View source for 4b55


==Crystal Structure of the Covalent Adduct Formed between Mycobacterium marinum Aryalamine N-acetyltransferase and Phenyl vinyl ketone a derivative of Piperidinols==
<StructureSection load='4b55' size='340' side='right'caption='[[4b55]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4b55]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_marinum Mycobacterium marinum]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B55 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B55 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=P18:3-HYDROXY-1-PHENYLPROPAN-1-ONE'>P18</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=4b55 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b55 OCA], [https://pdbe.org/4b55 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b55 RCSB], [https://www.ebi.ac.uk/pdbsum/4b55 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b55 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/B2HIZ6_MYCMM B2HIZ6_MYCMM] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Latent M. tuberculosis infection presents one of the major obstacles in the global eradication of tuberculosis (TB). Cholesterol plays a critical role in the persistence of M. tuberculosis within the macrophage during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the cholesterol sterol-ring degradation and is essential for intracellular survival. The ability of the NAT from M. tuberculosis (TBNAT) to utilise propionyl-CoA links it to the cholesterol-catabolism pathway. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. TBNAT has been investigated as a potential target for TB therapies. From a previous high-throughput screen, 3-benzoyl-4-phenyl-1-methylpiperidinol was identified as a selective inhibitor of prokaryotic NAT that exhibited antimycobacterial activity. The compound resulted in time-dependent irreversible inhibition of the NAT activity when tested against NAT from M. marinum (MMNAT). To further evaluate the antimycobacterial activity and the NAT inhibition of this compound, four piperidinol analogues were tested. All five compounds exert potent antimycobacterial activity against M. tuberculosis with MIC values of 2.3-16.9 microM. Treatment of the MMNAT enzyme with this set of inhibitors resulted in an irreversible time-dependent inhibition of NAT activity. Here we investigate the mechanism of NAT inhibition by studying protein-ligand interactions using mass spectrometry in combination with enzyme analysis and structure determination. We propose a covalent mechanism of NAT inhibition that involves the formation of a reactive intermediate and selective cysteine residue modification. These piperidinols present a unique class of antimycobacterial compounds that have a novel mode of action different from known anti-tubercular drugs.

Piperidinols that show anti-tubercular activity as inhibitors of arylamine N-acetyltransferase: an essential enzyme for mycobacterial survival inside macrophages.,Abuhammad A, Fullam E, Lowe ED, Staunton D, Kawamura A, Westwood IM, Bhakta S, Garner AC, Wilson DL, Seden PT, Davies SG, Russell AJ, Garman EF, Sim E PLoS One. 2012;7(12):e52790. doi: 10.1371/journal.pone.0052790. Epub 2012 Dec 28. PMID:23285185<ref>PMID:23285185</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4b55" style="background-color:#fffaf0;"></div>

==See Also==
*[[Arylamine N-acetyltransferase 3D structures|Arylamine N-acetyltransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mycobacterium marinum]]
[[Category: Abuhammad A]]
[[Category: Bhakta S]]
[[Category: Davies SG]]
[[Category: Fullam E]]
[[Category: Garman EF]]
[[Category: Garner AC]]
[[Category: Kawamura A]]
[[Category: Lowe ED]]
[[Category: Russell AJ]]
[[Category: Seden PT]]
[[Category: Sim E]]
[[Category: Staunton D]]
[[Category: Westwood IM]]
[[Category: Wilson DL]]