Enzymes
| UniProtKB help_outline | 2 proteins |
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- Name help_outline (7aS)-7a-methyl-1,5-dioxo-2,3,5,6,7,7a-hexahydro-1H-indene-carboxyl-CoA Identifier CHEBI:167100 Charge -4 Formula C32H42N7O19P3S InChIKeyhelp_outline DSMYBMHDKFUSQW-MOQSZCTQSA-J SMILEShelp_outline [C@@H]1(N2C3=C(C(=NC=N3)N)N=C2)O[C@H](COP(OP(OCC(C)([C@H](C(NCCC(NCCSC(C4=C5CCC([C@]5(CCC4=O)C)=O)=O)=O)=O)O)C)(=O)[O-])(=O)[O-])[C@H]([C@H]1O)OP([O-])([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 2 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H2O Identifier CHEBI:15377 (CAS: 7732-18-5) help_outline Charge 0 Formula H2O InChIKeyhelp_outline XLYOFNOQVPJJNP-UHFFFAOYSA-N SMILEShelp_outline [H]O[H] 2D coordinates Mol file for the small molecule Search links Involved in 6,264 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline (3E)-2-(2-carboxylatoethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA Identifier CHEBI:167101 Charge -5 Formula C32H43N7O20P3S InChIKeyhelp_outline YGPXJBGPTHBWOJ-FMCILZLBSA-I SMILEShelp_outline [C@@H]1(N2C3=C(C(=NC=N3)N)N=C2)O[C@H](COP(OP(OCC(C)([C@H](C(NCCC(NCCSC(C4=C([C@@H](CCC4=O)C)CCC([O-])=O)=O)=O)=O)O)C)(=O)[O-])(=O)[O-])[C@H]([C@H]1O)OP([O-])([O-])=O 2D coordinates Mol file for the small molecule Search links Involved in 2 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
- Name help_outline H+ Identifier CHEBI:15378 Charge 1 Formula H InChIKeyhelp_outline GPRLSGONYQIRFK-UHFFFAOYSA-N SMILEShelp_outline [H+] 2D coordinates Mol file for the small molecule Search links Involved in 9,521 reaction(s) Find molecules that contain or resemble this structure Find proteins in UniProtKB for this molecule
Cross-references
| RHEA:66360 | RHEA:66361 | RHEA:66362 | RHEA:66363 | |
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| Reaction direction help_outline | undefined | left-to-right | right-to-left | bidirectional |
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| MetaCyc help_outline |
Publications
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Catabolism of the last two steroid rings in Mycobacterium tuberculosis and other bacteria.
Crowe A.M., Casabon I., Brown K.L., Liu J., Lian J., Rogalski J.C., Hurst T.E., Snieckus V., Foster L.J., Eltis L.D.
Most mycolic acid-containing actinobacteria and some proteobacteria use steroids as growth substrates, but the catabolism of the last two steroid rings has yet to be elucidated. In <i>Mycobacterium tuberculosis</i>, this pathway includes virulence determinants and has been proposed to be encoded b ... >> More
Most mycolic acid-containing actinobacteria and some proteobacteria use steroids as growth substrates, but the catabolism of the last two steroid rings has yet to be elucidated. In <i>Mycobacterium tuberculosis</i>, this pathway includes virulence determinants and has been proposed to be encoded by the KstR2-regulated genes, which include a predicted coenzyme A (CoA) transferase gene (<i>ipdAB</i>) and an acyl-CoA reductase gene (<i>ipdC</i>). In the presence of cholesterol, Δ<i>ipdC</i> and Δ<i>ipdAB</i> mutants of either <i>M. tuberculosis</i> or <i>Rhodococcus jostii</i> strain RHA1 accumulated previously undescribed metabolites: 3aα-<i>H</i>-4α(carboxyl-CoA)-5-hydroxy-7aβ-methylhexahydro-1-indanone (5-OH HIC-CoA) and (<i>R</i>)-2-(2-carboxyethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA), respectively. A Δ<i>fadE32</i> mutant of <i>Mycobacterium smegmatis</i> accumulated 4-methyl-5-oxo-octanedioic acid (MOODA). Incubation of synthetic 5-OH HIC-CoA with purified IpdF, IpdC, and enoyl-CoA hydratase 20 (EchA20), a crotonase superfamily member, yielded COCHEA-CoA and, upon further incubation with IpdAB and a CoA thiolase, yielded MOODA-CoA. Based on these studies, we propose a pathway for the final steps of steroid catabolism in which the 5-member ring is hydrolyzed by EchA20, followed by hydrolysis of the 6-member ring by IpdAB. Metabolites accumulated by Δ<i>ipdF</i> and Δ<i>echA20</i> mutants support the model. The conservation of these genes in known steroid-degrading bacteria suggests that the pathway is shared. This pathway further predicts that cholesterol catabolism yields four propionyl-CoAs, four acetyl-CoAs, one pyruvate, and one succinyl-CoA. Finally, a Δ<i>ipdAB M. tuberculosis</i> mutant did not survive in macrophages and displayed severely depleted CoASH levels that correlated with a cholesterol-dependent toxicity. Our results together with the developed tools provide a basis for further elucidating bacterial steroid catabolism and virulence determinants in <i>M. tuberculosis.</i><b>IMPORTANCE</b> Bacteria are the only known steroid degraders, but the pathway responsible for degrading the last two steroid rings has yet to be elucidated. In <i>Mycobacterium tuberculosis</i>, this pathway includes virulence determinants. Using a series of mutants in <i>M. tuberculosis</i> and related bacteria, we identified a number of novel CoA thioesters as pathway intermediates. Analysis of the metabolites combined with enzymological studies establishes how the last two steroid rings are hydrolytically opened by enzymes encoded by the KstR2 regulon. Our results provide experimental evidence for novel ring-degrading enzymes, significantly advance our understanding of bacterial steroid catabolism, and identify a previously uncharacterized cholesterol-dependent toxicity that may facilitate the development of novel tuberculosis therapeutics. << Less
MBio 8:e00321-e00321(2017) [PubMed] [EuropePMC]
This publication is cited by 4 other entries.