Lactulose, a disaccharide widely used in pharmaceuticals and functional foods, is produced by lactose isomerization. Lactose and lactulose have an aldose-ketose relationship. Less than 25 % conversion of lactose into lactulose is achieved using the Lobry de Bruyn-Alberda van Ekenstein transformation with heating, whereas the conversion is increased to 80 % by the addition of an approximately equimolar concentration of the organogermanium compound 3-(trihydroxygermyl)propanoic acid (THGP) to the reaction mixture. To further understand this phenomenon, in this study, we analyzed the affinity between THGP and sugar isomers using 1 H nuclear magnetic resonance spectroscopy. For the dimethyl derivative of THGP with lactose and lactulose, the complex formation ratios at 0.1 M (1:1 mixing ratio) were 14 and 59 %, respectively, with complex formation constants of 1.8 and 43 M -1 , respectively. The complex formation capacity was approximately 24-fold higher for lactulose than for lactose. Moreover, THGP is considered to protect lactulose from alkaline degradation, resulting in high production yield of lactulose. Therefore, we concluded that high affinity for the isomerization product may promote isomerization and that promotion of sugar isomerization using an organogermanium compound is an effective method for converting lactose to lactulose.
INTRODUCTIONThe isomerized sugar known as high fructose syrup is a mixture sugar that is manufactured by conversion of half of the content of D-glucose into D-fructose using an enzymatic reaction catalyzed by glucose isomerase. Recently, D-fructose produced by this isomerization reaction has been used not only in sweeteners but also as a promising chemical intermediate from biomass. 1) Therefore, efficient conversion reactions for isomerized sugars are being investigated as a method for increasing the synthesis of such products.During the production of sweeteners, isomerization is generally stopped after conversion of approximately 42 % of the original substrate, to prevent changes in color and breakdown of the components. The reaction solution is then passed through an ion exchange resin, and the fructose content is concentrated to approximately 90 %. This concentrated mixture is then combined with D-glucose, normally yielding a product with 55 % isomerized sugar content. Therefore, improvement in the conversion ratio during the isomerization reaction is critical for the production of isomerized sugar.The reaction equivalent constant of glucose isomerase is approximately 1.0 (isomerization ratio of 50 %) at 60 C, but it increases to 1.348 (isomerization ratio of 57.4 %) at 100 C.2) The polarity of the reaction solvent also affects the isomerization ratio; for example, reaction in 85 % ethanol (v/v) yields an isomerization ratio of 55.9 %.3) However, isomerization at 100 C is not feasible because of inactivation of the enzyme, and reaction in ethanol-containing solutions proceeds only with 6 12 % D-glucose and at a temperature of 30 C. Therefore, neither of these modifications to the standard reaction conditions is effective. Some researchers have attempted to shift the equivalence to D-fructose by using reagents with different affinities for the isomers. For example, sodium borate and germanate (i.e., germanium dioxide) can be used as affinity reagents after solubilization under alkaline conditions. Indeed, addition of borate has been reported to increase the isomerization ratio to 88 %, 4) and addition of germanate has been reported to increase the isomerization ratio to 90 %. 5) However both of these compounds are associated with toxicity; thus, their use is limited.
Lactulose, a keto-type disaccharide widely used in pharmaceuticals and functional foods, is produced by the isomerization of lactose. The organogermanium compound poly-trans-[(2carboxyethyl) germasesquioxane] (Ge-132) is an effective reaction promoter for the conversion of lactose to lactulose because of its high affinity to ketoses. Herein, an effective method for the continuous production of lactulose syrup was developed using Ge-132 through the alkaline isomerization of lactose in a bench-scale plant. This plant carried out a continuous isomerization process using Ge-132, continuous two-step separation process for separating the sugar and Ge-132, a continuous purification and concentration processes for the lactulose syrup, and separation and purification processes for the recovery of Ge-132. In this bench-scale plant, lactulose-containing syrup (350 g/L lactulose, 92 g/L lactose, and 31 g/L galactose) was prepared. The syrup was produced at a rate of 37.7 mL/h, and the content of residual Ge-132 in the syrup was 2 mg/L. The separation process was a two-step separation system requiring an ordinary electrodialyzer and an electro deionizer, which allowed the separation of more than 99.6 % Ge-132 from the reaction mixture. Moreover, the majority of Ge-132 and sodium hydroxide were recovered through electrodialysis using a bipolar membrane. The proposed system is the first to represent the novel development of an effective continuous production system for lactulosecontaining syrup on the basis of the use of organogermanium compounds and incorporation of the electrodialysis technology.
We previously demonstrated that the organogermanium compound 3-(trihydroxygermyl)propanoic acid (THGP) enhances the enzymatic and alkaline isomerization of an aldose to a ketose through cis -diol complex formation by multiple mechanisms. Its higher affinity for the ketose than the aldose protects the ketose complex from alkaline decomposition. Furthermore, it has been reported that the aldose-ketose alkaline isomerization pathway includes 1,2-enediol. Therefore, we speculated that the complex-forming ability of THGP could also be applied to enediol, a transient intermediate of alkaline isomerization. To test this prediction, we analyzed the initial rates of glucose or lactose isomerization in a region where there was no substantial difference in pH with and without THGP addition. The results showed that THGP enhanced the rate of fructose or lactulose formation per unit time by approximately 2-fold compared to the control. This finding indicated that THGP could form a complex with the transition state of aldose-ketose alkaline isomerization.
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