7myg

From Proteopedia

(Difference between revisions)

Current revision

M. tb Ag85C modified by THL-10d

Structural highlights

7myg is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.51Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A85C_MYCTU The antigen 85 proteins (FbpA, FbpB, FbpC) are responsible for the high affinity of mycobacteria to fibronectin, a large adhesive glycoprotein, which facilitates the attachment of M.tuberculosis to murine alveolar macrophages (AMs). They also help to maintain the integrity of the cell wall by catalyzing the transfer of mycolic acids to cell wall arabinogalactan and through the synthesis of alpha,alpha-trehalose dimycolate (TDM, cord factor). They catalyze the transfer of a mycoloyl residue from one molecule of alpha,alpha-trehalose monomycolate (TMM) to another TMM, leading to the formation of TDM.^[1] ^[2]

Publication Abstract from PubMed

Tetrahydrolipstatin (THL, 1a) has been shown to inhibit both mammalian and bacterial alpha/beta hydrolases. In the case of bacterial systems, THL is a known inhibitor of several Mycobacterium tuberculosis hydrolases involved in mycomembrane biosynthesis. Herein we report a highly efficient eight-step asymmetric synthesis of THL using a route that allows modification of the THL alpha-chain substituent to afford compounds 1a through 1e. The key transformation in the synthesis was use of a (TPP)CrCl/Co2(CO)8-catalyzed regioselective and stereospecific carbonylation on an advanced epoxide intermediate to yield a trans-beta-lactone. These compounds are modest inhibitors of Ag85A and Ag85C, two alpha/beta hydrolases of M. tuberculosis involved in the biosynthesis of the mycomembrane. Among these compounds, 10d showed the highest inhibitory effect on Ag85A (34 +/- 22 muM) and Ag85C (66 +/- 8 muM), and its X-ray structure was solved in complex with Ag85C to 2.5 A resolution. In contrast, compound 1e exhibited the best-in-class MICs of 50 muM (25 mug/mL) and 16 muM (8.4 mug/mL) against M. smegmatis and M. tuberculosis H37Ra, respectively, using a microtiter assay plate. Combination of 1e with 13 well-established antibiotics synergistically enhanced the potency of few of these antibiotics in M. smegmatis and M. tuberculosis H37Ra. Compound 1e applied at concentrations 4-fold lower than its MIC enhanced the MIC of the synergistic antibiotic by 2-256-fold. In addition to observing synergy with first-line drugs, rifamycin and isoniazid, the MIC of vancomycin against M. tuberculosis H37Ra was 65 mug/mL; however, the MIC was lowered to 0.25 mug/mL in the presence of 2.1 mug/mL 1e demonstrating the potential of targeting mycobacterial hydrolases involved in mycomembrane and peptidoglycan biosynthesis.

Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species.,Khan SS, Sudasinghe TD, Landgraf AD, Ronning DR, Sucheck SJ ACS Infect Dis. 2021 Sep 3. doi: 10.1021/acsinfecdis.1c00283. PMID:34478259^[3]

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

References

↑ Abou-Zeid C, Garbe T, Lathigra R, Wiker HG, Harboe M, Rook GA, Young DB. Genetic and immunological analysis of Mycobacterium tuberculosis fibronectin-binding proteins. Infect Immun. 1991 Aug;59(8):2712-8. PMID:1830294
↑ Belisle JT, Vissa VD, Sievert T, Takayama K, Brennan PJ, Besra GS. Role of the major antigen of Mycobacterium tuberculosis in cell wall biogenesis. Science. 1997 May 30;276(5317):1420-2. PMID:9162010
↑ Khan SS, Sudasinghe TD, Landgraf AD, Ronning DR, Sucheck SJ. Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species. ACS Infect Dis. 2021 Sep 3. doi: 10.1021/acsinfecdis.1c00283. PMID:34478259 doi:http://dx.doi.org/10.1021/acsinfecdis.1c00283

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7myg"

Categories: Large Structures | Mycobacterium tuberculosis | Ronning DR | Sudasinghe TD

@@ Line 3: / Line 3: @@
 <StructureSection load='7myg' size='340' side='right'caption='[[7myg]], [[Resolution|resolution]] 2.51&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7myg]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MYG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MYG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7myg]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7MYG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7MYG FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.51&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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=7myg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7myg OCA], [https://pdbe.org/7myg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7myg RCSB], [https://www.ebi.ac.uk/pdbsum/7myg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7myg ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/A85C_MYCTU A85C_MYCTU] The antigen 85 proteins (FbpA, FbpB, FbpC) are responsible for the high affinity of mycobacteria to fibronectin, a large adhesive glycoprotein, which facilitates the attachment of M.tuberculosis to murine alveolar macrophages (AMs). They also help to maintain the integrity of the cell wall by catalyzing the transfer of mycolic acids to cell wall arabinogalactan and through the synthesis of alpha,alpha-trehalose dimycolate (TDM, cord factor). They catalyze the transfer of a mycoloyl residue from one molecule of alpha,alpha-trehalose monomycolate (TMM) to another TMM, leading to the formation of TDM.<ref>PMID:1830294</ref> <ref>PMID:9162010</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 24: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Ronning, D R]]
+[[Category: Mycobacterium tuberculosis]]
-[[Category: Sudasinghe, T D]]
+[[Category: Ronning DR]]
-[[Category: Alpha/beta-hydrolase fold]]
+[[Category: Sudasinghe TD]]
-[[Category: Mycolyltransferase]]
-[[Category: Transferase]]

7myg

From Proteopedia

Current revision

M. tb Ag85C modified by THL-10d

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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