α-Methyl Acyl CoA Racemase Provides <i>Mycobacterium tuberculosis</i> Catabolic Access to Cholesterol Esters

Lu, Rui; Schmitz, W.; Sampson, Nicole S.

doi:10.1021/acs.biochem.5b00911

Cited by 13 publications

(13 citation statements)

References 29 publications

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“…35 M. tuberculosis has specific enzymes and energy pathways for cholesterol metabolism. 36 In our previous study, we found that serum amyloid A was up-regulated in patients with TB, 9 which can promote the esterification of cholesterol. 37 In addition, IFN-γ is a delayed hypersensitivity protein, secreted by TH1 cells after being activated by M. tuberculosis .…”

Section: Discussionmentioning

confidence: 92%

Identification of potential lipid biomarkers for active pulmonary tuberculosis using ultra-high-performance liquid chromatography-tandem mass spectrometry

Han

Chen

et al. 2020

Exp Biol Med (Maywood)

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Early diagnosis of active pulmonary tuberculosis (TB) is the key to controlling the disease. Host lipids are nutrient sources for the metabolism of Mycobacterium tuberculosis. In this research work, we used ultra-high-performance liquid chromatography-tandem mass spectrometry to screen plasma lipids in TB patients, lung cancer patients, community-acquired pneumonia patients, and normal healthy controls. Principal component analysis, orthogonal partial least squares discriminant analysis, and K-means clustering algorithm analysis were used to identify lipids with differential abundance. A total of 22 differential lipids were filtered out among all subjects. The plasma phospholipid levels were decreased, while the cholesterol ester levels were increased in patients with TB. We speculate that the infection of M. tuberculosis may regulate the lipid metabolism of TB patients and may promote host-assisted bacterial degradation of phospholipids and accumulation of cholesterol esters. This may be related to the formation of lung cavities with caseous necrosis. The results of receiver operating characteristic curve analysis revealed four lipids such as phosphatidylcholine (PC, 12:0/22:2), PC (16:0/18:2), cholesteryl ester (20:3), and sphingomyelin (d18:0/18:1) as potential biomarkers for early diagnosis of TB. The diagnostic model was fitted by using logistic regression analysis and combining the above four lipids with a sensitivity of 92.9%, a specificity of 82.4%, and the area under the curve (AUC) value of 0.934 (95% CI 0.873 – 0.971). The machine learning method (10-fold cross-validation) demonstrated that the model had good accuracy (0.908 AUC, 85.3% sensitivity, and 85.9% specificity). The lipids identified in this study may serve as novel biomarkers in TB diagnosis. Our research may pave the foundation for understanding the pathogenesis of TB.

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Section: Discussionmentioning

confidence: 92%

Identification of potential lipid biomarkers for active pulmonary tuberculosis using ultra-high-performance liquid chromatography-tandem mass spectrometry

Han

Chen

et al. 2020

Exp Biol Med (Maywood)

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“…The complete degradation of cholesterol by bacteria or any organism is unusual, and only a relatively few gram-negative and Actinomyces species are known to do this (Yam et al 2011;Wipperman, Sampson and Thomas 2014). The M. tuberculosis genome contains a cluster of ∼80 genes (Van der Geize et al 2007) that encode proteins dedicated to the complex processes of cholesterol import, degradation and regulation (Capyk et al , 2011Yam et al 2009;Dresen et al 2010;Driscoll et al 2010;Lack et al 2010;Nesbitt et al 2010;Ouellet et al 2010;Griffin et al 2011Griffin et al , 2012Thomas et al 2011;Casabon et al 2013a,b;Casabon et al 2014;Wipperman et al 2013;Frank, Madrona and Ortiz de Montellano 2014;Yang et al 2014Yang et al , 2015Lu, Schmitz and Sampson 2015;Ho et al 2016;Crowe et al 2017).…”

Section: Cholesterol Utilization By M Tuberculosismentioning

confidence: 99%

Cholesterol and fatty acids grease the wheels of Mycobacterium tuberculosis pathogenesis

Wilburn

Fieweger

VanderVen

2018

Pathogens and Disease

151

177

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Tuberculosis is a distinctive disease in which the causative agent, Mycobacterium tuberculosis, can persist in humans for decades by avoiding clearance from host immunity. During infection, M. tuberculosis maintains viability by extracting and utilizing essential nutrients from the host, and this is a prerequisite for all of the pathogenic activities that are deployed by the bacterium. In particular, M. tuberculosis preferentially acquires and metabolizes host-derived lipids (fatty acids and cholesterol), and the bacterium utilizes these substrates to cause and maintain disease. In this review, we discuss our current understanding of lipid utilization by M. tuberculosis, and we describe how these pathways promote pathogenesis to fuel metabolic processes in the bacillus. Finally, we highlight weaknesses in these pathways that potentially can be targeted for drug discovery.

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“…The basic pathways of cholesterol ( a ) and β-sitosterol ( b ) side chain degradation containing analyzed metabolites [14,24,25,35,37]. …”

Section: Figures Scheme and Tablesmentioning

confidence: 99%

“…Recently, the substrate specificity of ChsE4-ChsE5 (rv3504-Rv3505) and ChsE3 (Rv3573c) have been described [34]. Moreover, Lu and co-workers demonstrated that ChsE4-ChsE5 specifically catalyzes the dehydrogenation of the (25 S )-3-oxocholest-4-en-26-oyl-CoA diastereomer in β-oxidation of the cholesterol side chain [35]. The igr (intracellular growth) operon is required for M. tuberculosis growth on cholesterol as a carbon source [11,23].…”

Section: Introductionmentioning

confidence: 99%

The Role of fadD19 and echA19 in Sterol Side Chain Degradation by Mycobacterium smegmatis

et al. 2016

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Abstract:Mycobacteria are able to degrade natural sterols and use them as a source of carbon and energy. Several genes which play an important role in cholesterol ring degradation have been described in Mycobacterium smegmatis. However, there are limited data describing the molecular mechanism of the aliphatic side chain degradation by Mycobacterium spp. In this paper, we analyzed the role of the echA19 and fadD19 genes in the degradation process of the side chain of cholesterol and β-sitosterol. We demonstrated that the M. smegmatis fadD19 and echA19 genes are not essential for viability. FadD19 is required in the initial step of the biodegradation of C-24 branched sterol side chains in Mycobacterium smegmatis mc 2 155, but not those carrying a straight chain like cholesterol. Additionally, we have shown that echA19 is not essential in the degradation of either substrate. This is the first report, to our knowledge, on the molecular characterization of the genes playing an essential role in C-24 branched side chain sterol degradation in M. smegmatis mc 2 155.

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α-Methyl Acyl CoA Racemase Provides Mycobacterium tuberculosis Catabolic Access to Cholesterol Esters

Cited by 13 publications

References 29 publications

Identification of potential lipid biomarkers for active pulmonary tuberculosis using ultra-high-performance liquid chromatography-tandem mass spectrometry

Identification of potential lipid biomarkers for active pulmonary tuberculosis using ultra-high-performance liquid chromatography-tandem mass spectrometry

Cholesterol and fatty acids grease the wheels of Mycobacterium tuberculosis pathogenesis

The Role of fadD19 and echA19 in Sterol Side Chain Degradation by Mycobacterium smegmatis

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