Synthetic Biology in the Natural Products Manufacturing

The Role of Natural Products in Drug Development

Natural products have always played a crucial role in drug development. In fact, many important drugs and drug precursors are derived from or inspired by natural products. From 1981 to 2019, a quarter of approved drugs originated from natural products or their derivatives. Natural products find extensive applications in medicine, supplements, cosmetics, fragrances, and more, rendering them immensely valuable in modern pharmaceuticals and related industries. Key drugs like artemisinin, paclitaxel, ginsenosides, morphine, resveratrol, and menthol are all extracted from plants.

Extraction of natural products.Extraction of natural products.

*The List of Natural Products from BOC Sciences

Limitations of Natural Products' Applications

However, traditional methods of plant natural product production face challenges. Limited resources of medicinal plants, harmful harvesting practices, long growth cycles, low levels of active ingredients, complex extraction processes, and high production costs pose significant hurdles. Moreover, chemical synthesis of natural products may encounter issues such as complex reaction processes, low yields, high costs, and environmental pollution. While plant tissue culture is one method to obtain plant natural products, it is characterized by long production cycles, intricate operations, high costs, and is not conducive to large-scale production.

Natural Product Production Based on Synthetic Biology

To overcome the limitations and challenges of natural product production, methods based on the principles of synthetic biology have emerged. By designing and creating microbial cell factories, the production capacity of microorganisms can be utilized to produce plant natural products, thereby reducing reliance on plant resources and achieving green and efficient synthesis. In recent years, synthetic biology has made significant progress, successfully synthesizing many important plant natural products into microorganisms, including artemisinin, paclitaxel, cannabinoids, and scopolamine. Synthetic biology methods can redefine the production of plant natural products, bringing more possibilities to the modern pharmaceutical field, while simultaneously reducing pressure on natural resources and contributing to sustainability. The continuous development of this field will help address the challenges faced by traditional plant natural product production, providing more options for drug development and healthcare.

What is Synthetic Biology?

Synthetic biology was initially proposed by B. Hobom in 1980 to describe genetic engineering techniques. With the development of molecular systems biology, it was reintroduced by E. Kool at the American Chemical Society meeting in 2000. In 2003, it was internationally defined as the study of artificial biological systems based on systems biology principles of genetic engineering and engineering methods. This encompasses the artificial design and synthesis of genes, DNA molecules, gene regulatory networks, and signal transduction pathways to whole cells, resembling modern integrated architectural engineering. It applies engineering principles and methods to biotechnological fields such as genetic engineering and cellular engineering. Synthetic biology, computational biology, and chemical biology together constitute the methodological foundation of systems biotechnology.

Synthetic Biology Cases for Natural Products

Microbial Recombinant Synthesis of Terpenoids

Terpenoids are a diverse group of compounds widely found in nature, with over 80,000 different terpenoids identified, many of which are active ingredients in medicinal plants. These compounds include artemisinin, paclitaxel, ginsenosides, and some carotenoids, which have significant applications in medicine, healthcare, agriculture, cosmetics, and other fields. Taking artemisinin as an example, it is an important antimalarial drug initially discovered from the traditional herb Artemisia annua by scientists including Tu Youyou from the China Academy of Chinese Medical Sciences. Previously, artemisinin was extracted directly from the Artemisia plant, but this method faced challenges of resource limitations and production efficiency. However, through synthetic biology methods, scientists have successfully transferred the production process of artemisinin to yeast. After a decade of research, they achieved fermentation-based production of artemisinin in yeast, with yields as high as 25 g/L, further synthesized through chemical reactions to produce artemisinin. It is estimated that this method can produce 35 tons of artemisinin annually in fermentation facilities of less than 100 cubic meters, equivalent to the cultivation area of nearly 3000 hectares of Artemisia. This work is considered a significant breakthrough in the use of engineered cells for the production of plant-derived natural products.

  • Terpenoid Fragrances

Terpenoid compounds play a significant role in the global fragrance market, being widely utilized in industries such as personal care products, food, and pharmaceuticals. Some important terpenoid compounds, such as santalol, patchouli alcohol, β-ocimene, and rose essential oil, serve as key ingredients in many products. Among these, β-ocimene is an effective anticancer drug extracted from plants of the ginger family. However, the low content and complex composition of β-ocimene from natural sources result in high separation costs. To address this issue, researchers utilized metabolic engineering and synthetic biology techniques to enhance the biosynthetic capability of terpenoids in brewer's yeast and improve product compatibility with the yeast. Subsequently, protein engineering was performed on germacrene A synthase, creating engineered bacteria with high germacrene A production, and a coupled process to thermally convert germacrene A into β-ocimene was successfully developed.

