D Mannose: What Is It Made From?

Since the research boom on proteins and nucleic acids in the early 20th century, the study of carbohydrates has experienced rapid development. In the 1960s, scientific research on carbohydrates could be categorized into three fields: carbohydrate chemistry, carbohydrate biology, and carbohydrate engineering [1]. As carbohydrate research has deepened, our understanding of carbohydrates has also continued to evolve. For example, researchers have utilized the chemical properties of sugars to synthesize various sugar derivatives, and the understanding of sugar functions has evolved from their role as carbon sources to a range of biological functions [1,2]. Additionally, in-depth studies have revealed that polysaccharides with multiple biological activities all contain D-mannose as a component, and subsequent reports have confirmed that D-mannose possesses various physiological activities.

D mannose is widely distributed in nature, with polysaccharides containing D-mannose units present in large quantities in plant cell walls and oligosaccharides, and free D-mannose is also found in some fruit peels [1,2]. Therefore, D-mannose can be prepared by extracting and purifying plant polysaccharides to obtain a pure product. Additionally, D-mannose can be synthesized chemically or through bioconversion methods. Currently, major domestic and international producers of D-mannose include Nanjing Reagent Co., Ltd., Hubei Jusheng Technology Co., Ltd., BioTech Pharmacal-Inc., Source Naturals, and NOW Foods. As a natural active monosaccharide, D-mannose has been widely used as a carbohydrate nutrient to address diseases such as diabetes and obesity. Additionally, D-mannose possesses anti-inflammatory and immune-modulating functions. In the human body, D-mannose is abundantly present in body fluids and tissue fluids, though it is not easily metabolized by the human body. However, it plays a significant role in immune regulation and glycoprotein synthesis [2,3]. Additionally, D-mannose is commonly used as a sweetener in the food industry, as a medication to prevent urinary tract infections in medicine, to prevent Salmonella infection in broiler chickens and increase egg production in animal husbandry, and in chemical synthesis to produce trifluoromannose and L-ribose derivatives [4].

1. Research Progress on the Preparation Technology of D-Mannose

The main methods for preparing D-mannose include extraction, chemical synthesis, and biological methods. Extraction is a commonly used method for preparing D-mannose, which involves hydrolyzing and separating plant polysaccharides and oligosaccharides to obtain D-mannose. This method requires a large amount of plant material and is influenced by geographical and seasonal factors. Chemical synthesis involves converting D-glucose through isomerization or extending the carbon chain of D-arabinose. Chemical methods are diverse and described in various literature, but they involve complex production processes and high costs. The biological method utilizes microbial fermentation or certain isomerases to convert monosaccharides or polysaccharides into D-mannose. This method has advantages such as mild reaction conditions and low cost. However, the reported isomerases used in current studies have low catalytic efficiency, and the products may contain a significant amount of by-products [4].

1.1 Extraction Method

1.1.1 Extraction Using Coffee Grounds as Raw Material

Coffee grounds are a byproduct of instant coffee production and contain abundant polysaccharides, primarily mannan oligosaccharides. Research indicates that mannan oligosaccharides can be hydrolyzed to D-mannose, which can further be reduced to mannanol, both of which play important roles as food additives [5].

At the end of the 20th century, Sun Zhongliang et al. [6] conducted preliminary studies on the hydrolysis process of mannan oligosaccharides. By adding acid, pressure, and setting a specific temperature, they hydrolyzed mannan oligosaccharides and found that a tubular reactor achieved the best hydrolysis effect at high temperatures and short reaction times. The reaction product solution was light brown in color, facilitating separation and purification. At the beginning of the 21st century, Huang Guangmin et al. [7,8] conducted process research on the production of D-mannose from coffee grounds using an acid hydrolysis method. Under conditions of sulfuric acid concentration of 1.5 mol/L to 3.0 mol/L, temperature of 100°C to 130°C, and reaction time of 80 minutes to 120 minutes, the yield of D-mannose in the hydrolysis solution was 28% to 30%. After subsequent steps including decolorization, evaporation concentration, crystallization separation, and drying, pure D-mannose was obtained. In 2015, Pei Jun et al. [9] invented a method for extracting high-purity D-mannose from coffee grounds. This method facilitates product separation during preparation, with a yield exceeding 60% and purity exceeding 98%, and the process is simple and cost-effective, making it suitable for industrial production.

