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5onc

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Revision as of 18:48, 15 November 2017

Catabolism of the Cholesterol Side Chain in Mycobacterium tuberculosis is Controlled by a Redox-Sensitive Thiol Switch

Structural highlights

5onc is a 2 chain structure with sequence from Myctu. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4ubt, 4ubv, 4ubw, 4ubu
Gene:	fadA5, LH57_19345, Rv3546 (MYCTU)
Activity:	Acetyl-CoA C-acyltransferase, with EC number 2.3.1.16
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[FADA5_MYCTU] Involved in the beta-oxidation of the cholesterol side chain (PubMed:19822655). It is important for utilization of cholesterol as a sole carbon source in vitro and for full virulence in the chronic stage of mouse lung infection (PubMed:19822655). Catalyzes the thiolysis of 3,22-dioxochol-4-en-24-oyl-CoA to yield 3-oxo-4-pregnene-20-carboxyl-CoA (3-OPC-CoA) and acetyl-CoA (PubMed:25482540). Also able to use acetoacetyl-CoA (AcAcCoA) as substrate (PubMed:19822655).^[1] ^[2]

Publication Abstract from PubMed

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a highly successful human pathogen and has infected approximately one-third of the world's population. Multiple drug resistant (MDR) and extensively drug resistant (XDR) TB strains and coinfection with HIV have increased the challenges of successfully treating this disease pandemic. The metabolism of host cholesterol by Mtb is an important factor for both its virulence and pathogenesis. In Mtb, the cholesterol side chain is degraded through multiple cycles of beta-oxidation and FadA5 (Rv3546) catalyzes side chain thiolysis in the first two cycles. Moreover, FadA5 is important during the chronic stage of infection in a mouse model of Mtb infection. Here, we report the redox control of FadA5 catalytic activity that results from reversible disulfide bond formation between Cys59-Cys91 and Cys93-Cys377. Cys93 is the thiolytic nucleophile, and Cys377 is the general acid catalyst for cleavage of the beta-keto-acyl-CoA substrate. The disulfide bond formed between the two catalytic residues Cys93 and Cys377 blocks catalysis. The formation of the disulfide bonds is accompanied by a large domain swap at the FadA5 dimer interface that serves to bring Cys93 and Cys377 in close proximity for disulfide bond formation. The catalytic activity of FadA5 has a midpoint potential of -220 mV, which is close to the Mtb mycothiol potential in the activated macrophage. The redox profile of FadA5 suggests that FadA5 is fully active when Mtb resides in the unactivated macrophage to maximize flux into cholesterol catabolism. Upon activation of the macrophage, the oxidative shift in the mycothiol potential will decrease the thiolytic activity by 50%. Thus, the FadA5 midpoint potential is poised to rapidly restrict cholesterol side chain degradation in response to oxidative stress from the host macrophage environment.

Catabolism of the Cholesterol Side Chain in Mycobacterium tuberculosis Is Controlled by a Redox-Sensitive Thiol Switch.,Lu R, Schaefer CM, Nesbitt NM, Kuper J, Kisker C, Sampson NS ACS Infect Dis. 2017 Aug 16. doi: 10.1021/acsinfecdis.7b00072. PMID:28786661^[3]

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

References

↑ Nesbitt NM, Yang X, Fontan P, Kolesnikova I, Smith I, Sampson NS, Dubnau E. A thiolase of Mycobacterium tuberculosis is required for virulence and production of androstenedione and androstadienedione from cholesterol. Infect Immun. 2010 Jan;78(1):275-82. doi: 10.1128/IAI.00893-09. Epub 2009 Oct 12. PMID:19822655 doi:http://dx.doi.org/10.1128/IAI.00893-09
↑ Schaefer CM, Lu R, Nesbitt NM, Schiebel J, Sampson NS, Kisker C. FadA5 a Thiolase from Mycobacterium tuberculosis: A Steroid-Binding Pocket Reveals the Potential for Drug Development against Tuberculosis. Structure. 2014 Dec 3. pii: S0969-2126(14)00355-4. doi:, 10.1016/j.str.2014.10.010. PMID:25482540 doi:http://dx.doi.org/10.1016/j.str.2014.10.010
↑ Lu R, Schaefer CM, Nesbitt NM, Kuper J, Kisker C, Sampson NS. Catabolism of the Cholesterol Side Chain in Mycobacterium tuberculosis Is Controlled by a Redox-Sensitive Thiol Switch. ACS Infect Dis. 2017 Aug 16. doi: 10.1021/acsinfecdis.7b00072. PMID:28786661 doi:http://dx.doi.org/10.1021/acsinfecdis.7b00072

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/5onc"

@@ Line 3: / Line 3: @@
 <StructureSection load='5onc' size='340' side='right' caption='[[5onc]], [[Resolution|resolution]] 2.19&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5onc]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ONC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ONC FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5onc]] is a 2 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=5ONC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ONC FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ubt|4ubt]], [[4ubv|4ubv]], [[4ubw|4ubw]], [[4ubu|4ubu]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">fadA5, LH57_19345, Rv3546 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Acetyl-CoA_C-acyltransferase Acetyl-CoA C-acyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.16 2.3.1.16] </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=5onc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5onc OCA], [http://pdbe.org/5onc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5onc RCSB], [http://www.ebi.ac.uk/pdbsum/5onc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5onc ProSAT]</span></td></tr>
@@ Line 25: / Line 26: @@
 </StructureSection>
 [[Category: Acetyl-CoA C-acyltransferase]]
+[[Category: Myctu]]
 [[Category: Kisker, C]]
 [[Category: Kuper, J]]

5onc

From Proteopedia

Revision as of 18:48, 15 November 2017

Catabolism of the Cholesterol Side Chain in Mycobacterium tuberculosis is Controlled by a Redox-Sensitive Thiol Switch

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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