Fermentation-Driven Biological Structural Modification of Natural Products

A special issue of Fermentation (ISSN 2311-5637). This special issue belongs to the section "Microbial Metabolism, Physiology & Genetics".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 5797

Special Issue Editors

School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400044, China
Interests: fundamental metabolic regulation; biomass utilization; synthetic biology; high-efficiency separation and purification; functional materials; artificial intelligence-based chemical engineering and synthetic biology
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Guest Editor
Collage of Biotechnology, Tianjin University of Science and Technology, Tianjin, China
Interests: biocatalysis; nanomaterials; enzyme; biomass energy; natural products
College of Food and Biological Engineering, Chengdu University, Chengdu, China
Interests: chemical engineering; biochemistry; metabolic engineering; biological catalysis
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Special Issue Information

Dear Colleagues,

Natural products are widely present in nature, with a wide variety of quantities and types, complex and diverse structures, and various physiological and pharmacological activities. Many active ingredients in natural products have anti-inflammatory, antibacterial, antiviral, antioxidant, anti-tumor, radiation-resistant, and immunomodulatory activities, and are now being used as drugs to treat various diseases. In the fermentation of natural products, microorganisms and enzymes can modify the structure and properties of compounds by adding, removing, or altering specific functional groups. Biological structural modifications mainly include glycosylation, deglycosylation, hydroxylation, acylation, phosphorylation, etc., which can greatly improve the physicochemical properties and biological activities of natural products, such as terpenes, flavonoids, polyketones, aromatics, amines, steroids, etc.; increase selectivity, yield, solubility, and stability; reduce the toxicity of compounds; enhance pharmacological activity; and prolong drug action time; and have become a research hotspot in the development of new drugs.

The aim of this Special Issue is to publish both recent innovative research results and review papers on the fermentation-driven biological structure modification of natural products.

Dr. Dan Wang
Dr. Yingjie Du
Dr. Jie Cheng
Guest Editors

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Keywords

  • natural products
  • glycosylation
  • hydroxylation
  • phosphorylation
  • modification method
  • structural diversity

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Published Papers (4 papers)

