Fermentation: The Natural Way to Produce Amino Acids

Amino acids are the building blocks of proteins and are responsible for maintaining normal physiological processes in organisms. From human muscle development and immune systems to plant photosynthesis and animal reproduction, amino acids are a necessity for almost every stage of life. As more people become interested in health and nutrition, the demand for amino acids is increasing. The technology of fermentation as an all-natural and efficient production technique has demonstrated huge promise in amino acid manufacturing. This environmentally friendly, sustainable production technology is a proven solution for the amino acid market, and it helps other industries become greener, healthier and more efficient.

Amino Acid Fermentation

The traditional approaches to the production of amino acids can be divided into two broad categories. The first consists in separating amino acids from organic proteins, like cystine extracted from keratin-laden fibres such as hair and hooves. But the process is constrained by poor extraction, high costs and scarcity. The second approach is chemical synthesis, which can yield greater quantities but involves harsh reaction conditions, high environmental pollution, and inability to purify the product. Consequently, scientists and industry have been trying to find a more cost-effective, sustainable and environmentally friendly amino acid manufacturing process. The production of amino acids through fermentation has been a promising alternative, using microbial metabolic processes in the right conditions to make simple nutrients into amino acids. This solution comes with several benefits, such as plentiful raw materials, predictable production, and excellent product quality that reflects today's ecological and sustainable development imperatives.

During the fermentation process, all amino acids are synthesized from intermediates of glycolysis, the pentose phosphate pathway, or the citric acid cycle. Humans can synthesize 11 of the 20 amino acids, referred to as non-essential amino acids. Interestingly, many wild-type microorganisms, such as wild-type Escherichia coli, can produce all 20 amino acids from a single carbon source. Unfortunately, wild-type microbes possess metabolic regulation systems that prevent overproduction of amino acids. To achieve high efficiency in the industrial production of target amino acids, modern biotechnology employs various strategies to modify microbial strains. For example, recombinant DNA technology is used to amplify the biosynthetic enzymes for specific amino acids, thereby boosting production. Additionally, introducing suitable surfactants into the culture medium can promote overproduction of certain amino acids, further enhancing yields.

Amino Acid Fermentation Pathway

The fundamental principle of amino acid fermentation involves utilizing the metabolic mechanisms of microorganisms to convert carbon sources, nitrogen sources, and other nutrients into amino acids under specific environmental conditions. During growth and reproduction, microorganisms carry out a series of complex enzyme-catalyzed reactions, breaking down simple carbon sources such as sugars and organic acids into intermediate products. Simultaneously, they utilize nitrogen sources to provide nitrogen atoms, ultimately synthesizing amino acids. Different amino acids are produced via distinct fermentation pathways. Below are some common amino acid fermentation pathways:

• Glutamic Acid Fermentation

Glutamic acid, an essential amino acid for humans, finds widespread applications in the food and pharmaceutical industries. Its fermentation primarily involves microorganisms such as Corynebacterium glutamicum. In the fermentation process, carbon sources such as glucose are initially metabolized through the glycolysis and tricarboxylic acid (TCA) cycle pathways to produce intermediates like α-ketoglutarate. Under the catalysis of glutamate dehydrogenase, α-ketoglutarate accepts an amino group to form glutamic acid. Additionally, glutamic acid can be further converted into other amino acids, such as alanine and aspartic acid, through transamination. The key to efficient glutamic acid fermentation lies in controlling the fermentation conditions to channel the microorganism's metabolism primarily toward glutamic acid synthesis, thereby increasing its yield and accumulation.

• Lysine Fermentation

Lysine is an important essential amino acid with significant demand in the feed and food industries. Its fermentation is also primarily carried out using bacteria such as Corynebacterium glutamicum. The lysine fermentation pathway shares similarities with glutamic acid fermentation but also exhibits unique characteristics. During the fermentation process, α-ketoglutarate is first converted into homoserine, which, under the action of lysine synthase, accepts an amino group to form lysine. To enhance lysine production, it is crucial to regulate the microbial metabolic pathways, suppress the synthesis of other amino acids, and redirect more carbon and nitrogen sources toward lysine synthesis. Furthermore, optimizing fermentation conditions, such as adjusting the composition of the culture medium, controlling fermentation temperature, and pH levels, is essential for promoting lysine synthesis and accumulation.

