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Combinatorial metabolic engineering of Bacillus subtilis enables the efficient biosynthesis of isoquercitrin from quercetin.

التفاصيل البيبلوغرافية
العنوان: Combinatorial metabolic engineering of Bacillus subtilis enables the efficient biosynthesis of isoquercitrin from quercetin.
المؤلفون: Niu T; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.; The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Huang C; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Wang R; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. wrffrw0801@shutcm.edu.cn.; The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. wrffrw0801@shutcm.edu.cn.; The MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. wrffrw0801@shutcm.edu.cn., Yang L; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.; The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.; The MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Zhao S; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.; The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.; The MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China., Wang Z; Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. ztwang@shutcm.edu.cn.; The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. ztwang@shutcm.edu.cn.; The MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. ztwang@shutcm.edu.cn.
المصدر: Microbial cell factories [Microb Cell Fact] 2024 Apr 20; Vol. 23 (1), pp. 114. Date of Electronic Publication: 2024 Apr 20.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: BioMed Central Country of Publication: England NLM ID: 101139812 Publication Model: Electronic Cited Medium: Internet ISSN: 1475-2859 (Electronic) Linking ISSN: 14752859 NLM ISO Abbreviation: Microb Cell Fact Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : BioMed Central, [2002-
مواضيع طبية MeSH: Quercetin*/*analogs & derivatives, Quercetin*/metabolism , Metabolic Engineering*, Bacillus subtilis/genetics ; Bacillus subtilis/metabolism ; Uridine Diphosphate/metabolism
مستخلص: Background: Isoquercitrin (quercetin-3-O-β-D-glucopyranoside) has exhibited promising therapeutic potentials as cardioprotective, anti-diabetic, anti-cancer, and anti-viral agents. However, its structural complexity and limited natural abundance make both bulk chemical synthesis and extraction from medical plants difficult. Microbial biotransformation through heterologous expression of glycosyltransferases offers a safe and sustainable route for its production. Despite several attempts reported in microbial hosts, the current production levels of isoquercitrin still lag behind industrial standards.
Results: Herein, the heterologous expression of glycosyltransferase UGT78D2 gene in Bacillus subtilis 168 and reconstruction of UDP-glucose (UDP-Glc) synthesis pathway led to the synthesis of isoquercitrin from quercetin with titers of 0.37 g/L and 0.42 g/L, respectively. Subsequently, the quercetin catabolism blocked by disruption of a quercetin dioxygenase, three ring-cleavage dioxygenases, and seven oxidoreductases increased the isoquercitrin titer to 1.64 g/L. And the hydrolysis of isoquercitrin was eliminated by three β-glucosidase genes disruption, thereby affording 3.58 g/L isoquercitrin. Furthermore, UDP-Glc pool boosted by pgi (encoding glucose-6-phosphate isomerase) disruption increased the isoquercitrin titer to 10.6 g/L with the yield on quercetin of 72% and to 35.6 g/L with the yield on quercetin of 77.2% in a 1.3-L fermentor.
Conclusion: The engineered B. subtilis strain developed here holds great potential for initiating the sustainable and large-scale industrial production of isoquercitrin. The strategies proposed in this study provides a reference to improve the production of other flavonoid glycosides by engineered B. subtilis cell factories.
(© 2024. The Author(s).)
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معلومات مُعتمدة: 82204557 National Natural Science Foundation of China; 82373989 National Natural Science Foundation of China; 2020M681371 China Postdoctoral Science Foundation; 2020373 Shanghai Post-doctoral Excellence Program
فهرسة مساهمة: Keywords: Bacillus subtilis; Biotransformation; Combinatorial metabolic engineering; Isoquercitrin; UDP-glucose
المشرفين على المادة: 0YX10VRV6J (isoquercitrin)
9IKM0I5T1E (Quercetin)
58-98-0 (Uridine Diphosphate)
تواريخ الأحداث: Date Created: 20240419 Date Completed: 20240422 Latest Revision: 20240426
رمز التحديث: 20240426
مُعرف محوري في PubMed: PMC11031953
DOI: 10.1186/s12934-024-02390-5
PMID: 38641799
قاعدة البيانات: MEDLINE
الوصف
تدمد:1475-2859
DOI:10.1186/s12934-024-02390-5