Abstract

Lactulose is a prebiotic that has found a wide application in medicine and food industry. Commercial lactulose is usually synthesized by isomerization in alkaline media at high temperatures. Enzymatic methods offer a more sustainable alternative and require more moderate processing conditions.
This review covers 44 years of scientific publications (1978–2022) on the enzymatic synthesis and purification of lactulose. The materials were retrieved from Scopus, Web of Science, PubMed, and Elibrary databases.
The enzymatic approach to lactose-to-lactulose conversion has two methods: isomerization (direct) and transgalactosylation (via hydrolysis). Isomerization exploits cellulose-2-epimerases, but their safety status is still rather vague. As a result, cellulose-2-epimerases are not commercial. Epilactose is a by-product of isomerization. Transgalactosylation involves β-galactosidases with an official international safety status (GRAS). It is available on the market, and its action mechanism is well understood. This article systematizes various data on the conditions for obtaining the maximal yields of lactulose by different enzymes.
The Kluyveromyces lactis yeast and the Aspergillus oryzae mold are the main sources of β-galactosidases in lactulose production. The yield can reach 30% if the processing conditions are optimal. Fructose remains the main problem in the production process. No scientific publications revealed a direct relationship between the maximal yields of lactulose and the molar fructose-tolactose ratios. Cellobiose epimerases make it possible to achieve high yields of lactulose (70–80%). However, these enzymes are associated with genetic engineering and mutagenesis, which challenges their safety status. The most promising trends in lactulose biotechnology include secondary dairy raw materials, immobilized enzymes, membrane reactors, complex production processes, lactose-to-lactulose conversion, and purification of final product.

Keywords

Lactulose, lactose, bioconversion, enzymes, yield, β-galactosidase, Kluyveromyces, Aspergillus, cellobiose-2-epimerase, trends

Contribution

S.A. Ryabtseva developed the research idea, designed the study, collected publications, translated them, analyzed the data, and wrote the manuscript. A.G. Khramtsov analyzed the data and revised the article. M.A. Shpak, A.D. Lodygin, G.S. Anisimov, S.N. Sazanova, and Yu.A. Tabakova collected publications, translated them, analyzed the data, and wrote the manuscript.

CONFLICTS OF INTEREST

The authors reported no conflict of interests regarding the publication of this article.

FUNDING

The research was supported by the Ministry of Science and Higher Education of the Russian Federation (Minobrnauka) as part of a comprehensive high-tech production project on the topic “The first Russian high-tech production of lactulose prebiotic and functional dairy ingredients for import substitution in medicine, veterinary, baby food, and medical preventive products for people and animals”, Decree No. 218 of the Government of the Russian Federation of April 9, 2010. The subsidies were allocated from the Federal Budget for the development of cooperation between state scientific institutions and the real sector of the economy as part of a comprehensive high-tech production project No. 075-11-2022-021 of 04/07/2022. The research was conducted on the premises of the North-Caucasus Federal University (NCFU).

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