8sf3: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8sf3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_infantum Leishmania infantum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8SF3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SF3 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8sf3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Leishmania_infantum Leishmania infantum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8SF3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SF3 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=COA:COENZYME+A'>COA</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]] 1.7Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=COA:COENZYME+A'>COA</scene></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=8sf3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sf3 OCA], [https://pdbe.org/8sf3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sf3 RCSB], [https://www.ebi.ac.uk/pdbsum/8sf3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sf3 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=8sf3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sf3 OCA], [https://pdbe.org/8sf3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sf3 RCSB], [https://www.ebi.ac.uk/pdbsum/8sf3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sf3 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/A4I093_LEIIN A4I093_LEIIN] | [https://www.uniprot.org/uniprot/A4I093_LEIIN A4I093_LEIIN] | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Leishmania, a protozoan parasite, is responsible for significant morbidity and mortality worldwide, manifesting as cutaneous, mucocutaneous, and visceral leishmaniasis. These diseases pose a substantial burden, especially in impoverished regions with limited access to effective medical treatments. Current therapies are toxic, have low efficacy, and face growing resistance. Understanding the metabolic pathways of Leishmania, particularly those differing from its host, can unveil potential therapeutic targets. In this study, we investigated the acetyl-CoA synthetase (ACS) enzyme from Leishmania infantum (LiAcs1), which, unlike many organisms, also exhibits acetoacetyl-CoA synthetase (KBC) activity. This dual functionality is unique among ANL superfamily enzymes and crucial for the parasite's reliance on leucine catabolism, energy production and sterol biosynthesis. Our biochemical characterization of LiAcs1 revealed its ability to utilize both acetate and acetoacetate substrates. Additionally, LiAcs1 displayed a distinct CoA substrate inhibition pattern, partially alleviated by acetoacetate. Structural analysis provided insights into the substrate binding flexibility of LiAcs1, highlighting a more promiscuous substrate pocket compared to other ACS or KBC-specific enzymes. Substrate mimetics elucidated its ability to accommodate both small and large AMP-ester derivatives, contributing to its dual ACS/KBC functionality. These findings not only advance our understanding of Leishmania metabolism but also present LiAcs1 as a promising drug target. The dual functionality of LiAcs1 underscores the potential for developing selective inhibitors that could disrupt critical metabolic pathways across Leishmania spp. as it appears this enzyme is highly conserved across this genus. This paves the way for developing novel effective treatments against this devastating disease. | |||
A single Leishmania adenylate forming enzyme of the ANL superfamily generates both acetyl- and acetoacetyl-CoA.,Jezewski AJ, Esan TE, Propp J, Fuller AJ, Daraji DG, Lail C 3rd, Staker BL, Woodward EL, Liu L, Battaile KP, Lovell S, Hagen TJ, Krysan DJ J Biol Chem. 2024 Oct 10:107879. doi: 10.1016/j.jbc.2024.107879. PMID:39395803<ref>PMID:39395803</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 8sf3" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||