2fyv: Difference between revisions

Revision as of 18:26, 21 February 2008

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

OverviewOverview

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.

About this StructureAbout this Structure

2FYV is a Single protein structure of sequence from Drosophila melanogaster with , , , and as ligands. Active as Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase, with EC number 3.2.1.114 Full crystallographic information is available from OCA.

ReferenceReference

Synthesis, enzymatic activity, and X-ray crystallography of an unusual class of amino acids., Chen W, Kuntz DA, Hamlet T, Sim L, Rose DR, Mario Pinto B, Bioorg Med Chem. 2006 Dec 15;14(24):8332-40. Epub 2006 Sep 28. PMID:17010621

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-[[Image:2fyv.jpg|left|200px]]<br /><applet load="2fyv" size="450" color="white" frame="true" align="right" spinBox="true"
+[[Image:2fyv.jpg|left|200px]]<br /><applet load="2fyv" size="350" color="white" frame="true" align="right" spinBox="true"
 caption="2fyv, resolution 1.900&Aring;" />
 '''Golgi alpha-mannosidase II complex with an amino-salacinol carboxylate analog'''<br />
 ==Overview==
-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.
+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.
 ==About this Structure==
-FYV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster] with NAG, PO4, ZN, W72 and MPD as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Mannosyl-oligosaccharide_1,3-1,6-alpha-mannosidase Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.114 3.2.1.114] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2FYV OCA].
+FYV is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Drosophila_melanogaster Drosophila melanogaster] with <scene name='pdbligand=NAG:'>NAG</scene>, <scene name='pdbligand=PO4:'>PO4</scene>, <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=W72:'>W72</scene> and <scene name='pdbligand=MPD:'>MPD</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Mannosyl-oligosaccharide_1,3-1,6-alpha-mannosidase Mannosyl-oligosaccharide 1,3-1,6-alpha-mannosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.114 3.2.1.114] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2FYV OCA].
 ==Reference==
@@ Line 15: / Line 15: @@
 [[Category: Single protein]]
 [[Category: Hamlet, T.]]
-[[Category: Kuntz, D.A]]
+[[Category: Kuntz, D A]]
-[[Category: Rose, D.R.]]
+[[Category: Rose, D R.]]
 [[Category: MPD]]
 [[Category: NAG]]
@@ Line 24: / Line 24: @@
 [[Category: glycosyl hydrolase family 38]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Wed Nov 21 10:51:07 2007''
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