Ginsenosides are important active ingredients in the valuable traditional Chinese medicine, ginseng, and American ginseng, possessing functions such as anti-tumor, blood sugar reduction, and immune promotion. The traditional method of synthesizing ginsenosides involves complex plant extraction processes, which are constrained by issues such as scarce raw materials, high costs, and low production efficiency. However, through synthetic biology methods, researchers have successfully constructed biosynthetic pathways for ginsenosides in microorganisms, achieving efficient synthesis and providing a new feasible approach for ginsenoside production.

  • Triterpenic Acids

Triterpenic acids are a class of high-value active components present in trace amounts in the wax of fruit peels, with various applications including antiviral properties, diabetes control, and skin repair. Traditionally, these compounds are usually obtained through extraction from their respective plants, which can be costly. To achieve efficient fermentation-based production of such pharmacologically active compounds, researchers developed a platform for rapid elucidation of biosynthetic pathways. For the first time, they identified a P450 enzyme, MAA45, capable of catalyzing the conversion of oleanolic acid and ursolic acid into hederagenin and corosolic acid, respectively. Based on this discovery, they created yeast cell factories capable of efficiently producing hederagenin and corosolic acid, achieving yields of 384 mg/L and 141 mg/L, respectively.

  • Carotenoids

Carotenoids have a wide range of applications in the fields of medicine, nutritional supplements, cosmetics, and food, including β-carotene, lycopene, and astaxanthin, among others. Researchers have achieved significant research results by systematically studying the regulatory mechanisms of microbial efficient synthesis of terpenoid compounds. They identified key rate-limiting steps, such as IspG and IspH, and achieved the co-expression of these two enzymes to address the issue of redox imbalance. Additionally, by regulating the expression of carotenoid conversion enzymes, they successfully increased the yield of astaxanthin, with the yield reaching 1.82 g/L in further work.

Paclitaxel is an extremely important anticancer drug. However, its extraction from natural sources is limited by insufficient supply and high production costs. Therefore, scientists have conducted extensive research and have successfully achieved the production of paclitaxel through synthetic biology methods to meet medical needs.

Microbial Recombinant Synthesis of Flavonoids

Flavonoid compounds are a class of secondary metabolites with diverse physiological activities, holding promising prospects for medical and health applications. The biosynthetic pathways of flavonoids are relatively well understood, typically starting from phenylalanine and undergoing a series of enzyme-catalyzed reactions to eventually produce various flavonoid compounds. However, the production of flavonoid compounds usually relies on extraction from plants, which is costly and limited in supply. Therefore, utilizing microbial recombinant synthesis methods for the production of flavonoid compounds has become an important research direction.

Iridoid is a bioactive secondary metabolite commonly found in certain plants such as Lonicera, Scutellaria, and Iris. They play significant roles in medicinal and healthcare fields, exhibiting activities such as anti-inflammatory, antioxidant, and antibacterial properties.

Berberine is a common alkaloid compound found in various plants such as Coptis, Berberis, and Phellodendron. It possesses multiple pharmacological effects including antimicrobial, anti-inflammatory, hypoglycemic, and hypolipidemic activities

Quercetin is a common flavonoid compound widely distributed in many plants such as onions, apples, tea leaves, and tomatoes. It exhibits various biological activities including antioxidant, anti-inflammatory, and anticancer properties, contributing to health benefits.

Microbial Recombinant Synthesis of Phenylpropanoids

Phenylpropanoid compounds represent an important class of natural compounds, encompassing compounds with diverse structures and pharmacological activities. In recent years, significant progress has been made in the field of microbial recombinant synthesis of phenylpropanoid compounds, covering the synthesis of various types of phenylpropanoid compounds.

Gastrodin is a crucial component in traditional Chinese medicine, possessing various pharmacological activities, including its use as an adjunctive treatment for neurasthenia, dizziness, headaches, and epilepsy. However, traditional production methods involving plant extraction and chemical synthesis are costly, and pose challenges for the conservation of wild plant resources like Gastrodia species. To address these issues, researchers have conducted studies on microbial recombinant synthesis of gastrodin.

Salidroside is one of the main active ingredients in traditional Tibetan medicine Rhodiola, exhibiting various biological activities such as anti-hypoxia and anti-fatigue effects. However, traditional methods of salidroside production primarily rely on plant extraction, leading to issues such as scarcity of wild plant resources, low salidroside content, and complex extraction processes, which have hindered its research and application. To overcome these challenges, researchers have conducted studies on microbial recombinant synthesis of salidroside, achieving a series of significant breakthroughs.

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