L-Glucose-Induced Gene Expression

Glucose is not only a deliciously sweet-tasting molecule, it is also an important constituent of the complex sugar chains in our body, called glycans. Glycolipids are one example that rely on the presence of glucose in our bodies. We further gain much of our energy by metabolizing molecules such as glucose. However, in our natural surroundings, glucose solely exists in the form of D-glucose. The mirror image form of glucose, L-glucose, is comparatively rare in nature and our enzymes are not equipped to metabolize it. Yet our sweet taste receptors still recognize L-glucose. Therefore, L-glucose has been suggested as a calorie-free sweetener.

Nature wouldn’t be nature if there wouldn’t be some weird microbe that has figured out how to break down L-glucose and capitalize on that rare but nutritious molecule. Related work has identified the soil bacterium Paracoccus species 43P as a species that is able to digest L-glucose. This tidbit is relevant because the same bacterium also has transcriptional regulators that can sense breakdown products of L-glucose (D-idonate specifically) and regulate gene expression accordingly. In synthetic biology, we are often hunting for safe, orthogonal, and effective inducers of gene expression. These can then be used to control the production of therapeutic proteins by implanted, genetically engineered cells upon consuming such an inducer.

We therefore hypothesized that L-glucose might constitute a suitable inducer candidate because of its potential to integrate it into patient lifestyle, similar to other molecules such as caffeine, without encountering the molecule by accident. Genetically engineering human cells with the addition of an L-glucose transporter, a metabolic pathway to convert L-glucose to D-idonate, and with the engineered transcriptional regulators that sense D-idonate, we demonstrated that it is indeed possible to control human gene expression with L-glucose. This work could be an interesting first step in leveraging the information density of natural glycans for synthetic biology. And, while there are still roadblocks for biomedical applications (such as the fact that L-glucose is rapidly cleared in mice), L-glucose indeed demonstrates excellent inducer qualities, such as orthogonality, safety, and effectivity.

You can read more about our work in the actual publication at the journal Biotechnology and Bioengineering.

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