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Frances Arnold, one of the founders of enzyme directed catalytic technology, won the Nobel Prize in Chemistry in October 2018.

Enzyme is a highly efficient, specific, mild, environmentally friendly catalyst. Traditional production and bioenzyme catalytic production generally result in longer processes, lower efficiency, faster equipment depreciation due to extreme reaction conditions, and greater worker health impact.

In the case of cephalosporin antibiotics, 13 steps of chemical synthesis were required before, and now only 2 steps of enzyme catalysis, and the latter is more environmentally friendly and safer, and the cost is only half of the former.

The difference between cephalosporin in chemical synthesis and enzyme-catalyzed synthesis (Source: Probe Capital)

Global Enzymes CompaniesNovozymes 2017 Financial Reporting Data Show that the global market for enzyme preparations in 2017 was 30.3 billion Danish kroner (about 4.584 billion US dollars). In 2008-2017, the global compound preparation market has a compound growth rate of 7.34%. Based on this growth rate, the global enzyme market is expected to be US$5.282 billion in 2019.

Source: “Probe Capital: Bioenzyme Industry Research 2019” Source: Industry Experts

From the application field, food and beverage, biofuels and detergents are the three main categories. Although the food industry and the washing industry add up to nearly half of the market segment, thisThe application of enzymes in these fields is relatively mature, and market demand is approaching saturation. At the same time, the application of enzymes in the pharmaceutical, chemical and environmental management industries started late and there is room for growth.

In addition, the above statistics are market data derived from the existing enzyme preparations in the market, but there are still more potential areas (such as the demand for specific enzymes in the fine chemical market), can be passed through the original enzyme The invention was developed as an application scenario for enzymes.

The current stage of development of biological enzyme preparations in various fields (Source: Yaodu)

Combined with The Environmental Protection Tax Law of the People’s Republic of China, the Water Pollution Prevention Act, and Safety Insurance, Sinopec issued the “Environmental Protection White Paper”, we can also see that China’s industrial production needs to evolve toward green and safe. 2016 State Council promulgated ““13th Five-Year” National Strategic Emerging Industry Development Plan It is also proposed to launch exhibition microbial genome engineering, enzyme molecular machines, cell factories and other new technologies, push dynamic cleaning biological processing methods, < Strong> “To accelerate the bio-economy into an important new economic form after the information economy, and provide new support for the construction of healthy China and beautiful China” slogan.

It should be noted that the low-end market in the enzyme preparation industry has weaker bargaining power and higher product repeatability. In the high-end market, enterprises mostly develop enzymes for customers on demand, so the bargaining power is higher. In foreign markets, companies with higher development have Novozymes, Dupont, Codexis< /a>etc. Domestic Azure Bio, Essentials are also exploring.

“Ningbo Enzyme Bioengineering Co., Ltd. (hereinafter referred to as “Enzyme Race”) is also recently contacted , a company that provides protein engineering and bio-enzyme catalyzed solutions. It has cooperated with many global pharmaceutical companies/chemical companies.

The main profit model is that after clarifying the customer’s industrial needs, Enzymes will develop the corresponding enzymes, and the research and development costs will be shared with the customers, but after the products enter the market, they will receive the profit share of the sales. The share ratio will be linked to the proportion of expenses incurred during the development phase. At the same time, enzyme racing organisms also have pure research and development and product sales services.

Bong Yong Koy, chairman of Enzymes, said that before the Chinese industry, the understanding of enzymes was relatively shallow, and enzyme catalysis was rarely used in pharmaceuticals, fine chemicals, materials and other fields. Even if a company realizes the advantages of bio-enzyme catalysis, it is difficult to find a suitable enzyme species.

After seeing this market gap and pain point, Huang Yong decided to come to China to start a business, that is, to create a company focused on the evolution of enzymes, mainly for domestic pharmaceutical, food, fine chemicals, materials, and other industries.

A brief introduction of “Enzyme directed evolution” technology. The directed evolution of enzymes is the process of simulating natural selection, allowing proteins or nucleic acids to evolve in the direction of the target, and ultimately obtaining enzymes that meet production requirements. Frances Arnold, one of the founders of the technology, won the Nobel Prize in Chemistry in October 2018.

