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3twd

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Revision as of 05:48, 13 July 2022

glmuC1 in complex with an antibacterial inhibitor

Structural highlights

3twd is a 2 chain structure with sequence from Ecoli. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	glmU, yieA, b3730, JW3708 (ECOLI)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[GLMU_ECOLI] Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain.^[1] ^[2]

Publication Abstract from PubMed

GlmU is a bifunctional enzyme that is essential for bacterial growth, converting D-glucosamine-1-phosphate into UDP-GlcNAc via acetylation and subsequent uridyl transfer. A biochemical screen of AstraZeneca's compound library using GlmU of Escherichia coli identified novel sulfonamide inhibitors of the acetyl transferase reaction. Steady state kinetics, ligand-observe NMR, isothermal titration calorimetry and X-ray crystallography showed that the inhibitors were competitive with acetyl-CoA substrate. Iterative chemistry efforts improved biochemical potency against Gram-negative isozymes 300-fold and afforded antimicrobial activity against a strain of Haemophilus influenzae lacking its major efflux pump. Inhibition of precursor incorporation into bacterial macromolecules was consistent with the antimicrobial activity being caused by disruption of peptidoglycan and fatty acid biosyntheses. Isolation and characterization of two different resistant mutant strains identified the GlmU acetyl transferase domain as the molecular target. These data, along with X-ray co-crystal structures, confirmed the binding mode of the inhibitors and explained their relative lack of potency against Gram-positive GlmU isozymes. This is the first example of antimicrobial compounds mediating their growth inhibitory effects specifically via GlmU.

In Vitro validation of the acetyl transferase activity of GlmU as an antibacterial target in Haemophilus influenzae.,Buurman ET, Andrews B, Gao N, Hu J, Keating TA, Lahiri S, Otterbein LR, Patten AD, Stokes SS, Shapiro AB J Biol Chem. 2011 Oct 7. PMID:21984832^[3]

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

References

↑ Mengin-Lecreulx D, van Heijenoort J. Copurification of glucosamine-1-phosphate acetyltransferase and N-acetylglucosamine-1-phosphate uridyltransferase activities of Escherichia coli: characterization of the glmU gene product as a bifunctional enzyme catalyzing two subsequent steps in the pathway for UDP-N-acetylglucosamine synthesis. J Bacteriol. 1994 Sep;176(18):5788-95. PMID:8083170
↑ Gehring AM, Lees WJ, Mindiola DJ, Walsh CT, Brown ED. Acetyltransfer precedes uridylyltransfer in the formation of UDP-N-acetylglucosamine in separable active sites of the bifunctional GlmU protein of Escherichia coli. Biochemistry. 1996 Jan 16;35(2):579-85. PMID:8555230 doi:http://dx.doi.org/10.1021/bi952275a
↑ Buurman ET, Andrews B, Gao N, Hu J, Keating TA, Lahiri S, Otterbein LR, Patten AD, Stokes SS, Shapiro AB. In Vitro validation of the acetyl transferase activity of GlmU as an antibacterial target in Haemophilus influenzae. J Biol Chem. 2011 Oct 7. PMID:21984832 doi:10.1074/jbc.M111.274068

1 Structural highlights
2 Function
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/3twd"

@@ Line 1: / Line 1: @@
 ==glmuC1 in complex with an antibacterial inhibitor==
-<StructureSection load='3twd' size='340' side='right' caption='[[3twd]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+<StructureSection load='3twd' size='340' side='right'caption='[[3twd]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3twd]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TWD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3TWD FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3twd]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Ecoli Ecoli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3TWD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TWD FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOB:4-({5-[(4-AMINOPHENYL)(PHENYL)SULFAMOYL]-2,4-DIMETHOXYPHENYL}AMINO)-4-OXOBUTANOIC+ACID'>GOB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOB:4-({5-[(4-AMINOPHENYL)(PHENYL)SULFAMOYL]-2,4-DIMETHOXYPHENYL}AMINO)-4-OXOBUTANOIC+ACID'>GOB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">glmU, yieA, b3730, JW3708 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">glmU, yieA, b3730, JW3708 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83333 ECOLI])</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=3twd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3twd OCA], [http://pdbe.org/3twd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3twd RCSB], [http://www.ebi.ac.uk/pdbsum/3twd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3twd ProSAT]</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=3twd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3twd OCA], [https://pdbe.org/3twd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3twd RCSB], [https://www.ebi.ac.uk/pdbsum/3twd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3twd ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/GLMU_ECOLI GLMU_ECOLI]] Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain.<ref>PMID:8083170</ref> <ref>PMID:8555230</ref>
+[[https://www.uniprot.org/uniprot/GLMU_ECOLI GLMU_ECOLI]] Catalyzes the last two sequential reactions in the de novo biosynthetic pathway for UDP-N-acetylglucosamine (UDP-GlcNAc). The C-terminal domain catalyzes the transfer of acetyl group from acetyl coenzyme A to glucosamine-1-phosphate (GlcN-1-P) to produce N-acetylglucosamine-1-phosphate (GlcNAc-1-P), which is converted into UDP-GlcNAc by the transfer of uridine 5-monophosphate (from uridine 5-triphosphate), a reaction catalyzed by the N-terminal domain.<ref>PMID:8083170</ref> <ref>PMID:8555230</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 3twd" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[N-acetylglucosamine-1-phosphate uridyltransferase|N-acetylglucosamine-1-phosphate uridyltransferase]]
 == References ==
 <references/>
@@ Line 24: / Line 27: @@
 </StructureSection>
 [[Category: Ecoli]]
+[[Category: Large Structures]]
 [[Category: Lahiri, S]]
 [[Category: Otterbein, L]]

3twd

From Proteopedia

Revision as of 05:48, 13 July 2022

glmuC1 in complex with an antibacterial inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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