2xbn

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(Difference between revisions)

Revision as of 14:01, 11 August 2016

INHIBITION OF THE PLP-DEPENDENT ENZYME SERINE PALMITOYLTRANSFERASE BY CYCLOSERINE: EVIDENCE FOR A NOVEL DECARBOXYLATIVE MECHANISM OF INACTIVATION

Structural highlights

2xbn is a 1 chain structure with sequence from "bacillus_devorans"_zimmermann_1890 "bacillus devorans" zimmermann 1890. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	2w8u, 2w8v, 2jgt, 2w8t, 2jg2, 2w8j, 2w8w
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Cycloserine (CS, 4-amino-3-isoxazolidone) is a cyclic amino acid mimic that is known to inhibit many essential pyridoxal 5'-phosphate (PLP)-dependent enzymes. Two CS enantiomers are known; d-cycloserine (DCS, also known as Seromycin) is a natural product that is used to treat resistant Mycobacterium tuberculosis infections as well as neurological disorders since it is a potent NMDA receptor agonist, and l-cycloserine (LCS) is a synthetic enantiomer whose usefulness as a drug has been hampered by its inherent toxicity arising through inhibition of sphingolipid metabolism. Previous studies on various PLP-dependent enzymes revealed a common mechanism of inhibition by both enantiomers of CS; the PLP cofactor is disabled by forming a stable 3-hydroxyisoxazole/pyridoxamine 5'-phosphate (PMP) adduct at the active site where the cycloserine ring remains intact. Here we describe a novel mechanism of CS inactivation of the PLP-dependent enzyme serine palmitoyltransferase (SPT) from Sphingomonas paucimobilis. SPT catalyses the condensation of l-serine and palmitoyl-CoA, the first step in the de novo sphingolipid biosynthetic pathway. We have used a range of kinetic, spectroscopic and structural techniques to postulate that both LCS and DCS inactivate SPT by transamination to form a free pyridoxamine 5'-phosphate (PMP) and beta-aminooxyacetaldehyde that remain bound at the active site. We suggest this occurs by ring opening of the cycloserine ring followed by decarboxylation. Enzyme kinetics show that inhibition is reversed by incubation with excess PLP and that LCS is a more effective SPT inhibitor than DCS. UV-visible spectroscopic data, combined with site-directed mutagenesis, suggest that a mobile Arg(378) residue is involved in cycloserine inactivation of SPT.

Inhibition of the PLP-dependent enzyme serine palmitoyltransferase by cycloserine: evidence for a novel decarboxylative mechanism of inactivation.,Lowther J, Yard BA, Johnson KA, Carter LG, Bhat VT, Raman MC, Clarke DJ, Ramakers B, McMahon SA, Naismith JH, Campopiano DJ Mol Biosyst. 2010 May 5. PMID:20445930^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lowther J, Yard BA, Johnson KA, Carter LG, Bhat VT, Raman MC, Clarke DJ, Ramakers B, McMahon SA, Naismith JH, Campopiano DJ. Inhibition of the PLP-dependent enzyme serine palmitoyltransferase by cycloserine: evidence for a novel decarboxylative mechanism of inactivation. Mol Biosyst. 2010 May 5. PMID:20445930 doi:10.1039/c003743e

1 Structural highlights
2 Evolutionary Conservation
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2xbn"

@@ Line 1: / Line 1: @@
 ==INHIBITION OF THE PLP-DEPENDENT ENZYME SERINE PALMITOYLTRANSFERASE BY CYCLOSERINE: EVIDENCE FOR A NOVEL DECARBOXYLATIVE MECHANISM OF INACTIVATION==
 <StructureSection load='2xbn' size='340' side='right' caption='[[2xbn]], [[Resolution|resolution]] 1.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2xbn]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Sphingomonas_paucimobilis Sphingomonas paucimobilis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XBN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XBN FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2xbn]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_devorans"_zimmermann_1890 "bacillus devorans" zimmermann 1890]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2XBN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2XBN FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=PMP:4-DEOXY-4-AMINOPYRIDOXAL-5-PHOSPHATE'>PMP</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2w8u|2w8u]], [[2w8v|2w8v]], [[2jgt|2jgt]], [[2w8t|2w8t]], [[2jg2|2jg2]], [[2w8j|2w8j]], [[2w8w|2w8w]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2xbn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xbn OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2xbn RCSB], [http://www.ebi.ac.uk/pdbsum/2xbn PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2xbn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2xbn OCA], [http://pdbe.org/2xbn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2xbn RCSB], [http://www.ebi.ac.uk/pdbsum/2xbn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2xbn ProSAT]</span></td></tr>
 </table>
 == Evolutionary Conservation ==
@@ Line 15: / Line 16: @@
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2xbn ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 25: / Line 26: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2xbn" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 32: / Line 34: @@
 __TOC__
 </StructureSection>
-[[Category: Sphingomonas paucimobilis]]
+[[Category: Bacillus devorans zimmermann 1890]]
 [[Category: Bhat, V T]]
 [[Category: Campopiano, D J]]

2xbn

From Proteopedia

Revision as of 14:01, 11 August 2016

INHIBITION OF THE PLP-DEPENDENT ENZYME SERINE PALMITOYLTRANSFERASE BY CYCLOSERINE: EVIDENCE FOR A NOVEL DECARBOXYLATIVE MECHANISM OF INACTIVATION

Structural highlights

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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