Regulating cellular metabolism and morphology to achieve high-yield synthesis of hyaluronan with controllable molecular weights
Abstract High-yield biosynthesis of hyaluronan (HA) with controllable molecular weights (MWs) remains challenging due to the poorly understood function of Class I HA synthase (HAS) and the metabolic imbalance between HA biosynthesis and cellular growth. Here, we systematically characterize HAS to id...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56950-3 |
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| author | Litao Hu Sen Xiao Jieyu Sun Faying Wang Guobin Yin Wenjie Xu Jianhua Cheng Guocheng Du Jian Chen Zhen Kang |
| author_facet | Litao Hu Sen Xiao Jieyu Sun Faying Wang Guobin Yin Wenjie Xu Jianhua Cheng Guocheng Du Jian Chen Zhen Kang |
| author_sort | Litao Hu |
| collection | DOAJ |
| description | Abstract High-yield biosynthesis of hyaluronan (HA) with controllable molecular weights (MWs) remains challenging due to the poorly understood function of Class I HA synthase (HAS) and the metabolic imbalance between HA biosynthesis and cellular growth. Here, we systematically characterize HAS to identify crucial regions involved in HA polymerization, secretion, and MW control. We construct HAS mutants that achieve complete HA secretion and expand the MW range from 300 to 1400 kDa. By dynamically regulating UDP-glucose 6-dehydrogenase activity and applying an adaptive evolution approach, we recover cell normal growth with increased metabolic capacities. Final titers and productivities for high MW HA (500 kDa) and low MW HA (10 kDa) reach 45 g L−1 and 105 g L−1, 0.94 g L−1 h−1 and 1.46 g L−1 h−1, respectively. Our findings advance our understanding of HAS function and the interplay between cell metabolism and morphology, and provide a shape-guided engineering strategy to optimize microbial cell factories. |
| format | Article |
| id | doaj-art-49430ba0ba4a42cda4f6c8085c7290cd |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-49430ba0ba4a42cda4f6c8085c7290cd2025-08-20T02:01:33ZengNature PortfolioNature Communications2041-17232025-02-0116111310.1038/s41467-025-56950-3Regulating cellular metabolism and morphology to achieve high-yield synthesis of hyaluronan with controllable molecular weightsLitao Hu0Sen Xiao1Jieyu Sun2Faying Wang3Guobin Yin4Wenjie Xu5Jianhua Cheng6Guocheng Du7Jian Chen8Zhen Kang9The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan UniversityThe Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan UniversityThe Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan UniversityThe Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan UniversityThe Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan UniversityThe Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan UniversityInstitute of Future Food Technology, JITRIThe Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan UniversityThe Science Center for Future Foods, Jiangnan UniversityThe Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan UniversityAbstract High-yield biosynthesis of hyaluronan (HA) with controllable molecular weights (MWs) remains challenging due to the poorly understood function of Class I HA synthase (HAS) and the metabolic imbalance between HA biosynthesis and cellular growth. Here, we systematically characterize HAS to identify crucial regions involved in HA polymerization, secretion, and MW control. We construct HAS mutants that achieve complete HA secretion and expand the MW range from 300 to 1400 kDa. By dynamically regulating UDP-glucose 6-dehydrogenase activity and applying an adaptive evolution approach, we recover cell normal growth with increased metabolic capacities. Final titers and productivities for high MW HA (500 kDa) and low MW HA (10 kDa) reach 45 g L−1 and 105 g L−1, 0.94 g L−1 h−1 and 1.46 g L−1 h−1, respectively. Our findings advance our understanding of HAS function and the interplay between cell metabolism and morphology, and provide a shape-guided engineering strategy to optimize microbial cell factories.https://doi.org/10.1038/s41467-025-56950-3 |
| spellingShingle | Litao Hu Sen Xiao Jieyu Sun Faying Wang Guobin Yin Wenjie Xu Jianhua Cheng Guocheng Du Jian Chen Zhen Kang Regulating cellular metabolism and morphology to achieve high-yield synthesis of hyaluronan with controllable molecular weights Nature Communications |
| title | Regulating cellular metabolism and morphology to achieve high-yield synthesis of hyaluronan with controllable molecular weights |
| title_full | Regulating cellular metabolism and morphology to achieve high-yield synthesis of hyaluronan with controllable molecular weights |
| title_fullStr | Regulating cellular metabolism and morphology to achieve high-yield synthesis of hyaluronan with controllable molecular weights |
| title_full_unstemmed | Regulating cellular metabolism and morphology to achieve high-yield synthesis of hyaluronan with controllable molecular weights |
| title_short | Regulating cellular metabolism and morphology to achieve high-yield synthesis of hyaluronan with controllable molecular weights |
| title_sort | regulating cellular metabolism and morphology to achieve high yield synthesis of hyaluronan with controllable molecular weights |
| url | https://doi.org/10.1038/s41467-025-56950-3 |
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