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Cholesterol metabolism mycobacterium tuberculosis

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https://www.readbyqxmd.com/read/27856345/drug-targeting-of-heme-proteins-in-mycobacterium-tuberculosis
#1
REVIEW
Kirsty J McLean, Andrew W Munro
TB, caused by the human pathogen Mycobacterium tuberculosis (Mtb, causes more deaths than any other infectious disease. Iron is crucial for Mtb to infect the host and to sustain infection, with Mtb encoding large numbers of iron-binding proteins. Many of these are hemoproteins with key roles, including defense against oxidative stress, cellular signaling and regulation, host cholesterol metabolism, and respiratory processes. Various heme enzymes in Mtb are validated drug targets and/or products of genes essential for bacterial viability or survival in the host...
November 14, 2016: Drug Discovery Today
https://www.readbyqxmd.com/read/27847019/expression-profile-of-mce4-operon-of-mycobacterium-tuberculosis-following-environmental-stress
#2
Nisha Rathor, Kushal Garima, Naresh Kumar Sharma, Anshika Narang, Mandira Varma-Basil, Mridula Bose
BACKGROUND: The mce4 operon is one of the four mce operons with eight genes (yrbE4A, yrbE4B, mce4A, mce4B, mce4C, mce4D, mce4E and mce4F) of Mycobacterium tuberculosis. It expresses in the later phase of infection and imports cholesterol for long term survival of the bacilli. To cause latent infection, M. tuberculosis undergoes metabolic reprogramming of its genes to survive in the hostile environment like low availability of oxygen and nutrition depletion inside the host. OBJECTIVE: To analyze real time expression profile of mce4 operon under various stress conditions...
September 2016: International Journal of Mycobacteriology
https://www.readbyqxmd.com/read/27804278/mycobacterium-smegmatis-is-a-suitable-cell-factory-for-the-production-of-steroidic-synthons
#3
Beatriz Galán, Iria Uhía, Esther García-Fernández, Igor Martínez, Esther Bahíllo, Juan L de la Fuente, José L Barredo, Lorena Fernández-Cabezón, José L García
A number of pharmaceutical steroid synthons are currently produced through the microbial side-chain cleavage of natural sterols as an alternative to multi-step chemical synthesis. Industrially, these synthons have been usually produced through fermentative processes using environmental isolated microorganisms or their conventional mutants. Mycobacterium smegmatis mc(2) 155 is a model organism for tuberculosis studies which uses cholesterol as the sole carbon and energy source for growth, as other mycobacterial strains...
November 2, 2016: Microbial Biotechnology
https://www.readbyqxmd.com/read/27718364/uptake-and-metabolism-of-fluorescent-steroids-by-mycobacterial-cells
#4
Yaroslav Faletrov, Anna Brzostek, Renata Plocinska, Jarosław Dziadek, Elena Rudaya, Irina Edimecheva, Vladimir Shkumatov
Fluorescent steroids BODIPY-cholesterol (BPCh) and 7-nitrobenzoxadiazole-4-amino-(NBD)-labeled 22-NBD-chelesterol (22NC) as well as synthesized 20-(NBD)-pregn-5-en-3β-ol (20NP) were found to undergo bioconversions by Mycobacterium tuberculosis H37Rv and M. smegmatis mc(2) 155. The major fluorescent products were determined to be 4-en-3-one derivatives of the compounds. Degradation of NBD fluorophore was also detected in the cases of 22NC and 20NP, but neither NBD degradation nor steroidal part modification were observed for the synthesized 3-(NBD)-cholestane...
October 5, 2016: Steroids
https://www.readbyqxmd.com/read/27677638/discovery-and-biophysical-evaluation-of-first-low-nanomolar-hits-targeting-cyp125-of-m-%C3%A2-tuberculosis
#5
Christian Brengel, Andreas Thomann, Alexander Schifrin, Jens Eberhard, Rolf W Hartmann
Tuberculosis, which is predominantly caused by Mycobacterium tuberculosis (Mtb), is still the most lethal bacterial infection with 1.5 million casualties in 2014. Moreover, the fact that the appearance of resistant mutants and long-term treatment are coupled with economic problems in developing countries hampers an efficient therapy. Interference with the essential cholesterol metabolism of Mtb could be a promising novel strategy to fight Mtb infections. CYP125, a P450 enzyme in Mtb, has been shown to play an important role in this metabolic pathway...