• Threonine Fermentation

Threonine is another essential amino acid with significant applications in the food, pharmaceutical, and feed industries. Threonine fermentation primarily employs bacteria such as Corynebacterium threoninegenum. Its fermentation pathway is more complex and involves multiple enzyme-catalyzed reactions. During the process, α-ketoglutarate is first converted into homoserine, which is then methylated under the action of threonine synthase to produce threonine. The critical factors for threonine fermentation include enhancing the activity of threonine synthase and optimizing fermentation conditions to direct the microbial metabolism predominantly toward threonine synthesis, thereby increasing its yield. Additionally, genetic engineering techniques can be employed to modify microbial metabolic pathways, enhancing their ability to synthesize threonine.

Amino Acid Fermentation Process

The process of fermenting amino acids mainly includes several key stages: raw material preparation, strain selection and cultivation, fermentation process control, and product extraction and purification. Each of these steps plays a crucial role in determining the final amino acid product's quality and yield.

• Raw Material Preparation

Raw materials are the foundation of amino acid fermentation, primarily consisting of carbon sources, nitrogen sources, inorganic salts, and growth factors. Carbon sources serve as the main energy material for microbial growth and metabolism, with common examples being glucose, sucrose, and starch. Different amino acid fermentations have varying carbon source requirements. For example, glucose is the primary carbon source in glutamic acid fermentation, while sucrose is also an effective carbon source in lysine fermentation. Nitrogen sources, such as ammonium salts, urea, and peptone, supply the nitrogen atoms necessary for amino acid synthesis. Inorganic salts like phosphate and sulfate provide essential ions for microbial growth, maintaining cell osmotic pressure and enzyme activity. Growth factors, including vitamins and amino acids, are sometimes synthesized by microorganisms but can be supplemented during fermentation to promote microbial growth and metabolism, thus increasing amino acid production. During raw material preparation, various nutrients should be carefully selected and proportioned according to the specific fermentation process and the microbial nutritional needs. Additionally, raw materials may require pre-treatment, such as saccharification of carbon sources and sterilization of nitrogen sources, to ensure their quality and stability. To reduce production costs, cheaper raw materials like corn starch and molasses can be utilized, properly treated and converted to suitable carbon sources for fermentation.

• Strain Selection and Cultivation

The selection of a high-quality strain is one of the most important factors in amino acid fermentation. Strain development typically includes natural selection, mutagenesis breeding, and genetic engineering. Natural selection involves isolating microorganisms from nature that have the ability to synthesize amino acids, followed by domestication and cultivation to adapt them to the fermentation environment. Mutagenesis breeding involves treating microorganisms with physical or chemical mutagens and then screening for high-yield amino acid-producing mutants. Genetic engineering involves using gene manipulation techniques to introduce genes related to amino acid synthesis into host microorganisms or modifying the host's own genes to enhance amino acid production.

Strain selection for fermentation must meet specific amino acid production requirements. Combining various breeding methods is often necessary to optimize and improve strains. For instance, in glutamic acid fermentation, a combination of mutagenesis breeding and genetic engineering has successfully developed mutant strains of Corynebacterium glutamicum that produce several times more glutamic acid than wild-type strains. Additionally, strict preservation and rejuvenation techniques should be applied to maintain the stability of the selected strains' genetic traits and fermentation performance.

