Total Chemical Synthesis of Correctly Folded Disulfide-Rich Proteins Using a Removable O-Linked β-N-Acetylglucosamine Strategy
Disulfide-rich proteins are useful as drugs or tool molecules in biomedical studies, but their synthesis is complicated by the difficulties associated with their folding. Here, we describe a removable glycosylation modification (RGM) strategy that expedites the chemical synthesis of correctly folded proteins with multiple or even interchain disulfide bonds. Our strategy comprises the introduction of simple O-linked β-N-acetylglucosamine (O-GlcNAc) groups at the Ser/Thr sites that effectively improve the folding of disulfide-rich proteins by stabilization of their folding intermediates. After folding, the O-GlcNAc groups can be efficiently removed using O-GlcNAcase (OGA) to afford the correctly folded proteins. Using this strategy, we completed the synthesis of correctly folded hepcidin, an iron-regulating hormone bearing four pairs of disulfide-bonds, and the first total synthesis of correctly folded interleukin-5 (IL-5), a 26 kDa homodimer cytokine responsible for eosinophil growth and differentiation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:144 |
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| Enthalten in: |
Journal of the American Chemical Society - 144(2022), 1 vom: 12. Jan., Seite 349-357 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Shi, Wei-Wei [VerfasserIn] |
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| Links: |
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| Themen: |
Acetylglucosamine |
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| Anmerkungen: |
Date Completed 03.03.2022 Date Revised 03.03.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/jacs.1c10091 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM33513940X |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Disulfide-rich proteins are useful as drugs or tool molecules in biomedical studies, but their synthesis is complicated by the difficulties associated with their folding. Here, we describe a removable glycosylation modification (RGM) strategy that expedites the chemical synthesis of correctly folded proteins with multiple or even interchain disulfide bonds. Our strategy comprises the introduction of simple O-linked β-N-acetylglucosamine (O-GlcNAc) groups at the Ser/Thr sites that effectively improve the folding of disulfide-rich proteins by stabilization of their folding intermediates. After folding, the O-GlcNAc groups can be efficiently removed using O-GlcNAcase (OGA) to afford the correctly folded proteins. Using this strategy, we completed the synthesis of correctly folded hepcidin, an iron-regulating hormone bearing four pairs of disulfide-bonds, and the first total synthesis of correctly folded interleukin-5 (IL-5), a 26 kDa homodimer cytokine responsible for eosinophil growth and differentiation | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Shi, Chaowei |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Tong-Yue |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yu-Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yong-Kang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xu-Han |e verfasserin |4 aut | |
| 700 | 1 | |a Bierer, Donald |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Ji-Shen |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Lei |e verfasserin |4 aut | |
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