Efficient Alkaline Isomerization of Lactose to Lactulose in the Presence of an Organogermanium Compound

Abstract

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.

An Organogermanium Compound Enhances the Initial Reaction Rate of Alkaline Isomerization of an Aldose into a Ketose through Enediol Complex Formation

“…Previously, we reported that 3-(trihydroxygermyl)propanoic acid (THGP) enhances the yields of glucose-to-fructose enzymatic and alkaline isomerization reactions, as well as that of lactose-to-lactulose alkaline isomerization. 1) 2) 3) THGP is a hydrolysate of the organogermanium compound poly- trans -[(2-carboxyethyl)germasesquioxane] (Ge-132), the biological safety of which has been confirmed. We also revealed that the driving force for the isomerization-promoting effect of THGP is its high complex formation ability for the cis -diol moieties of saccharides.…”

“…We also revealed that the driving force for the isomerization-promoting effect of THGP is its high complex formation ability for the cis -diol moieties of saccharides. 1) 2) 4) 5) The complex formation ability of THGP with fructose, which is cis -diol rich, is 40-fold higher than that with glucose, and the complex formation ability with lactulose is 24-fold higher than that with lactose. 1) 2) Due to the difference in affinity, the reverse isomerization reaction is suppressed in glucose-fructose enzymatic isomerization so that the fructose yield increases 1.6-fold.…”

“…As a result, alkaline decomposition of ketose was suppressed, enabling a 2.4-fold increase in fructose yield and a 3.2-fold increase in lactulose yield relative to that of the control. 1) 2) In the alkaline decomposition of ketose, the pH of the reaction is lowered by the organic acid origin of the Nef-Isbell mechanism, 6) suppressing the alkaline isomerization reaction. However, the protection of ketose by THGP suppresses the generation of organic acids and prevents a decrease in the pH.…”

Efficient Continuous Production of Lactulose Syrup by Alkaline Isomerization Using an Organogermanium Compound

“…We previously reported 6) 7) that the organogermanium compound poly- trans -[(2-carboxyethyl)germasesquioxane] (commonly known as Ge-132) significantly promoted the isomerization of an aldose to a ketose, such as glucose to fructose, or lactose to lactulose, with an isomerization ratio of approximately 80 %. Ge-132 is a water-soluble polymer having the formula [(GeCH 2 CH 2 COOH) 2 O 3 ] n and is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP) monomers in aqueous solution.…”

“… 18) In terms of the isomerization mechanism, we found that the cis -diol moiety of ketose and the oxyanion of THGP promote the reaction on the ketose side by forming a stable complex with a molar ratio of 1:1. 6) 7) In addition, various compounds can form a complex with the cis -diol moiety of a sugar, including boric acid, germanium dioxide, or sodium aluminate, and the formation of such complexes can promote the isomerization of lactose to lactulose. 19) 20) 21) However, the application of these compounds in food production is considered difficult from the viewpoint of safety.…”