September 28, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27672155/inhibiting-mycobacterium-tuberculosis-within-and-without
#6
REVIEW
Stewart T Cole
Tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of Mycobacterium tuberculosis Intensive efforts have been made in the past 15 years to find leads for drug development so that better, more potent drugs inhibiting new targets could be produced and thus shorten treatment duration. Initial attempts focused on repurposing drugs that had been developed for other therapeutic areas but these agents did not meet their goals in clinical trials...
November 5, 2016: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/27164097/genome-wide-transcriptome-profiling-of-mycobacterium-smegmatis-mc%C3%A2-155-cultivated-in-minimal-media-supplemented-with-cholesterol-androstenedione-or-glycerol
#7
Qun Li, Fanglan Ge, Yunya Tan, Guangxiang Zhang, Wei Li
Mycobacterium smegmatis strain MC² 155 is an attractive model organism for the study of M. tuberculosis and other mycobacterial pathogens, as it can grow well using cholesterol as a carbon resource. However, its global transcriptomic response remains largely unrevealed. In this study, M. smegmatis MC² 155 cultivated in androstenedione, cholesterol and glycerol supplemented media were collected separately for a RNA-Sequencing study. The results showed that 6004, 6681 and 6348 genes were expressed in androstenedione, cholesterol and glycerol supplemented media, and 5891 genes were expressed in all three conditions, with 237 specially expressed in cholesterol added medium...
2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27155346/immune-oxysterols-role-in-mycobacterial-infection-and-inflammation
#8
Saikou Y Bah, Paul Dickinson, Thorsten Forster, Beate Kampmann, Peter Ghazal
Infection remains an important cause of morbidity and mortality. Natural defenses to infection are mediated by intrinsic/innate and adaptive immune responses. While our understanding is considerable it is incomplete and emerging areas of research such as those related to the immune-metabolic axis are only beginning to be appreciated. There is increasing evidence showing a connection between immune signaling and the regulation of sterol and fatty acid metabolism. In particular, metabolic intermediates of cholesterol biosynthesis and its oxidized metabolites (oxysterols) have been shown to regulate adaptive immunity and inflammation and for innate immune signaling to regulate the dynamics of cholesterol synthesis and homeostasis...
May 4, 2016: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/26544033/chewing-the-fat-lipid-metabolism-and-homeostasis-during-m-tuberculosis-infection
#9
REVIEW
Rustin R Lovewell, Christopher M Sassetti, Brian C VanderVen
The interplay between Mycobacterium tuberculosis lipid metabolism, the immune response and lipid homeostasis in the host creates a complex and dynamic pathogen-host interaction. Advances in imaging and metabolic analysis techniques indicate that M. tuberculosis preferentially associates with foamy cells and employs multiple physiological systems to utilize exogenously derived fatty-acids and cholesterol. Moreover, novel insights into specific host pathways that control lipid accumulation during infection, such as the PPARγ and LXR transcriptional regulators, have begun to reveal mechanisms by which host immunity alters the bacterial micro-environment...
February 2016: Current Opinion in Microbiology
https://www.readbyqxmd.com/read/26391209/the-essential-role-of-cholesterol-metabolism-in-the-intracellular-survival-of-mycobacterium-leprae-is-not-coupled-to-central-carbon-metabolism-and-energy-production
#10
Maria Angela M Marques, Marcia Berrêdo-Pinho, Thabatta L S A Rosa, Venugopal Pujari, Robertha M R Lemes, Leticia M S Lery, Carlos Adriano M Silva, Ana Carolina R Guimarães, Georgia C Atella, William H Wheat, Patrick J Brennan, Dean C Crick, John T Belisle, Maria Cristina V Pessolani
UNLABELLED: Mycobacterium leprae induces the formation of lipid droplets, which are recruited to pathogen-containing phagosomes in infected macrophages and Schwann cells. Cholesterol is among the lipids with increased abundance in M. leprae-infected cells, and intracellular survival relies on cholesterol accumulation. The present study investigated the capacity of M. leprae to acquire and metabolize cholesterol. In silico analyses showed that oxidation of cholesterol to cholest-4-en-3-one (cholestenone), the first step of cholesterol degradation catalyzed by the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD), is apparently the only portion of the cholesterol catabolic pathway seen in Mycobacterium tuberculosis preserved by M...
