Engineered Biosensors for High-Throughput Metabolite Detection
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Solution Overview
Problem
Current methods for producing therapeutic plant metabolites are bottlenecked by low-throughput analytical techniques, making it difficult to scale production and engineer efficient biosensors for these metabolites.
Innovation Solution
Engineering substrate-promiscuous regulators to create biosensors that can interact more efficiently with input signals, allowing for high-throughput screening and pathway engineering of therapeutic plant metabolites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If low-throughput analytical methods are used for assessing strain and pathway performance, then measurement precision can be maintained, but productivity is severely limited
Solution Approach 1:
The patent applies universality by engineering substrate-promiscuous regulators that can detect multiple different therapeutic plant metabolites (e.g., artemisinic acid, cannabinoids, opiates, tropane alkaloids) using a single biosensor platform. This multi-functional capability enables high-throughput screening across diverse metabolite classes without requiring separate analytical methods for each compound, thereby resolving the contradiction between productivity and device complexity.
Solution Approach 2:
The patent employs parameter changes by modifying the substrate binding properties of regulators through directed evolution and rational design. By changing the chemical parameters of the regulator-ligand interaction (binding affinity, specificity, and promiscuity), the system achieves both high throughput and accurate detection of various metabolites, overcoming the limitation of traditional low-throughput methods while maintaining measurement precision.
2Adaptability or versatility
If genetic biosensors are evolved to recognize alternative ligands, then adaptability improves, but measurement precision and binding affinity typically only achieve modest changes
Solution Approach 1:
The patent applies local quality by making specific localized modifications to the substrate binding pocket of regulators rather than global changes throughout the protein structure. By focusing mutagenesis and design efforts on the local binding interface, the system achieves both high adaptability to recognize diverse metabolites and maintains high measurement precision through optimized local interactions between the regulator and target ligand.
Solution Approach 2:
The patent employs dynamics by creating regulators with tunable binding characteristics that can adapt their affinity and specificity based on the target metabolite. The engineered substrate-promiscuous regulators dynamically adjust their binding properties through conformational changes and induced fit mechanisms, enabling both broad adaptability across metabolite classes and high precision detection of individual compounds.
3Productivity
If substrate-promiscuous regulators are engineered for increased efficiency, then productivity of biosensing improves, but device complexity increases
Solution Approach 1:
The patent applies preliminary action by pre-engineering substrate-promiscuous regulators with broad binding capabilities before deploying them for specific metabolite detection. The regulators are预先 designed and evolved to recognize multiple metabolite classes, which simplifies subsequent application and reduces the overall engineering complexity compared to developing separate specialized sensors for each metabolite, thereby improving productivity while managing device complexity.
Data Source
AI summary
Disclosed herein are substrate-promiscuous regulators which have been engineered to function as highly efficient biosensors. These engineered biosensors are significantly more specific to the target ligand than their naturally occurring counterparts, and are able to generate a detectable output signal upon exposure to the input signal (target ligand). Also disclosed of methods of making engineered biosensors based on a naturally occurring substrate-promiscuous regulator. Also disclosed are methods of using these biosensors to make a product, such as cell-based bioengineering platforms. Lastly, disclosed are kits, nucleic acids, and proteins related to the biosensors disclosed herein.