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==Inhibitors of 4-Phosphopanthetheine Adenylyltransferase (PPAT)== | |||
<StructureSection load='4nah' size='340' side='right' caption='[[4nah]], [[Resolution|resolution]] 2.38Å' scene=''> | |||
{ | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4nah]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Staaw Staaw]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NAH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4NAH FirstGlance]. <br> | |||
==Function== | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2VJ:2-[(2-{(1S,2S)-2-[(3,4-DICHLOROBENZYL)CARBAMOYL]CYCLOHEXYL}-6-ETHYLPYRIMIDIN-4-YL)SULFANYL]-1H-IMIDAZOLE-5-CARBOXYLIC+ACID'>2VJ</scene>, <scene name='pdbligand=AGS:PHOSPHOTHIOPHOSPHORIC+ACID-ADENYLATE+ESTER'>AGS</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nat|4nat]], [[4nau|4nau]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">coaD, MW1007 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=196620 STAAW])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Pantetheine-phosphate_adenylyltransferase Pantetheine-phosphate adenylyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.3 2.7.7.3] </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=4nah FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nah OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4nah RCSB], [http://www.ebi.ac.uk/pdbsum/4nah PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/COAD_STAAW COAD_STAAW]] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate (By similarity). | [[http://www.uniprot.org/uniprot/COAD_STAAW COAD_STAAW]] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate (By similarity). | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening of the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition of PPAT isozymes from several species, with the most potent inhibition of enzymes from Gram-positive species. Mode-of-inhibition studies with Streptococcus pneumoniae and Staphylococcus aureus PPAT demonstrated representatives of this series to be reversible inhibitors competitive with phosphopantetheine and uncompetitive with ATP, binding to the enzyme-ATP complex. The potency of this series was optimized using structure-based design, and inhibition of cell growth of Gram-positive species was achieved. Mode-of-action studies, using generation of resistant mutants with targeted sequencing as well as constructs that overexpress PPAT, demonstrated that growth suppression was due to inhibition of PPAT. An effect on bacterial burden was demonstrated in mouse lung and thigh infection models, but further optimization of dosing requirements and compound properties is needed before these compounds can be considered for progress into clinical development. These studies validated PPAT as a novel target for antibacterial therapy. | |||
Discovery of inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) to validate PPAT as a target for antibacterial therapy.,de Jonge BL, Walkup GK, Lahiri SD, Huynh H, Neckermann G, Utley L, Nash TJ, Brock J, San Martin M, Kutschke A, Johnstone M, Laganas V, Hajec L, Gu RF, Ni H, Chen B, Hutchings K, Holt E, McKinney D, Gao N, Livchak S, Thresher J Antimicrob Agents Chemother. 2013 Dec;57(12):6005-15. doi: 10.1128/AAC.01661-13. , Epub 2013 Sep 16. PMID:24041904<ref>PMID:24041904</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Pantetheine-phosphate adenylyltransferase]] | [[Category: Pantetheine-phosphate adenylyltransferase]] | ||
[[Category: Lahiri, S D | [[Category: Staaw]] | ||
[[Category: Lahiri, S D]] | |||
[[Category: Phosphopanthetheine]] | [[Category: Phosphopanthetheine]] | ||
[[Category: Phosphopanthetheine adenylyltransferase]] | [[Category: Phosphopanthetheine adenylyltransferase]] | ||
[[Category: Transferase-transferase inhibitor complex]] | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 04:17, 25 December 2014
Inhibitors of 4-Phosphopanthetheine Adenylyltransferase (PPAT)Inhibitors of 4-Phosphopanthetheine Adenylyltransferase (PPAT)
Structural highlights
Function[COAD_STAAW] Reversibly transfers an adenylyl group from ATP to 4'-phosphopantetheine, yielding dephospho-CoA (dPCoA) and pyrophosphate (By similarity). Publication Abstract from PubMedInhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening of the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition of PPAT isozymes from several species, with the most potent inhibition of enzymes from Gram-positive species. Mode-of-inhibition studies with Streptococcus pneumoniae and Staphylococcus aureus PPAT demonstrated representatives of this series to be reversible inhibitors competitive with phosphopantetheine and uncompetitive with ATP, binding to the enzyme-ATP complex. The potency of this series was optimized using structure-based design, and inhibition of cell growth of Gram-positive species was achieved. Mode-of-action studies, using generation of resistant mutants with targeted sequencing as well as constructs that overexpress PPAT, demonstrated that growth suppression was due to inhibition of PPAT. An effect on bacterial burden was demonstrated in mouse lung and thigh infection models, but further optimization of dosing requirements and compound properties is needed before these compounds can be considered for progress into clinical development. These studies validated PPAT as a novel target for antibacterial therapy. Discovery of inhibitors of 4'-phosphopantetheine adenylyltransferase (PPAT) to validate PPAT as a target for antibacterial therapy.,de Jonge BL, Walkup GK, Lahiri SD, Huynh H, Neckermann G, Utley L, Nash TJ, Brock J, San Martin M, Kutschke A, Johnstone M, Laganas V, Hajec L, Gu RF, Ni H, Chen B, Hutchings K, Holt E, McKinney D, Gao N, Livchak S, Thresher J Antimicrob Agents Chemother. 2013 Dec;57(12):6005-15. doi: 10.1128/AAC.01661-13. , Epub 2013 Sep 16. PMID:24041904[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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