December 2015: Journal of Bacteriology
https://www.readbyqxmd.com/read/26348625/%C3%AE-methyl-acyl-coa-racemase-provides-mycobacterium-tuberculosis-catabolic-access-to-cholesterol-esters
#11
Rui Lu, Werner Schmitz, Nicole S Sampson
Metabolism of cholesterol by Mycobacterium tuberculosis (Mtb) contributes to its pathogenesis. We show that ChsE4-ChsE5 (Rv3504/Rv3505) specifically catalyzes dehydrogenation of the (25S)-3-oxo-cholest-4-en-26-oyl-CoA diastereomer in cholesterol side chain β-oxidation. Thus, a dichotomy between the supply of both 25R and 25S metabolic precursors by upstream cytochrome P450s and the substrate stereospecificity of ChsE4-ChsE5 exists. We reconcile the dilemma of 25R metabolite production by demonstrating that mycobacterial MCR (Rv1143) can efficiently epimerize C25 diastereomers of 3-oxo-cholest-4-en-26-oyl-CoA...
September 22, 2015: Biochemistry
https://www.readbyqxmd.com/read/26197389/deletion-of-cyp125-confers-increased-sensitivity-to-azoles-in-mycobacterium-tuberculosis
#12
Paul Carroll, Tanya Parish
Mycobacterium tuberculosis is able to utilize cholesterol as a carbon source, and this ability is linked to its virulence in macrophages and in the mouse model of infection. The M. tuberculosis cytochrome P450 Cyp125 plays a key role in cholesterol metabolism being involved in the first steps of its degradation. Cyp125 is a cholesterol hydroxylase which is essential for cholesterol catabolism in M. bovis BCG and some strains of M. tuberculosis. We generated an unmarked, in-frame deletion of Cyp125 in M. tuberculosis H37Rv...
2015: PloS One
https://www.readbyqxmd.com/read/26161441/unraveling-cholesterol-catabolism-in-mycobacterium-tuberculosis-chse4-chse5-%C3%AE-2%C3%AE-2-acyl-coa-dehydrogenase-initiates-%C3%AE-oxidation-of-3-oxo-cholest-4-en-26-oyl-coa
#13
Meng Yang, Rui Lu, Kip E Guja, Matthew F Wipperman, Johnna R St Clair, Amber C Bonds, Miguel Garcia-Diaz, Nicole S Sampson
The metabolism of host cholesterol by Mycobacterium tuberculosis (Mtb) is an important factor for both its virulence and pathogenesis, although how and why cholesterol metabolism is required is not fully understood. Mtb uses a unique set of catabolic enzymes that are homologous to those required for classical β-oxidation of fatty acids but are specific for steroid-derived substrates. Here, we identify and assign the substrate specificities of two of these enzymes, ChsE4-ChsE5 (Rv3504-Rv3505) and ChsE3 (Rv3573c), that carry out cholesterol side chain oxidation in Mtb...
February 13, 2015: ACS Infectious Diseases
https://www.readbyqxmd.com/read/26155739/the-mycobacterial-p55-efflux-pump-is-required-for-optimal-growth-on-cholesterol
#14
Santiago Ramón-García, Gordon R Stewart, Zhao Kun Hui, William W Mohn, Charles J Thompson
Cholesterol catabolism is thought to be a key factor contributing to the pathogenesis of Mycobacterium tuberculosis. Previous epistasis and mutant screening studies predicted that the P55 efflux pump (Rv1410c) positively interacts with the Mce4 transporter, a major cholesterol import system of M. tuberculosis and is needed for optimal growth in vitro, in macrophages, and in vivo. Using a combination of cell growth kinetic techniques, cholesterol consumption, and [4-(14)C]cholesterol uptake studies, we demonstrated that the Mycobacterium bovis BCG rv1410c gene indeed is needed for optimal in vitro growth on cholesterol and other carbon sources...
2015: Virulence
https://www.readbyqxmd.com/read/25956932/lipid-metabolism-and-type-vii-secretion-systems-dominate-the-genome-scale-virulence-profile-of-mycobacterium-tuberculosis-in-human-dendritic-cells
#15
Tom A Mendum, Huihai Wu, Andrzej M Kierzek, Graham R Stewart
BACKGROUND: Mycobacterium tuberculosis continues to kill more people than any other bacterium. Although its archetypal host cell is the macrophage, it also enters, and survives within, dendritic cells (DCs). By modulating the behaviour of the DC, M. tuberculosis is able to manipulate the host's immune response and establish an infection. To identify the M. tuberculosis genes required for survival within DCs we infected primary human DCs with an M. tuberculosis transposon library and identified mutations with a reduced ability to survive...