Enzyme directed evolutionary process: 1. Introduce a random mutation into the gene (DNA) of the enzyme to be altered; 2. These genes are inserted into the bacterium. . Bacteria use this as a template to produce enzymes that are randomly mutated;3. By testing these altered enzymes, those enzymes that exhibit the highest catalytic efficiency for the target chemical reaction are selected. Out, bad enzymes are discarded (4. New random mutations are introduced into the genes of the selected enzymes. This cycle starts again.

(Source: Nobel Prize Website)

The enzyme racing organism has developed its own directed evolution platform BioEngine® through independent research and development, which can create non-naturally existing enzymes “from scratch”. The workflow is:

• After clarifying production requirements, the need to analyze chemical structures, the platform then builds a specific base enzyme library based on known protein functions and computer recommendations.

• After the basic enzyme library is created, the researchers select sites for gene mutation and recombination, and then pass high-throughput screening to obtain sex.After relatively good enzyme species, the gene mutation and recombination are performed again, and the cycle is repeated until an optimal enzyme that satisfies the industrialization level is obtained. Among them, the optimal enzyme in the case has evolved to achieve 40 residue mutations.

Enzyme Directed Evolution Platform BioEngine® Workflow (Source: Enzyme Race)

The platform can support the simultaneous evolution of six enzyme species. Since the algorithm, software, hardware, and process are designed from the perspective of directed evolution, the enzyme engineering constructed by this platform is 50% shorter than the traditional protein engineering cycle. Normal 1 year, fast for half a year, slow for one and a half years, can achieve the creation of an enzyme species from scratch.

In addition, Enzymes also built a 2,900-square-meter R&D center and a 1,400-square-meter fermentation plant, and the pilot production phase was handed over to the cooperative factory to construct an industrialized enzyme platform. Combined with the BioEngine® platform, the company is able to offer its customers a complete solution for the development of enzymes to industrialization.

Huang Yong Kai pointed out that in terms of patents, it is now publicly available: Enzyme competition has obtained 1 patent authorization, 6 patents are being declared, and 4 PCT applications and 2 System software copyright.

In terms of revenue, enzymes are mainly earned through three sections: R&D services, product operations, and trade products. Beginning next year, after the first customer’s products are introduced to the market, product operating revenue will grow rapidly, which will become the focus of future revenue and profit growth.

In addition, the enzyme competition has also established four wholly-owned subsidiaries: Enzyme Racing Germany, Enzyme Racing Singapore, Ningbo Birman Pharmaceutical Technology Co., Ltd. and Ninghai Lanshuai Bioengineering Co., Ltd. to meet the company’s overseas market. Development, external sales and manufacturing needs.

Core team:

• Chairman Huang Yongkai, Ph.D., Ph.D., National University of Singapore, Served as Director of Codexis Singapore R&D Center, Deputy Director of Merck (Singapore), Teaching Guide of National University of Singapore , led team to develop more than 100 enzymes of Merck, Novartis and other giants project, applied for 14 international patents.

• President Lu Zhenlin, former general manager of Ningbo Madison Medical Technology Co., Ltd. , has many years of experience in the production, sales and trade of intermediates and drugs.

• Executive Vice President Thomas Daussmann, Ph.D. in Microbiology, Kaiserslautern University, Germany, former Executive Officer of Codexis USA, Vice President and General Manager of Singapore R&D Center, General Manager of Jülich Fine Chemicals (In 2005, the company was acquired by Codexis and joined the latter management team); earlier, he was the director of research and development at Juelich Enzyme Products.

• Chen Haibin, Vice President of R&D, Ph.D., Ph.D., Chemical and Molecular Bioengineering, National University of Singapore, Scientific at the Codexis Singapore R&D Center, formerly Nine And Nord’s senior researcher.

Before, Enzymes also received the A round of financing from Dachen Venture Capital and Oriental Fuhai in 2017. At present, Enzyme Racing is further upgrading its technology platform and opening up the market.

Globally, American company Codexis is the “leader” in the field. With CodeEvolver technology platform, it develops and produces highly optimized proteins to meet the needs of the food industry, bio-pharmaceuticals, fine chemicals and other fields. It has established cooperative relations with pharmaceutical companies such as Novartis, GSK and Merck. The company was listed on NASDAQ in 2010 (NASDAQ: CDXS), with a market capitalization of approximately $1.02 billion in early August 2019.

So, as the demand for the industry rises, whether there will be biotech companies of the same type in China is worth watching.