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6wyi

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Crystal structure of EchA19, enoyl-CoA hydratase from Mycobacterium tuberculosis

Structural highlights

6wyi is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.915Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ECH19_MYCTU Degradation of the cholesterol side chain involves 3 multistep beta-oxidation cycles, this may be involved in the second cycle (Probable). Hydrates 3-OCDO-CoA ((22E)-3-oxo-chol-4,22-dien-24-oyl-CoA) to make (22R)-HOCO-CoA (3-oxo-chol-4-ene-(22R)-hydroxy-24-oyl-CoA). Also acts on octenoyl-CoA. Not active on (E)-3-OCDS-CoA ((E)-3-oxocholest-4,24-dien-26-oyl-CoA) or 3-OPDC-CoA (3-oxo-4,17-pregnadiene-20-carboxyl-CoA). Hydrates the same substrate as ChsH3, but the 2 enzymes make different stereoisomers of the product (PubMed:32649175, PubMed:33826843).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Cholesterol is a major carbon source for Mycobacterium tuberculosis (Mtb) during infection, and cholesterol utilization plays a significant role in persistence and virulence within host macrophages. Elucidating the mechanism by which cholesterol is degraded may permit identification of new therapeutic targets. Here, we characterized EchA19 (Rv3516), an enoyl-CoA hydratase involved in cholesterol side chain catabolism. Steady-state kinetics assays demonstrated that EchA19 preferentially hydrates cholesterol enoyl-CoA metabolite 3-oxo-chol-4,22-diene-24-oyl-CoA, an intermediate of side chain beta-oxidation. In addition, succinyl-CoA, a downstream catabolite of propionyl-CoA that forms during cholesterol degradation, covalently modifies targeted mycobacterial proteins, including EchA19. Inspection of a 1.9 A resolution X-ray crystallography structure of Mtb EchA19 suggests that succinylation of Lys132 and Lys139 may perturb enzymatic activity by modifying the entrance to the substrate binding site. Treatment of EchA19 with succinyl-CoA revealed that these two residues are hotspots for succinylation. Replacement of these specific lysine residues with negatively-charged glutamate reduced the rate of catalytic hydration of 3-oxo-chol-4,22-diene-24-oyl-CoA by EchA19, as does succinylation of EchA19. Our findings suggest that succinylation is a negative feedback regulator of cholesterol metabolism, thereby adding another layer of complexity to Mtb physiology in the host. These regulatory pathways are potential non-catabolic targets for antimicrobial drugs.

Post-translational succinylation of Mycobacterium tuberculosis enoyl-CoA hydratase EchA19 slows catalytic hydration of cholesterol catabolite 3-oxo-chol-4,22-diene-24-oyl-CoA.,Bonds A, Yuan T, Werman J, Jang J, Lu R, Nesbitt NM, Garcia-Diaz M, Sampson NS ACS Infect Dis. 2020 Jul 10. doi: 10.1021/acsinfecdis.0c00329. PMID:32649175^[5]