May 9, 2015: BMC Genomics
https://www.readbyqxmd.com/read/25675247/novel-inhibitors-of-cholesterol-degradation-in-mycobacterium-tuberculosis-reveal-how-the-bacterium-s-metabolism-is-constrained-by-the-intracellular-environment
#16
Brian C VanderVen, Ruth J Fahey, Wonsik Lee, Yancheng Liu, Robert B Abramovitch, Christine Memmott, Adam M Crowe, Lindsay D Eltis, Emanuele Perola, David D Deininger, Tiansheng Wang, Christopher P Locher, David G Russell
Mycobacterium tuberculosis (Mtb) relies on a specialized set of metabolic pathways to support growth in macrophages. By conducting an extensive, unbiased chemical screen to identify small molecules that inhibit Mtb metabolism within macrophages, we identified a significant number of novel compounds that limit Mtb growth in macrophages and in medium containing cholesterol as the principle carbon source. Based on this observation, we developed a chemical-rescue strategy to identify compounds that target metabolic enzymes involved in cholesterol metabolism...
February 2015: PLoS Pathogens
https://www.readbyqxmd.com/read/25649146/comprehensive-insights-into-transcriptional-adaptation-of-intracellular-mycobacteria-by-microbe-enriched-dual-rna-sequencing
#17
Rienk A Rienksma, Maria Suarez-Diez, Hans-Joachim Mollenkopf, Gregory M Dolganov, Anca Dorhoi, Gary K Schoolnik, Vitor Ap Martins Dos Santos, Stefan He Kaufmann, Peter J Schaap, Martin Gengenbacher
BACKGROUND: The human pathogen Mycobacterium tuberculosis has the capacity to escape eradication by professional phagocytes. During infection, M. tuberculosis resists the harsh environment of phagosomes and actively manipulates macrophages and dendritic cells to ensure prolonged intracellular survival. In contrast to other intracellular pathogens, it has remained difficult to capture the transcriptome of mycobacteria during infection due to an unfavorable host-to-pathogen ratio. RESULTS: We infected the human macrophage-like cell line THP-1 with the attenuated M...
February 5, 2015: BMC Genomics
https://www.readbyqxmd.com/read/25645564/characterization-of-novel-acyl-coenzyme-a-dehydrogenases-involved-in-bacterial-steroid-degradation
#18
Amanda Ruprecht, Jaymie Maddox, Alexander J Stirling, Nicole Visaggio, Stephen Y K Seah
UNLABELLED: The acyl coenzyme A (acyl-CoA) dehydrogenases (ACADs) FadE34 and CasC, encoded by the cholesterol and cholate gene clusters of Mycobacterium tuberculosis and Rhodococcus jostii RHA1, respectively, were successfully purified. Both enzymes differ from previously characterized ACADs in that they contain two fused acyl-CoA dehydrogenase domains in a single polypeptide. Site-specific mutagenesis showed that only the C-terminal ACAD domain contains the catalytic glutamate base required for enzyme activity, while the N-terminal ACAD domain contains an arginine required for ionic interactions with the pyrophosphate of the flavin adenine dinucleotide (FAD) cofactor...
April 2015: Journal of Bacteriology
https://www.readbyqxmd.com/read/25484217/purification-crystallization-and-preliminary-x-ray-crystallographic-studies-of-kstr2-ketosteroid-regulatory-protein-from-mycobacterium-tuberculosis
#19
Stephanie S Dawes, Sharon L Kendall, Edward N Baker, J Shaun Lott
KstR2 (Rv3557c) is one of two TetR-family transcriptional repressors of cholesterol metabolism in Mycobacterium tuberculosis. The ability to degrade cholesterol fully is important for pathogenesis, and therefore this repressor was expressed, purified and crystallized. Crystals of KstR2 diffracted to better than 1.9 Å resolution and belonged to space group C2, with unit-cell parameters a = 72.3, b = 90.3, c = 49.7 Å, α = γ = 90, β = 128.2°.
December 1, 2014: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/25482540/fada5-a-thiolase-from-mycobacterium-tuberculosis-a-steroid-binding-pocket-reveals-the-potential-for-drug-development-against-tuberculosis
#20
COMPARATIVE STUDY
Christin M Schaefer, Rui Lu, Natasha M Nesbitt, Johannes Schiebel, Nicole S Sampson, Caroline Kisker
With the exception of HIV, tuberculosis (TB) is the leading cause of mortality among infectious diseases. The urgent need to develop new antitubercular drugs is apparent due to the increasing number of drug-resistant Mycobacterium tuberculosis (Mtb) strains. Proteins involved in cholesterol import and metabolism have recently been discovered as potent targets against TB. FadA5, a thiolase from Mtb, is catalyzing the last step of the β-oxidation reaction of the cholesterol side-chain degradation under release of critical metabolites and was shown to be of importance during the chronic stage of TB infections...
January 6, 2015: Structure
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