• Fermentation Process Control

The control of the fermentation process is the core of amino acid production and involves regulating parameters such as temperature, pH, oxygen concentration, and stirring speed. Temperature is a critical factor affecting microbial growth and metabolism. Different microorganisms and amino acid fermentation processes have specific temperature requirements. Generally, amino acid fermentation is conducted at temperatures between 30-37 °C. Too high or too low a temperature can hinder microbial growth and metabolism, leading to reduced amino acid yield. pH is another key factor affecting enzyme activity and microbial growth during fermentation. Different amino acid fermentations require different pH levels. For example, the pH for glutamic acid fermentation is typically maintained between 7.0 and 7.5, while lysine fermentation requires a pH range of 7.5-8.0. pH adjustments during fermentation are made by adding acids or bases to maintain the appropriate range. Oxygen concentration is essential for aerobic fermentation, as it promotes microbial growth and amino acid synthesis. Sufficient oxygen supply is ensured by controlling stirring speed and aeration. Stirring also helps improve nutrient distribution and fermentation efficiency.

• Product Extraction and Purification

Once fermentation is complete, the amino acids in the fermentation broth need to be extracted and purified to obtain high-purity products. Common extraction methods include ion exchange, solvent extraction, and crystallization. Ion exchange uses the ion properties of amino acids to separate them from the fermentation broth via ion exchange resins. Solvent extraction exploits the solubility differences of amino acids in various solvents to isolate them using organic solvents. Crystallization involves controlling the concentration and temperature of the fermentation broth to allow amino acids to crystallize, which are then separated from the remaining liquid by centrifugation or filtration. Extraction methods must be chosen based on the properties of the amino acid and the nature of the fermentation broth. Parameters should be optimized to improve extraction yield and purity. For instance, in glutamic acid extraction, ion exchange methods are commonly used to achieve extraction yields above 90% by optimizing factors such as resin type, flow rate, and temperature. After extraction, the crude amino acid product undergoes further purification to remove impurities and residual microorganisms. Common purification techniques include refined crystallization and chromatography. Refined crystallization enhances purity through multiple crystallization steps, while chromatography separates amino acids from other impurities based on differences in migration speed. These purification methods can increase amino acid purity to over 99%, meeting the purity requirements for various applications in food, pharmaceuticals, and other industries.

Fermented Amino Acid Benefits

• Reduced Pollution: The fermentation process primarily utilizes microbial metabolic activities, leading to significantly lower waste water, waste gas, and waste residue generation compared to chemical synthesis methods.
• Resource Utilization of Waste: The residue from fermentation contains microbial biomass and unused nutrients, which can be converted into organic fertilizers, achieving a circular use of waste.
• Mild Process: Compared to chemical methods, which are energy-intensive and highly polluting, fermentation takes place under mild conditions, at low temperatures, and with minimal environmental impact.
• High Purity: The main metabolic product of fermentation is amino acids, which have a low impurity content and high purity, meeting safety standards required in the food and pharmaceutical industries.
• No Pollution Risks: The fermentation process is conducted under strict sterile conditions, effectively preventing the introduction of harmful substances.
• Avoidance of Harmful Residues: Fermentation avoids the potential heavy metal ions or organic solvent residues that may occur during chemical synthesis, making it more suitable for applications that require high safety standards.
• Inexpensive Raw Materials: The primary raw materials used in fermentation are carbon and nitrogen sources, which are abundant and have stable prices.
• Diverse Production: Fermentation can produce a wide range of amino acids, and customized production can be achieved by optimizing fermentation conditions.
• Technological Scalability: With the advancement of biotechnology, there is still room for improvement in fermentation efficiency and cost reduction, offering vast prospects for future industrial development.

Amino Acid Fermentation Products

Fermentation can currently produce a variety of important amino acids. Common examples include glutamic acid for monosodium glutamate (MSG) production, lysine and threonine for animal feed, and phenylalanine and tryptophan as ingredients in food and pharmaceuticals. Additionally, branched-chain amino acids like valine, leucine, and isoleucine are widely used in sports nutrition and medicine, while histidine plays a key role in the pharmaceutical and food industries. By optimizing microbial strains and fermentation processes, amino acids such as arginine and proline can also be produced efficiently, facilitating their broad applications in medicine, food, and agriculture. Based on this, BOC Sciences specializes in amino acid fermentation production services, offering high-efficiency and sustainable solutions using advanced microbial technologies and optimized fermentation processes. The company provides customized services and can develop and produce a range of amino acids, including glutamic acid, lysine, tryptophan, and more, according to customer requirements. With a professional team and a strict quality control system, BOC Sciences ensures product purity and stability, serving industries such as food, feed, pharmaceuticals, and others, helping customers achieve innovation and sustainable development goals.

