期刊
MICROBIAL CELL FACTORIES
卷 18, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12934-019-1117-x
关键词
Malonyl-CoA; Corynebacterium glutamicum; Noreugenin; Metabolic engineering; Acetyl-CoA carboxylase
资金
- Bioeconomy Science Center (BioSC) as part of the FocusLab project HyImPAct-Hybrid processes for important precursor and active pharmaceutical ingredients [325 - 400 002 13]
- Enabling Spaces Program Helmholtz Innovation Labs of the German Helmholtz Association
Background; In the last years, different biotechnologically relevant microorganisms have been engineered for the synthesis of plant polyphenols such as flavonoids and stilbenes. However, low intracellular availability of malonyl-CoA as essential precursor for most plant polyphenols of interest is regarded as the decisive bottleneck preventing high product titers. Results: In this study, Corynebacterium glutamicum, which emerged as promising cell factory for plant polyphenol production, was tailored by rational metabolic engineering towards providing significantly more malonyl-CoA for product synthesis. This was achieved by improving carbon source uptake, transcriptionalderegulation of accBC and accD1 encoding the two subunits of the acetyl-CoA carboxylase (ACC), reduced flux into the tricarboxylic acid (TCA) cycle, and elimination of anaplerotic carboxylation of pyruvate. The constructed strains were used for the synthesis of the pharmacologically interesting plant pentaketide noreugenin, which is produced by plants such as Aloe arborescens from five molecules of malonyl-CoA. In this context, accumulation of the C-1/C-6 cyclized intermediate 1-(2,4,6-trihydroxyphenyl)butane-1,3-dione (TPBD) was observed, which could be fully cyclized to the bicyclic product noreugenin by acidification. Conclusion: The best strain C. glutamicum Nor2 C5 mufasO(BCD1) P-O6-iolT1 Delta pyc allowed for synthesis of 53.32mg/L (0.278 mM) noreugenin in CGXII mediumsupplemented with casamino acids within 24 h.
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