Pathway Profiling in Mycobacterium tuberculosis

Thomas, Suzanne T.; VanderVen, Brian C.; Sherman, David R.; Russell, David G.; Sampson, Nicole S.

doi:10.1074/jbc.m111.313643

Cited by 91 publications

(73 citation statements)

References 45 publications

(80 reference statements)

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“…S2 in the supplemental material). This pattern is consistent with concurrent side-chain and nucleus degradation by Actinobacteria, as recently established for cholesterol degradation (17,36) and bile acid degradation (27). In contrast, bile acid degradation by Proteobacteria involves complete degradation of the side chain to a keto group, prior to the initial ring cleavage reaction, which opens ring B (9,12).…”

Section: Discussionsupporting

confidence: 86%

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Actinobacterial Acyl Coenzyme A Synthetases Involved in Steroid Side-Chain Catabolism

et al. 2014

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Section: Discussionsupporting

confidence: 86%

“…strain Chol1 (10)(11)(12). Conversely, cholesterol catabolism has been extensively studied in Actinobacteria, especially M. tuberculosis and Rhodococcus species (13)(14)(15)(16)(17). During microbial degradation of steroids, the side chains are degraded via a process similar to the ␤-oxidation of fatty acids.…”

mentioning

confidence: 99%

Actinobacterial Acyl Coenzyme A Synthetases Involved in Steroid Side-Chain Catabolism

et al. 2014

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“…Furthermore, an Mtb mutant lacking the igr operon, which removes the last three carbons of the steroid side chain, accumulated a hexahydroindanone metabolite that contained a three-carbon side chain (Thomas et al, 2011). Therefore, the presence of a side chain precludes further catabolism of rings C & D and results in a buildup of metabolites ( vide infra ).…”

Section: Steroid C and D Ring Degradationmentioning

confidence: 99%

Pathogen roid rage: Cholesterol utilization byMycobacterium tuberculosis

Wipperman

Sampson

Thomas

2014

Critical Reviews in Biochemistry and Molecular Biology

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The ability of science and medicine to control the pathogen Mycobacterium tuberculosis (Mtb) requires an understanding of the complex host environment within which it resides. Pathological and biological evidence overwhelmingly demonstrate how the mammalian steroid cholesterol is present throughout the course of infection. Better understanding Mtb requires a more complete understanding of how it utilizes molecules like cholesterol in this environment to sustain the infection of the host. Cholesterol uptake, catabolism, and broader utilization are important for maintenance of the pathogen in the host and it has been experimentally validated to contribute to virulence and pathogenesis. Cholesterol is catabolized by at least three distinct sub-pathways, two for the ring system and one for the side chain, yielding dozens of steroid intermediates with varying biochemical properties. Our ability to control this worldwide infectious agent requires a greater knowledge of how Mtb uses cholesterol to its advantage throughout the course of infection. Herein, the current state of knowledge of cholesterol metabolism by Mtb is reviewed from a biochemical perspective with a focus on the metabolic genes and pathways responsible for cholesterol steroid catabolism.

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“…The central helix α4 of eight amino acids and adjacent flexible loop in ChsH2 N generates an even more flexible active site with a larger pocket. The enlarged pocket in ChsH1-ChsH2 N makes it possible to accommodate steroid CoA thioesters as substrates, consistent with its function in cholesterol degradation in Mtb (12) (Figure 6c; Supplementary Table 1, Supporting Information). …”

Section: Resultsmentioning

confidence: 54%

A Distinct MaoC-like Enoyl-CoA Hydratase Architecture Mediates Cholesterol Catabolism in Mycobacterium tuberculosis

et al. 2014

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The Mycobacterium tuberculosis (Mtb) igr operon plays an essential role in Mtb cholesterol metabolism, which is critical for pathogenesis during the latent stage of Mtb infection. Here we report the first structure of a heterotetrameric MaoC-like enoyl-CoA hydratase, ChsH1-ChsH2, which is encoded by two adjacent genes from the igr operon. We demonstrate that ChsH1-ChsH2 catalyzes the hydration of a steroid enoyl-CoA, 3-oxo-4,17-pregnadiene-20-carboxyl-CoA, in the modified β-oxidation pathway for cholesterol side chain degradation. The ligand-bound and apoenzyme structures of ChsH1-ChsH2N reveal an unusual, modified hot-dog fold with a severely truncated central α-helix that creates an expanded binding site to accommodate the bulkier steroid ring system. The structures show quaternary structure shifts that accommodate the four rings of the steroid substrate and offer an explanation for why the unusual heterotetrameric assembly is utilized for hydration of this steroid. The unique αβ heterodimer architecture utilized by ChsH1-ChsH2 to bind its distinctive substrate highlights an opportunity for the development of new antimycobacterial drugs that target a pathway specific to Mtb.

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Pathway Profiling in Mycobacterium tuberculosis

Cited by 91 publications

References 45 publications

Actinobacterial Acyl Coenzyme A Synthetases Involved in Steroid Side-Chain Catabolism

Actinobacterial Acyl Coenzyme A Synthetases Involved in Steroid Side-Chain Catabolism

Pathogen roid rage: Cholesterol utilization byMycobacterium tuberculosis

A Distinct MaoC-like Enoyl-CoA Hydratase Architecture Mediates Cholesterol Catabolism in Mycobacterium tuberculosis

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