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Uncovering novel pathways for enhancing hyaluronan synthesis in recombinant Lactococcus lactis: Genome-scale metabolic modelling and experimental validation

View ORCID ProfileAbinaya Badri, View ORCID ProfileKarthik Raman, View ORCID ProfileGuhan Jayaraman
doi: https://doi.org/10.1101/244699
Abinaya Badri
aDepartment of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai – 600 036, INDIA
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Karthik Raman
aDepartment of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai – 600 036, INDIA
bInitiative for Biological Systems Engineering, IIT Madras
cRobert Bosch Centre for Data Science and Artificial Intelligence (RBC-DSAI), IIT Madras
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  • For correspondence: guhanj@iitm.ac.in kraman@iitm.ac.in
Guhan Jayaraman
aDepartment of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai – 600 036, INDIA
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  • For correspondence: guhanj@iitm.ac.in kraman@iitm.ac.in
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Abstract

Hyaluronan (HA) is a naturally occurring high-value polysaccharide with important medical applications. HA is commercially produced from pathogenic microbial sources. HA-producing recombinant cell factories that are being developed with GRAS organisms are comparatively less productive than the best natural producers. The metabolism of these recombinant systems needs to be more strategically engineered to achieve significant improvement. Here, we use a genome-scale metabolic network model to account for the entire metabolic network of the cell to predict strategies for improving HA production. We here analyze the metabolic network of Lactococcus lactis adapted to produce HA, and identify non-conventional overexpression and knock-out strategies to enhance HA flux.

To experimentally validate our predictions, we identify an alternate route for enhancement of HA synthesis, originating from the nucleoside inosine, which has the capacity to function in parallel with the traditionally known route from glucose. Adopting this strategy resulted in a 2.8-fold increase in HA yield. The strategies identified and the experimental results show that the cell is capable of involving a larger subset of metabolic pathways in HA production. Apart from being the first report of the use of a nucleoside to improve HA production, our study shows how experimental results enable model refinement. Overall, we point out that well-constructed genome-scale metabolic models could be very potent tools to derive efficient strategies to improve biosynthesis of important high-value products.

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Posted March 16, 2018.
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Uncovering novel pathways for enhancing hyaluronan synthesis in recombinant Lactococcus lactis: Genome-scale metabolic modelling and experimental validation
Abinaya Badri, Karthik Raman, Guhan Jayaraman
bioRxiv 244699; doi: https://doi.org/10.1101/244699
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Uncovering novel pathways for enhancing hyaluronan synthesis in recombinant Lactococcus lactis: Genome-scale metabolic modelling and experimental validation
Abinaya Badri, Karthik Raman, Guhan Jayaraman
bioRxiv 244699; doi: https://doi.org/10.1101/244699

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