2024 AIChE Annual Meeting

Harnessing the Biosynthetic Machinery of Natural Products for Biomanufacturing

Biomanufacturing offers a sustainable alternative to petrochemical processes for producing commodity chemicals, such as biofuels, dyes, and monomers as it relies on renewable biomass-derived feedstocks rather than rapidly depleting and pollutive fossil fuels. To date, most engineered biosynthetic pathways for manufacturing bulk chemicals have relied exclusively on monofunctional enzymes. However, nature has also provided us with another type of underutilized enzymes known as polyketide synthases (PKSs). Type I polyketide synthases, in particular, are modular and versatile enzymes capable of producing an extensive array of natural products such as erythromycin, an antibiotic used to treat bacterial infections. PKSs are unique in their ability to generate compounds with elongated carbon chains and uncommon functional groups, such as terminal alkenes or alkynes. By leveraging their biosynthetic capabilities alongside monofunctional enzymes and synthetic chemistry, new pathways for synthesizing valuable chemicals can be unlocked.

Despite existing tools for retrobiosynthesis and de novo metabolic pathway design, no current platform effectively integrates PKSs with both biological and chemical systems. To address this limitation, we developed TridentSynth (tridentsynth.ese.lbl.gov), an open-source web tool that combines the chimeric PKS design software RetroTide with the pathway design tool DORAnet, providing a unified platform for constructing complex biosynthetic pathways. We deployed TridentSynth on the web by utilizing a stack of modern web development technologies for both ease of use and broad compatibility. Streamlit’s simplicity and user-friendly interface allows users to easily interact with the application and input their own data into the program. On the backend, Django manages jobs based on users requests, chosen for its robustness and scalability. To facilitate communication between the front and back ends, Celery serves as an asynchronous task queue and Redis as a message broker. The entire application is containerized using Docker, providing a consistent development environment and ensuring compatibility across different systems. This microservice-based architecture enabled the creation of a scalable and easily deployable application. By streamlining the process of pathway exploration and analysis, TridentSynth facilitates the discovery of novel chemical routes and supports more efficient and innovative biomanufacturing practices.