Glycosyltransferases in human milk oligosaccharide synthesis: structural mechanisms and rational design.

Journal: Current opinion in biotechnology
Published Date: Jun 1, 2025

Abstract

Human milk oligosaccharides (HMOs) play a pivotal role in infant health through their multifunctional bioactive properties. Recent advances in synthetic biology have revolutionized microbial platforms for HMO biosynthesis, with glycosyltransferases (GTs) emerging as indispensable biocatalytic tools that drive enzymatic lactose glycosylation to generate diversified oligosaccharides. This review systematically analyzes GT structural biology, elucidating conserved domains and catalytic mechanisms through crystallographic studies. We summarize contemporary optimization strategies for enhancing GT functionality, including solubility enhancement, catalytic efficiency improvement, and substrate specificity engineering via structure-guided rational design. Emerging deep learning algorithms demonstrate transformative potential in GT modifications and de novo design, providing innovative solutions to overcome bottlenecks in industrial-scale HMO synthesis. These approaches establish a framework for the precision engineering of carbohydrate-active enzymes.

Authors

  • Yangyang Li
    Institute of Urology, The Third Affiliated Hospital of Shenzhen University, Shenzhen, 518000, P. R. China.
  • Guocheng Du
    Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China; Science Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, China.
  • Jian Chen
    School of Pharmacy, Shanghai Jiaotong University, Shanghai, China.
  • Xueqin Lv
    Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, Jiangnan University, Wuxi 214122, China; Science Center for Future Foods, Ministry of Education, Jiangnan University, Wuxi 214122, China.
  • Long Liu
    Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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