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Research

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13 pages, 2715 KiB  
Article
Retinal Production by Precision Fermentation of Saccharomyces cerevisiae
by Hye-Seon Hwang, Kwang-Rim Baek and Seung-Oh Seo
Fermentation 2025, 11(4), 214; https://doi.org/10.3390/fermentation11040214 - 14 Apr 2025
Viewed by 290
Abstract
Retinoids, including retinol, retinal, and retinoic acid, are a group of vitamin A derivatives with skin-improving effects. Retinoic acid is highly effective for skin anti-aging but can cause irritation, requiring a prescription. Retinol, a less irritating alternative, needs conversion to retinal and then [...] Read more.
Retinoids, including retinol, retinal, and retinoic acid, are a group of vitamin A derivatives with skin-improving effects. Retinoic acid is highly effective for skin anti-aging but can cause irritation, requiring a prescription. Retinol, a less irritating alternative, needs conversion to retinal and then retinoic acid in the skin, whereas direct absorption of retinal enhances efficacy by bypassing this conversion process. This study aimed to produce retinal through precision fermentation using metabolically engineered Saccharomyces cerevisiae. The introduction of heterologous retinal biosynthetic genes and overexpression of the truncated HMG-CoA reductase (tHMG1) and acetyl-CoA acetyltransferase (ERG10) genes in the mevalonate (MVA) pathway increased retinal production up to 10.2 mg/L. At the same time, ethanol was produced as a major byproduct in S. cerevisiae. To address this, a pyruvate decarboxylase (Pdc)-deficient S. cerevisiae strain, incapable of producing ethanol, was employed. Overexpression of ERG10 and tHMG1 in the Pdc-deficient S. cerevisiae harboring the retinal biosynthetic plasmids achieved a retinal production up to 117.4 mg/L in the dodecane layer without ethanol through a two-phase in situ fermentation and extraction. This study demonstrates that eliminating pyruvate decarboxylase activity effectively redirects carbon flux toward retinal biosynthesis in the recombinant S. cerevisiae, offering a promising approach for sustainable retinal production through precision fermentation. Full article
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14 pages, 3447 KiB  
Article
Enhancement of the Degradation of Phytosterol Side Chains in Mycolicibacterium by Eliminating the Redox Sensitivity of Key Thiolase and Augmenting Cell Activity
by Xiuling Zhou, Yuying Liu, Fuyi Li, Yang Huang, Hongzhuan Xuan and Yang Zhang
Fermentation 2024, 10(12), 627; https://doi.org/10.3390/fermentation10120627 - 8 Dec 2024
Viewed by 810
Abstract
Androstenedione (AD) is a vital intermediate in the synthesis of steroid drugs, making its efficient production critical in the steroid drug industry. Acetyl-CoA acetyltransferase (FadA5), a thiolase enzyme, plays an important role in the metabolic process of degrading phytosterol side chains in Mycolicibacterium [...] Read more.
Androstenedione (AD) is a vital intermediate in the synthesis of steroid drugs, making its efficient production critical in the steroid drug industry. Acetyl-CoA acetyltransferase (FadA5), a thiolase enzyme, plays an important role in the metabolic process of degrading phytosterol side chains in Mycolicibacterium to produce AD. This work is the first systematic analysis of the role of FadA5 in the transformation of phytosterols by Mycolicibacterium to produce AD. The relationship between redox potential and AD production was examined using resting cells, and it was confirmed that FadA5 is a key enzyme for AD production. Mutating the 87th cysteine of FadA5 to alanine reduced its redox effect, enhancing the substrate tolerance and biotransformation capacity of the strain. Co-expressing Vitreoscilla hemoglobin (VHb) and propionyl-CoA metabolized the transcription activator (PrpR), decreased intracellular reactive oxygen species levels, and improved cell viability. The AD yield of MSP-fA5C87A-VP/ΔfA5 was 2.541 g/L, an increase of 16.83% over the control strain. Using a repeated batch fermentation process, the production efficiency of the MSP-fA5C87A-VP/ΔfA5 strain was 0.658 g/L/d, which was 1.82 times higher than that of the control strain. These findings provide a theoretical basis for understanding and regulating steroid side-chain catabolism in Mycolicibacterium and offer support for the rational modification of industrial strains for steroidal drug precursor production. Full article
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17 pages, 3044 KiB  
Article
Effects of Eurotium cristatum Fermentation on Tartary Buckwheat Leaf Tea: Sensory Analysis, Volatile Compounds, Non-Volatile Profile and Antioxidant Activity
by Liangzhen Jiang, Xiao Han, Luo Wang, Haonan Zheng, Gen Ma, Xiao Wang, Yuanmou Tang, Xiaoqin Zheng, Changying Liu, Yan Wan and Dabing Xiang
Fermentation 2024, 10(7), 369; https://doi.org/10.3390/fermentation10070369 - 19 Jul 2024
Cited by 1 | Viewed by 1408
Abstract
Background: Eurotium cristatum (E. cristatum) is the probiotic fungus in Fu-brick tea, with which fermentation brings a unique flavor and taste and health-promoting effects. Tartary buckwheat leaves are rich in functional active substances such as flavonoids and phenolic compounds, yet are [...] Read more.
Background: Eurotium cristatum (E. cristatum) is the probiotic fungus in Fu-brick tea, with which fermentation brings a unique flavor and taste and health-promoting effects. Tartary buckwheat leaves are rich in functional active substances such as flavonoids and phenolic compounds, yet are not effectively utilized. Methods: Tartary buckwheat leaves were processed into raw green tea first and subsequently fermented with E. cristatum to develop a novel fermented leaf tea. The tea quality was evaluated by the aspects of the sensory scores by E-tongue, the volatile compounds by HS-SPME-GC-MS, the non-volatile profile by biochemical and UPLC-MS/MS methods and the antioxidant activity by the colorimetric assay. Results: Fermented leaf tea displayed a golden yellow color, a unique “flower” aroma and a dark-tea taste, with an improved sensory acceptability. Fermentation raised the content of volatile heterocyclic and aromatic compounds, alkenes and other aromatic components, which produced a unique floral flavor. The proportion of sour, bitter and astringency accounting non-volatile compounds such as phenolic acids and amino acids decreased, while the proportion of umami and sweet accounting substances such as responsible amino acids increased. Fermented leaf tea displayed a relative stronger total antioxidant activity against ABTS. Conclusion: E. cristatum fermentation exerted positive effects on Tartary buckwheat leaf tea quality. Full article
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Review

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16 pages, 1114 KiB  
Review
Advances and Challenges in Biomanufacturing of Glycosylation of Natural Products
by Shunyang Hu, Bangxu Wang, Liang Pei, Jisheng Wang, Ya Gan, Liangzhen Jiang, Bingliang Liu, Jie Cheng and Wei Li
Fermentation 2024, 10(7), 349; https://doi.org/10.3390/fermentation10070349 - 9 Jul 2024
Cited by 2 | Viewed by 2883
Abstract
Glycosylation is one of the most common and important modifications in natural products (NPs), which can alter the biological activities and properties of NPs, effectively increase structural diversity, and improve pharmacological activities. The biosynthesis of glycosylation in natural products involves multiple complex biological [...] Read more.
Glycosylation is one of the most common and important modifications in natural products (NPs), which can alter the biological activities and properties of NPs, effectively increase structural diversity, and improve pharmacological activities. The biosynthesis of glycosylation in natural products involves multiple complex biological processes, which are coordinated by many enzymes. UDP-glycosyltransferases (UGTs) play a crucial role in glycosylation modification, and have attracted long-term and widespread research attention. UGTs can catalyze the O-, C-, S-, and N-glycosylation of different substrates, producing a variety of glycosides with broad biological activity, while improving the solubility, stability, bioavailability, pharmacological activity, and other functions of NPs. In recent years, the rapid development of synthetic biology and advanced manufacturing technologies, especially the widespread application of artificial intelligence in the field of synthetic biology, has led to a series of new discoveries in the biosynthesis of NP glycosides by UGT. This work summarizes the latest progress and challenges in the field of NP glycosylation, covering the research results and potential applications of glycosylated derivatives of terpenes, flavonoids, polyphenols, aromatic compounds, and other compounds in terms of biogenesis. Looking to the future, research may leverage artificial intelligence-driven synthetic biology techniques to decipher genes related to the synthetic pathway, which is expected to further promote the large-scale synthesis and application of glycosylated NPs, and increase the diversity of NPs in the pharmaceutical, functional food, and cosmetic industries. Full article
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