1.1.2 Extraction using palm seeds as raw material

Palm trees are abundantly found in southern provinces of China and belong to the palm family. The leaves, flowers, roots, and bark of palm trees are all used in traditional medicine. In the 1980s, Fang Jinian et al. [10] referenced the degradation conditions of bamboo polysaccharides and other materials. They added 80% concentrated sulfuric acid to crushed palm tree seeds, diluted the sulfuric acid concentration to 2N, and refluxed at 100°C for 5–6 hours. After separation, concentration, crystallization, purification, and drying, D-mannose was obtained with a yield of 30%. Subsequently, Pan Ziguo [1] from Zhejiang University further studied the extraction and purification process of D-mannitol based on this method. Using palm tree seeds as the raw material, the liquid containing D-mannitol was extracted through acid hydrolysis, alkali neutralization, and enzymatic reaction. The liquid was then decolorized with activated carbon, concentrated, and separated using silica gel. The liquid containing pure D-mannitol was desalted using ion exchange resin, Finally, D-mannitol crystals were crystallized, with a crystallization yield of 86.7% and a total yield of 48.4%. This method improved product yield, reduced production costs, and minimized pollution, providing essential foundational data for the industrial-scale production of the target product and the extraction, separation, and purification of intermediate liquids.

1.2 Chemical Synthesis Method

The commonly used chemical synthesis method for preparing D-mannose involves using chemical reagents to induce a differential isomerization reaction in glucose. However, this method requires strict control of acid concentration and temperature during processing. In 1975, Takemura [11] described a patent method using molybdic acid as a catalyst, heating a D-glucose solution at temperatures of 110°C to 160°C and pH of 2.3 to 4.5, which converted part of the glucose into D-mannose with a yield of 30% to 36%. Due to the low yield and impurity content of the product, this method is not suitable for large-scale production. pH 2.3–4.5. Due to the instability of molybdic acid, in 2003, Liu Chunyan [12] hydrolyzed sucrose (T = 100°C, pH = 2.0) for 2 hours, yielding 50% D-glucose and 50% D-fructose. The mixture was then heated with 0.15% (NH₄)₂MoO₄ (pH = 3.0) at 100°C for 2 hours, resulting in a D-mannose yield of 30%. Subsequently, Zhao Guanghui et al. [13] used 1% (NH₄)₂MoO₄ (pH = 3.0) to catalyze the reaction at 150°C for 2 hours, achieving a maximum glucose conversion rate of 32.3%. The chemical synthesis method for preparing D-mannose has low yield and is operationally cumbersome, making it suitable only for small-scale laboratory preparation.

1.3 Biological Method

1.3.1 Biological Fermentation Method

There are two methods for producing D-mannose using biological methods: biological fermentation and biological conversion. The biological fermentation method involves fermenting polysaccharides or monosaccharides using microorganisms to obtain D-mannose, with numerous literature reports available. In a 2007 literature review by Hu Zhaohui et al. [14], it was noted that mannose proteins can be easily obtained from yeast through enzymatic hydrolysis or heating at high temperatures. Subsequently, Yang B et al. [15] found that the monosaccharide composition of SSLO (where xylose and mannose constitute the SSLO molecular chain) in soy sauce residue differs from that of oligosaccharides in soybeans, suggesting that D-mannose may be derived from microbial fermentation. In 2013, Charchoghlyan H et al. [16] isolated a bacterial strain named M. chitosanitabida from soil, which, upon hydrolysis of EPS, produced high levels of extracellular polysaccharides (ESP) composed of glucose, mannose, and galactose (molecular weight ratio 18:6:1). This indicates that obtaining free D-mannose through microbial fermentation is not straightforward.

1.3.2    Bioconversion method

Bioconversion is a method that uses enzymatic reactions to convert fructose or glucose into D-mannose under mild temperature, pressure, and pH conditions. The enzymes involved in these enzymatic reactions include D-mannose isomerase, cellobiose isomerase, and D-lyxose isomerase, which are widely available. According to reports, D-mannose isomerase from Bacillus subtilis M-1 converts approximately 25% of fructose into D-galactose when the pH is 8.0–8.5 and the fructose concentration increases from 5% to 40% [17]. In 2015, Jiang Bo et al. [18] designed a production process for efficiently converting D-fructose to D-mannose using D-mannose isomerase from Pseudomonas pseudomallei, and applied for a patent (CN201510195854.4). This method is suitable for large-scale production and provides a new approach for the enzymatic industrial preparation of D-mannose. Compared to D-mannose isomerase, cellulose isomerase is the only enzyme capable of converting glucose into D-mannose; however, this enzyme has low conversion efficiency and produces a large amount of byproducts (D-fructose) during the conversion process, making it unsuitable for large-scale industrial production [5]. Additionally, the use of D-lyxose isomerase for D-mannose synthesis has garnered significant attention from researchers. Huang Jiawei et al. [5] synthesized a thermostable D-lactulose isomerase from a heat-resistant microorganism and applied it to D-mannose synthesis. They found that the enzyme exhibited good thermal stability under neutral and weakly alkaline conditions at temperatures of 70°C to 75°C, with Co₂ significantly enhancing enzyme activity, making it suitable for D-lactulose conversion, and also demonstrating good catalytic efficiency toward fructose.

