Structure of Golgi alpha-mannosidase II: a target for inhibition of growth and metastasis of cancer cells.

Abstract

Golgi alpha-mannosidase II, a key enzyme in N-glycan processing, is a target in the development of anti- cancer therapies. The crystal structure of Drosophila Golgi alpha-mannosidase II in the absence and presence of the anti-cancer agent swainsonine and the inhibitor deoxymannojirimycin reveals a novel protein fold with an active site zinc intricately involved both in the substrate specificity of the enzyme and directly in the catalytic mechanism. Identification of a putative GlcNAc binding pocket in the vicinity of the active site cavity provides a model for the binding of the GlcNAcMan(5)GlcNAc(2) substrate and the consecutive hydrolysis of the alpha1,6- and alpha1,3-linked mannose residues. The enzyme-inhibitor interactions observed provide insight into the catalytic mechanism, opening the door to the design of novel inhibitors of alpha-mannosidase II.

• Authors: J M van den Elsen, D A Kuntz, D R Rose
• Journal: The EMBO journal (EMBO J) Vol. 20 Issue 12 Pg. 3008-17 (Jun 15 2001) ISSN: 0261-4189 [Print] England
• PMID: 11406577 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Enzyme Inhibitors
• 1-Deoxynojirimycin
• Mannosidases
• mannosyl-oligosaccharide 1,3 - 1,6-alpha-mannosidase
• Swainsonine

Topics

• 1-Deoxynojirimycin (pharmacology)
• Amino Acid Sequence
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Binding Sites
• Catalysis
• Cell Division
• Cell Line
• Crystallography, X-Ray
• Drosophila melanogaster (chemistry)
• Enzyme Inhibitors (pharmacology)
• Gene Expression
• Mannosidases (antagonists & inhibitors, chemistry, genetics)
• Models, Molecular
• Molecular Sequence Data
• Neoplasm Metastasis
• Protein Structure, Secondary
• Substrate Specificity
• Swainsonine (pharmacology)
• Tumor Cells, Cultured