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<p>Peptide <i>O</i>-glycosylation relies on the coordinated action of glycosyltransferases across the endoplasmic reticulum (ER) and Golgi apparatus. However, the molecular mechanisms driving aberrant glycosylation in cancer remain poorly understood. Here we show an in vitro one-pot synthetic biology approach that simulates divergent glycosylation pathways to map the synthesis of mucin 1 (MUC1) tumor-associated antigens. By modeling the cancer-associated relocation of initiation enzymes (GALNTs) to the ER, we demonstrate that this spatial shift leads to complete GalNAc (Tn antigen) occupancy. This occurs because ER localization extends reaction times and prevents inhibition by downstream Golgi enzymes. Furthermore, combined kinetic and computer reaction dynamic simulations reveal that ST6GALNAC1 exclusively drives α−2-6 sialylation, with a strict preference for the T13 site on fully glycosylated MUC1. This suggests that cancer-associated sTn upregulation is directly linked to T13 occupancy. Ultimately, this systems modeling approach decodes the enzyme localization and substrate specificities fundamental to tumourigenesis.</p>

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An in vitro approach for simulating divergent Golgi O-glycosylation of tumor-associated MUC1 from normal MUC1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Abdullateef Nashed,
  • Kyllen Dilsook,
  • Tharindu Senapathi,
  • Kevin J. Naidoo

摘要

Peptide O-glycosylation relies on the coordinated action of glycosyltransferases across the endoplasmic reticulum (ER) and Golgi apparatus. However, the molecular mechanisms driving aberrant glycosylation in cancer remain poorly understood. Here we show an in vitro one-pot synthetic biology approach that simulates divergent glycosylation pathways to map the synthesis of mucin 1 (MUC1) tumor-associated antigens. By modeling the cancer-associated relocation of initiation enzymes (GALNTs) to the ER, we demonstrate that this spatial shift leads to complete GalNAc (Tn antigen) occupancy. This occurs because ER localization extends reaction times and prevents inhibition by downstream Golgi enzymes. Furthermore, combined kinetic and computer reaction dynamic simulations reveal that ST6GALNAC1 exclusively drives α−2-6 sialylation, with a strict preference for the T13 site on fully glycosylated MUC1. This suggests that cancer-associated sTn upregulation is directly linked to T13 occupancy. Ultimately, this systems modeling approach decodes the enzyme localization and substrate specificities fundamental to tumourigenesis.