2  Research Progress on the Application of D-Mannitol

2.1    Application of D-Mannitol in the Food Industry

D-mannitol has stable properties, a sweet taste, and low calories, making it commonly used as a sweetener and food additive that can be consumed directly. Currently, the main countries producing food-grade D-mannitol are China and the United States, with products primarily available in capsule or powder form [3]. Adding D-mannose to food can improve texture. Elghaouth et al. [19] demonstrated that inoculating D-mannose into apples nearing spoilage reduced the diameter of rot spots. Yang Bingxun et al. [20] used high-performance liquid chromatography to confirm that D-mannose enhances the immune function beverages.

2.2 Applications of D-mannose in the pharmaceutical industry

Research indicates that D-mannose possesses diverse physiological activities, including enhancing immunity, improving the immune system, and treating common diseases such as diabetes. It is currently the only carbohydrate nutrient used in clinical applications within the pharmaceutical industry. Wang Shuting [21] demonstrated that D-mannose can form polymeric bundles with doxorubicin as a targeted drug, enabling targeted cancer therapy and reducing the toxic side effects of the drug. Ranta [22] used D-mannose as a raw material to prepare an immunostimulant linked to the cell wall mannans of Candida albicans. Kamel [23] synthesized a series of novel Schiff bases using D-mannose as a synthetic intermediate, and demonstrated that these compounds possess antitumor activity. Dengler et al. [24] innovatively utilized D-mannose to improve non-viral gene therapy.

2.3 Applications of D-mannose in the aquaculture industry

Excessive use of antibiotics in aquaculture can lead to the proliferation of drug-resistant bacteria and environmental pollution [25,26]. Van [26] and Zhang Zhaofu [27] et al. demonstrated that D-mannose has an inhibitory effect on Salmonella infection in chicks, with no side effects, and can serve as an alternative to antibiotics for treating Salmonella infections. Berge et al. [28] demonstrated that adding D-mannose to livestock feed inhibits the proliferation of pathogens in the intestine, protects intestinal health, enhances immune and disease resistance, and improves feed utilization.

2.4 Applications of D-mannose in the field of chemical synthesis

D-mannose can be synthesized into various derivatives and plays an important role in clinical applications [29]. Yang Zhi-jie et al. [30] used D-mannose as a starting material and, through acetylation, hydrolysis, and sulfonation, prepared trifluoromannose with a purity of 99%. In nature, the primary structural form of nucleosides is D-ribose, while L-ribose is an isomer of D-ribose. Compared to D-ribose, L-ribose exhibits better antiviral and antitumor activity and lower cytotoxicity [31]. Currently, L-ribose is primarily synthesized chemically, typically using D-mannose as the starting material, which is converted into L-ribose through D-mannose acid-1,4-lactonization [31,32]. Takahashi et al. [32,33] demonstrated that D-mannose can be synthesized into L-ribose through eight steps, including cyclization, under Mitsunobu conditions. Seo et al. [32,34] improved the yield by using D-mannose acid-1,4-lactone as raw material to prepare L-ribose.

2.5 Applications of D-mannose in the cosmetics industry

Aloe vera possesses functions such as sun protection, beauty enhancement, and moisturization [35], with glucuronic acid and β-(1→4)-mannan long-chain polymers being its primary bioactive components [36]. Studies have shown that D-mannose has skin conditioning effects, making the skin softer and smoother after washing [37]. Wivell et al. [38] demonstrated that when the molar ratio of D-glucose, D-glucuronic acid, and D-mannose is 2.8:2.0:2.0, the skin moisturizing and cleansing effects are optimal.

2.6 Applications of D-mannose in biochemical research

Joersbo et al. [39] used D-mannose as a transgenic cell screening agent to screen transformed sugar beets, achieving a germination rate of up to 30% of explants. Additionally, D-mannose-resistant cells were shown to be suitable for primary transgenic rice under various cultivation conditions. Wang et al. [40] found that D-mannose had a good effect on the protoplast transformation of corn in a polyethylene glycol medium.

3 Summary and Outlook

The production process for D-mannose preparation primarily involves extraction methods, which are labor-intensive, susceptible to seasonal and regional variations in raw materials, and prone to environmental damage and pollution. Chemical synthesis is suitable for small-scale laboratory production but not for large-scale industrial production. Biological methods have been a research hotspot in recent years, as they are simple, green, and safe. However, most of the isomerases discovered so far have low catalytic activity, are easily affected by reaction conditions, and can disrupt production processes, while the enzymes themselves are expensive. Therefore, identifying a low-cost isomerase with high catalytic efficiency and stability is a major challenge for current researchers.

The widespread application of D-mannose has created a broad market prospect, especially as it can serve as a substitute for high-calorie sugars and a new food additive, offering significant market application value. In the field of fine chemicals, D-mannose not only reduces costs but also, due to its natural properties and excellent skin care effects, brings significant economic benefits to enterprises. In the pharmaceutical field, drugs modified with D-mannose exhibit significant anti-inflammatory, anti-cancer, and anti-tumor effects, offering promising prospects for future applications in new drug development.

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