What are Amino Acids Used For?

From an economic perspective, the raw materials used in fermentation are primarily inexpensive substances such as carbon and nitrogen sources, which are widely available and relatively stable in price. Moreover, the fermentation process is relatively simple, easy to control, and efficient, enabling large-scale industrial production. Additionally, fermentation processes can be optimized by improving fermentation conditions and microbial strain performance, further reducing production costs and enhancing economic benefits. As a result, high-purity amino acids produced by fermentation can be directly used in high-value sectors such as food and pharmaceuticals.

• Food Industry

• Flavoring Production: Glutamic acid is the main component of monosodium glutamate (MSG). The glutamic acid produced by fermentation can be further processed into MSG, which is widely used in food flavoring to enhance the umami taste of food. Other amino acids such as aspartic acid and glycine can also be used to produce compound seasonings to meet the flavor needs of different foods.
• Nutritional Supplements: Essential amino acids such as lysine and methionine, produced by fermentation, can be added to foods, particularly infant food, food for the elderly, and sports nutrition foods, to supplement the body's nutritional requirements and enhance the nutritional value of the food.
• Functional Food Development: Some amino acids have specific physiological functions, such as arginine, which promotes growth hormone secretion and enhances immune function. These amino acids, produced through fermentation, can be used to develop functional foods to meet consumer demand for health products.

• Feed Industry

• Enhancing Feed Nutritional Value: Adding amino acids produced by fermentation to animal feed can balance the amino acid composition, improving the nutritional value and utilization rate of the feed, promoting animal growth and development. For example, lysine and threonine are common limiting amino acids in pig and poultry feed. Adding these amino acids produced by fermentation can significantly improve feed conversion rates and reduce feed costs.
• Improving Animal Health and Production Performance: Some amino acids, such as tryptophan and valine, not only provide nutrition but also help regulate animal physiological functions. When these amino acids, produced by fermentation, are added to feed, they can improve animal health, enhance immunity, and increase disease resistance, thus boosting production performance and farming efficiency.

• Pharmaceutical Industry

• Raw Materials for Drug Synthesis: Many amino acids are important raw materials for the synthesis of pharmaceutical drugs. High-purity amino acids produced by fermentation can be used to synthesize a variety of amino acid-based drugs, such as amino acid injection solutions and oral solutions, used to treat malnutrition, liver diseases, kidney diseases, and more, meeting the demands of the pharmaceutical market.
• Biopharmaceuticals: In the biopharmaceutical field, amino acids produced by fermentation can be used to culture microorganisms or cells to produce recombinant protein drugs, vaccines, and other biologics. For instance, tryptophan produced by fermentation can be used to cultivate microorganisms such as E. coli for the expression and production of recombinant protein drugs like insulin.

• Cosmetics Industry

• Moisturizing and Repairing Functions: Some amino acids, such as glycine and alanine, have excellent moisturizing properties and can be used as moisturizers in cosmetics to retain skin moisture and alleviate dry skin. Additionally, certain amino acids have skin barrier-repairing and skin cell regeneration functions, making them suitable for developing repair-based cosmetics, such as amino acid masks and serums.
• Antioxidant and Whitening Effects: Some amino acids and their derivatives possess antioxidant and whitening effects. They can eliminate free radicals, inhibit melanin production, and reduce skin discoloration and wrinkles. Amino acids produced by fermentation can be used to produce antioxidant and whitening cosmetics, catering to consumers' needs for beauty and skincare products.

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