2FYV

Golgi alpha-mannosidase II complex with an amino-salacinol carboxylate analog

Summary for 2FYV

• Entry DOI: 10.2210/pdb2fyv/pdb
• Related: 1HTY 1HWW 1HXK 1PS3 1QWN 1QWU 1QX1 1R33 1R34 1TQS 1TQT 1TQU 1TQW 2ALW 2F18 2F1A 2F1B 2F7O 2F7P 2F7Q 2F7R
• Descriptor: putative golgi alpha-mannosidase II, 2-acetamido-2-deoxy-beta-D-glucopyranose, PHOSPHATE ION, ... (7 entities in total)
• Functional Keywords: glycosyl hydrolase family 38, hydrolase
• Biological source: Drosophila melanogaster (fruit fly)
• Total number of polymer chains: 1
• Total formula weight: 120512.66

Authors

Kuntz, D.A.,Hamlet, T.,Rose, D.R. (deposition date: 2006-02-08, release date: 2006-12-26, Last modification date: 2024-10-30)

Primary citation

Chen, W.,Kuntz, D.A.,Hamlet, T.,Sim, L.,Rose, D.R.,Mario Pinto, B.
Synthesis, enzymatic activity, and X-ray crystallography of an unusual class of amino acids.
Bioorg.Med.Chem., 14:8332-8340, 2006

PubMed Abstract: The synthesis of two novel amino acids, nitrogen analogues of the naturally occurring glycosidase inhibitor, salacinol, containing a carboxylate inner salt are described, along with the crystal structure of one of these analogues in the active site of Drosophila melanogaster Golgi mannosidase II (dGMII). Salacinol, a naturally occurring sulfonium ion, is one of the active principals in the aqueous extracts of Salacia reticulata that are traditionally used in Sri Lanka and India for the treatment of diabetes. The synthetic strategy relies on the nucleophilic attack of 2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-imino l- or d-arabinitol at the least hindered carbon of 5,6-anhydro-2,3-di-O-benzyl-l-ascorbic acid to yield coupled adducts. Deprotection, stereoselective catalytic reduction, and hydrolysis of the coupled products give the target compounds. The compound derived from d-arabinitol inhibits dGMII, one of the critical enzymes in the glycoprotein processing pathway, with an IC(50) of 0.3mM. Inhibition of GMII has been identified as a target for control of metastatic cancer. An X-ray crystal structure of the complex of this compound with dGMII provides insight into the requirements for an effective inhibitor. The same compound inhibits recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with a K(i) value of 21microM.

PubMed: 17010621
DOI: 10.1016/j.bmc.2006.09.004

Experimental method

X-RAY DIFFRACTION (1.9 Å)