3v4n: Difference between revisions

Latest revision as of 06:15, 17 October 2024

The Biochemical and Structural Basis for Inhibition of Enterococcus faecalis HMG-CoA Synthatse, mvaS, by Hymeglusin

Structural highlights

3v4n is a 4 chain structure with sequence from Enterococcus faecalis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.6Å
Ligands:	BTB, SNC
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HMGCS_ENTFL Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Functions in the mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP), a key precursor for the biosynthesis of isoprenoid compounds.^[1] ^[2]

Publication Abstract from PubMed

Hymeglusin (1233A, F244, L-659-699) is established as a specific beta-lactone inhibitor of eukaryotic hydroxymethylglutaryl-CoA synthase (HMGCS). Inhibition results from formation of a thioester adduct to the active site cysteine. In contrast, the effects of hymeglusin on bacterial HMG-CoA synthase, mvaS, have been minimally characterized. Hymeglusin blocks growth of Enterococcus faecalis. After removal of the inhibitor from culture media, a growth curve inflection point at 3.1 h is observed (vs 0.7 h for the uninhibited control). Upon hymeglusin inactivation of purified E. faecalis mvaS, the thioester adduct is more stable than that measured for human HMGCS. Hydroxylamine cleaves the thioester adduct; substantial enzyme activity is restored at a rate that is 8-fold faster for human HMGCS than for mvaS. Structural results explain these differences in enzyme-inhibitor thioester adduct stability and solvent accessibility. The E. faecalis mvaS-hymeglusin cocrystal structure (1.95 A) reveals virtually complete occlusion of the bound inhibitor in a narrow tunnel that is largely sequestered from bulk solvent. In contrast, eukaryotic (Brassica juncea) HMGCS binds hymeglusin in a more solvent-exposed cavity.

Biochemical and structural basis for inhibition of Enterococcus faecalis hydroxymethylglutaryl-CoA synthase, mvaS, by hymeglusin.,Skaff DA, Ramyar KX, McWhorter WJ, Barta ML, Geisbrecht BV, Miziorko HM Biochemistry. 2012 Jun 12;51(23):4713-22. doi: 10.1021/bi300037k. Epub 2012 May, 25. PMID:22510038^[3]

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

References

↑ Sutherlin A, Hedl M, Sanchez-Neri B, Burgner JW 2nd, Stauffacher CV, Rodwell VW. Enterococcus faecalis 3-hydroxy-3-methylglutaryl coenzyme A synthase, an enzyme of isopentenyl diphosphate biosynthesis. J Bacteriol. 2002 Aug;184(15):4065-70. PMID:12107122 doi:10.1128/JB.184.15.4065-4070.2002
↑ VanNice JC, Skaff DA, Wyckoff GJ, Miziorko HM. Expression in Haloferax volcanii of 3-hydroxy-3-methylglutaryl coenzyme A synthase facilitates isolation and characterization of the active form of a key enzyme required for polyisoprenoid cell membrane biosynthesis in halophilic archaea. J Bacteriol. 2013 Sep;195(17):3854-62. PMID:23794621 doi:10.1128/JB.00485-13
↑ Skaff DA, Ramyar KX, McWhorter WJ, Barta ML, Geisbrecht BV, Miziorko HM. Biochemical and structural basis for inhibition of Enterococcus faecalis hydroxymethylglutaryl-CoA synthase, mvaS, by hymeglusin. Biochemistry. 2012 Jun 12;51(23):4713-22. doi: 10.1021/bi300037k. Epub 2012 May, 25. PMID:22510038 doi:https://dx.doi.org/10.1021/bi300037k

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Sutherlin A, Hedl M, Sanchez-Neri B, Burgner JW 2nd, Stauffacher CV, Rodwell VW. Enterococcus faecalis 3-hydroxy-3-methylglutaryl coenzyme A synthase, an enzyme of isopentenyl diphosphate biosynthesis. J Bacteriol. 2002 Aug;184(15):4065-70. PMID:12107122 doi:10.1128/JB.184.15.4065-4070.2002

[2] VanNice JC, Skaff DA, Wyckoff GJ, Miziorko HM. Expression in Haloferax volcanii of 3-hydroxy-3-methylglutaryl coenzyme A synthase facilitates isolation and characterization of the active form of a key enzyme required for polyisoprenoid cell membrane biosynthesis in halophilic archaea. J Bacteriol. 2013 Sep;195(17):3854-62. PMID:23794621 doi:10.1128/JB.00485-13

[3] Skaff DA, Ramyar KX, McWhorter WJ, Barta ML, Geisbrecht BV, Miziorko HM. Biochemical and structural basis for inhibition of Enterococcus faecalis hydroxymethylglutaryl-CoA synthase, mvaS, by hymeglusin. Biochemistry. 2012 Jun 12;51(23):4713-22. doi: 10.1021/bi300037k. Epub 2012 May, 25. PMID:22510038 doi:https://dx.doi.org/10.1021/bi300037k

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='3v4n' size='340' side='right'caption='[[3v4n]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3v4n]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/"enterococcus_proteiformis"_thiercelin_and_jouhaud_1903 "enterococcus proteiformis" thiercelin and jouhaud 1903]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V4N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3V4N FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3v4n]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Enterococcus_faecalis Enterococcus faecalis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V4N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3V4N FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.6&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SNC:S-NITROSO-CYSTEINE'>SNC</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=SNC:S-NITROSO-CYSTEINE'>SNC</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3v4x|3v4x]]</div></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">mvaS ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1351 "Enterococcus proteiformis" Thiercelin and Jouhaud 1903])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Hydroxymethylglutaryl-CoA_synthase Hydroxymethylglutaryl-CoA synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.3.10 2.3.3.10] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3v4n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v4n OCA], [https://pdbe.org/3v4n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3v4n RCSB], [https://www.ebi.ac.uk/pdbsum/3v4n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3v4n ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/HMGCS_ENTFL HMGCS_ENTFL] Catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Functions in the mevalonate (MVA) pathway leading to isopentenyl diphosphate (IPP), a key precursor for the biosynthesis of isoprenoid compounds.<ref>PMID:12107122</ref> <ref>PMID:23794621</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Enterococcus proteiformis thiercelin and jouhaud 1903]]
+[[Category: Enterococcus faecalis]]
-[[Category: Hydroxymethylglutaryl-CoA synthase]]
 [[Category: Large Structures]]
-[[Category: Geisbrecht, B V]]
+[[Category: Geisbrecht BV]]
-[[Category: McWhorter, W J]]
+[[Category: McWhorter WJ]]
-[[Category: Miziorko, H M]]
+[[Category: Miziorko HM]]
-[[Category: Ramyar, K X]]
+[[Category: Ramyar KX]]
-[[Category: Skaff, D A]]
+[[Category: Skaff DA]]
-[[Category: Hydroxymethylglutaryl-coa synthase]]
-[[Category: Nitrosylation]]
-[[Category: Transferase-inhibitor complex]]

3v4n: Difference between revisions

Latest revision as of 06:15, 17 October 2024

The Biochemical and Structural Basis for Inhibition of Enterococcus faecalis HMG-CoA Synthatse, mvaS, by Hymeglusin

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools