbial consortia to mimic conditions in nature [33], a process which was instrumental in discovering dihydrofarnesol production in Candida albicans [34] as well as in finding a variety of products only produced by co-cultures of marine actinomycetes with their natural competitors [35]
This review has summarized many of the challenges associated with drug production in a heterologous host and has presented both traditional and recently developed solutions to those challenges
Summary
Small molecules derived from natural organisms offer a wide range of useful applications. Drug synthesis using the chemical route, as mentioned above, is not always an efficient alternative due to the complexity of some of these organic molecules with many chiral centers and different functional groups Because of these limitations, an alternative approach, which synthesizes small molecule drugs in a heterologous host (e.g., E. coli or S. cerevisiae) by expressing the biosynthetic pathways, is attracting increasing. Holding a great promise of drug synthesis in a heterologous host, it is not always easy to achieve efficient production due to challenges such as unknown production pathways, poor gene expression in the heterologous host, or bottlenecks in an unbalanced biosynthesis pathway To overcome these issues, many efforts have been committed, such as creating easier expression vector assembly techniques [11] and employing pathway balancing algorithms [10]. We offer our perspectives on some cutting-edge breakthroughs in synthetic biology and their potential applications in assisting metabolic engineering for the production of small molecule drugs
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