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

References

↑ Bonds A, Yuan T, Werman J, Jang J, Lu R, Nesbitt NM, Garcia-Diaz M, Sampson NS. Post-translational succinylation of Mycobacterium tuberculosis enoyl-CoA hydratase EchA19 slows catalytic hydration of cholesterol catabolite 3-oxo-chol-4,22-diene-24-oyl-CoA. ACS Infect Dis. 2020 Jul 10. doi: 10.1021/acsinfecdis.0c00329. PMID:32649175 doi:http://dx.doi.org/10.1021/acsinfecdis.0c00329
↑ Yuan T, Werman JM, Yin X, Yang M, Garcia-Diaz M, Sampson NS. Enzymatic beta-Oxidation of the Cholesterol Side Chain in Mycobacterium tuberculosis Bifurcates Stereospecifically at Hydration of 3-Oxo-cholest-4,22-dien-24-oyl-CoA. ACS Infect Dis. 2021 Apr 7. doi: 10.1021/acsinfecdis.1c00069. PMID:33826843 doi:http://dx.doi.org/10.1021/acsinfecdis.1c00069
↑ Bonds A, Yuan T, Werman J, Jang J, Lu R, Nesbitt NM, Garcia-Diaz M, Sampson NS. Post-translational succinylation of Mycobacterium tuberculosis enoyl-CoA hydratase EchA19 slows catalytic hydration of cholesterol catabolite 3-oxo-chol-4,22-diene-24-oyl-CoA. ACS Infect Dis. 2020 Jul 10. doi: 10.1021/acsinfecdis.0c00329. PMID:32649175 doi:http://dx.doi.org/10.1021/acsinfecdis.0c00329
↑ Yuan T, Werman JM, Yin X, Yang M, Garcia-Diaz M, Sampson NS. Enzymatic beta-Oxidation of the Cholesterol Side Chain in Mycobacterium tuberculosis Bifurcates Stereospecifically at Hydration of 3-Oxo-cholest-4,22-dien-24-oyl-CoA. ACS Infect Dis. 2021 Apr 7. doi: 10.1021/acsinfecdis.1c00069. PMID:33826843 doi:http://dx.doi.org/10.1021/acsinfecdis.1c00069
↑ Bonds A, Yuan T, Werman J, Jang J, Lu R, Nesbitt NM, Garcia-Diaz M, Sampson NS. Post-translational succinylation of Mycobacterium tuberculosis enoyl-CoA hydratase EchA19 slows catalytic hydration of cholesterol catabolite 3-oxo-chol-4,22-diene-24-oyl-CoA. ACS Infect Dis. 2020 Jul 10. doi: 10.1021/acsinfecdis.0c00329. PMID:32649175 doi:http://dx.doi.org/10.1021/acsinfecdis.0c00329

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6wyi"

Categories: Large Structures | Mycobacterium tuberculosis H37Rv | Bonds AC | Garcia-Diaz M | Sampson NS

@@ Line 3: / Line 3: @@
 <StructureSection load='6wyi' size='340' side='right'caption='[[6wyi]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6wyi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WYI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6WYI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6wyi]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6WYI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6WYI FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.915&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">echA19, Rv3516 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></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=6wyi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wyi OCA], [http://pdbe.org/6wyi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6wyi RCSB], [http://www.ebi.ac.uk/pdbsum/6wyi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6wyi 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=6wyi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6wyi OCA], [https://pdbe.org/6wyi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6wyi RCSB], [https://www.ebi.ac.uk/pdbsum/6wyi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6wyi ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/ECH19_MYCTU ECH19_MYCTU] Degradation of the cholesterol side chain involves 3 multistep beta-oxidation cycles, this may be involved in the second cycle (Probable). Hydrates 3-OCDO-CoA ((22E)-3-oxo-chol-4,22-dien-24-oyl-CoA) to make (22R)-HOCO-CoA (3-oxo-chol-4-ene-(22R)-hydroxy-24-oyl-CoA). Also acts on octenoyl-CoA. Not active on (E)-3-OCDS-CoA ((E)-3-oxocholest-4,24-dien-26-oyl-CoA) or 3-OPDC-CoA (3-oxo-4,17-pregnadiene-20-carboxyl-CoA). Hydrates the same substrate as ChsH3, but the 2 enzymes make different stereoisomers of the product (PubMed:32649175, PubMed:33826843).<ref>PMID:32649175</ref> <ref>PMID:33826843</ref> <ref>PMID:32649175</ref> <ref>PMID:33826843</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 17: / Line 19: @@
 </div>
 <div class="pdbe-citations 6wyi" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Enoyl-CoA hydratase 3D structures|Enoyl-CoA hydratase 3D structures]]
 == References ==
 <references/>
@@ Line 22: / Line 27: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Myctu]]
+[[Category: Mycobacterium tuberculosis H37Rv]]
-[[Category: Bonds, A C]]
+[[Category: Bonds AC]]
-[[Category: Garcia-Diaz, M]]
+[[Category: Garcia-Diaz M]]
-[[Category: Sampson, N S]]
+[[Category: Sampson NS]]
-[[Category: Cholesterol metabolism]]
-[[Category: Enoyl-coa hydratase]]
-[[Category: Lyase]]
-[[Category: Mycobacterium tuberculosis]]

6wyi

From Proteopedia

Current revision

Crystal structure of EchA19, enoyl-CoA hydratase from Mycobacterium tuberculosis

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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