4aa7: Difference between revisions

Revision as of 07:55, 18 August 2022

E.coli GlmU in complex with an antibacterial inhibitor

Structural highlights

4aa7 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:	R82, SO4
Related:	1hv9, 1fwy, 1fxj
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

A novel arylsulfonamide-containing series of compounds represented by 1, discovered by highthroughput screening, inhibit the acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetylt ransferase (GlmU). X-ray structure determination confirmed that inhibitor binds at the site occupied by acetyl-CoA, indicating that series is competitive with this substrate. This letter documents our early hit-to-lead evaluation of the chemical series and some of the findings that led to improvement in in-vitro potency against Gram-negative and Gram-positive bacterial isozymes, exemplified by compound 40.

Inhibitors of acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetylt ransferase (GlmU). Part 1: Hit to lead evaluation of a novel arylsulfonamide series.,Green OM, McKenzie AR, Shapiro AB, Otterbein L, Ni H, Patten A, Stokes S, Albert R, Kawatkar S, Breed J Bioorg Med Chem Lett. 2012 Feb 15;22(4):1510-9. Epub 2012 Jan 14. PMID:22297115^[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:https://dx.doi.org/10.1021/bi952275a
↑ Green OM, McKenzie AR, Shapiro AB, Otterbein L, Ni H, Patten A, Stokes S, Albert R, Kawatkar S, Breed J. Inhibitors of acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetylt ransferase (GlmU). Part 1: Hit to lead evaluation of a novel arylsulfonamide series. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1510-9. Epub 2012 Jan 14. PMID:22297115 doi:10.1016/j.bmcl.2012.01.016

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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:https://dx.doi.org/10.1021/bi952275a

[3] Green OM, McKenzie AR, Shapiro AB, Otterbein L, Ni H, Patten A, Stokes S, Albert R, Kawatkar S, Breed J. Inhibitors of acetyltransferase domain of N-acetylglucosamine-1-phosphate-uridyltransferase/glucosamine-1-phosphate-acetylt ransferase (GlmU). Part 1: Hit to lead evaluation of a novel arylsulfonamide series. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1510-9. Epub 2012 Jan 14. PMID:22297115 doi:10.1016/j.bmcl.2012.01.016

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='4aa7' size='340' side='right'caption='[[4aa7]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4aa7]] 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=4AA7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=4AA7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4aa7]] 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=4AA7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4AA7 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R82:N-(2,4-DIMETHOXY-5-{[(2R)-2-METHYL-2,3-DIHYDRO-1H-INDOL-1-YL]SULFONYL}PHENYL)ACETAMIDE'>R82</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1hv9|1hv9]], [[1fwy|1fwy]], [[1fxj|1fxj]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1hv9|1hv9]], [[1fwy|1fwy]], [[1fxj|1fxj]]</div></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=4aa7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4aa7 OCA], [http://pdbe.org/4aa7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4aa7 RCSB], [http://www.ebi.ac.uk/pdbsum/4aa7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4aa7 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=4aa7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4aa7 OCA], [https://pdbe.org/4aa7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4aa7 RCSB], [https://www.ebi.ac.uk/pdbsum/4aa7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4aa7 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 ==

4aa7: Difference between revisions

Revision as of 07:55, 18 August 2022

E.coli GlmU in complex with an antibacterial inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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