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Cholesterol metabolism mycobacterium tuberculosis

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https://www.readbyqxmd.com/read/29067283/small-molecule-mediated-restoration-of-mitochondrial-function-augments-anti-mycobacterial-activity-of-human-macrophages-subjected-to-cholesterol-induced-asymptomatic-dyslipidemia
#1
Suman Asalla, Krishnaveni Mohareer, Sharmistha Banerjee
Mycobacterium tuberculosis (M.tb) infection manifests into tuberculosis (TB) in a small fraction of the infected population that comprises the TB susceptible group. Identifying the factors potentiating susceptibility to TB persistence is one of the prime agenda of TB control programs. Recently, WHO recognized diabetes as a risk factor for TB disease progression. The closely related pathological state of metabolic imbalance, dyslipidemia, is yet another emerging risk factor involving deregulation in host immune responses...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28988960/pdim-and-sl1-accumulation-in-mycobacterium-tuberculosis-is-associated-with-mce4a-expression
#2
Pooja Singh, Rajesh Sinha, Gaurav Tyagi, Naresh Kumar Sharma, Neeraj K Saini, Amita Chandolia, Ashok Kumar Prasad, Mandira Varma-Basil, Mridula Bose
Lipid metabolism forms the heart and soul of Mycobacterium tuberculosis life cycle. Starting from macrophage invasion at cholesterol rich micro-domains to a sustainable survival for infection by utilizing cholesterol, Mycobacterium displays the nexus of metabolic pathways around host derived lipids. mce4 operon acts as cholesterol import system in M. tuberculosis and here we demonstrate role of mce4A gene of this operon in cholesterol catabolism. Here M. tuberculosis H37Rv overexpressing Rv3499c (mce4A) recombinant was used as a model to decipher the metabolic flux during intake and utilization of host lipids by mycobacteria...
October 5, 2017: Gene
https://www.readbyqxmd.com/read/28771131/comparative-proteomic-profiles-reveal-characteristic-mycobacterium-tuberculosis-proteins-induced-by-cholesterol-during-dormancy-conditions
#3
Lazaro Garcia-Morales, Lizbel Leon-Solis, Irma E Monroy-Muñoz, Moises Talavera-Paulin, Jeanet Serafin-López, Iris Estrada-Garcia, Sandra Rivera-Gutierrez, Jorge F Cerna-Cortes, Addy C Helguera-Repetto, Jorge A Gonzalez-Y-Merchand
Cholesterol has been reported to play an important role during Mycobacterium tuberculosis infection and during its dormant state inside the host. We present the determination of proteomic profiles of M. tuberculosis H37Rv in the presence of cholesterol as the sole carbon source under exponential growth and in two in vitro dormancy phases (NRP1 and NRP2). Using 2D-PAGE, we detected that M. tuberculosis expressed a high diversity of proteins in both exponential and non-replicative phases. We also found that cholesterol was involved in the overexpression of some proteins related to sulfur metabolism (CysA2), electron transport (FixB), cell wall synthesis (Ald), iron storage (BfrB), protein synthesis (Tig and EF-Tu) and dormancy maintenance (HspX and TB 31...
August 4, 2017: Microbiology
https://www.readbyqxmd.com/read/28464471/chemical-activation-of-adenylyl-cyclase-rv1625c-inhibits-growth-of-mycobacterium-tuberculosis-on-cholesterol-and-modulates-intramacrophage-signaling
#4
Richard M Johnson, Guangchun Bai, Christopher M DeMott, Nilesh K Banavali, Christine R Montague, Caroline Moon, Alexander Shekhtman, Brian VanderVen, Kathleen A McDonough
Mycobacterium tuberculosis (Mtb) uses a complex 3', 5'-cyclic AMP (cAMP) signaling network to sense and respond to changing environments encountered during infection, so perturbation of cAMP signaling might be leveraged to disrupt Mtb pathogenesis. However, understanding of cAMP signaling pathways is hindered by the presence of at least 15 distinct adenylyl cyclases (ACs). Recently, the small molecule V-58 was shown to inhibit Mtb replication within macrophages and stimulate cAMP production in Mtb. Here we determined that V-58 rapidly and directly activates Mtb AC Rv1625c to produce high levels of cAMP regardless of the bacterial environment or growth medium...
July 2017: Molecular Microbiology
https://www.readbyqxmd.com/read/28250431/novel-protein-acetyltransferase-rv2170-modulates-carbon-and-energy-metabolism-in-mycobacterium-tuberculosis
#5
Wonsik Lee, Brian C VanderVen, Suzanne Walker, David G Russell
Recent data indicate that the metabolism of Mycobacterium tuberculosis (Mtb) inside its host cell is heavily dependent on cholesterol and fatty acids. Mtb exhibits a unique capacity to co-metabolize different carbon sources and the products from these substrates are compartmentalized metabolically. Isocitrate lies at one of the key nodes of carbon metabolism and can feed into either the glyoxylate shunt (via isocitrate lyase) or the TCA cycle (via isocitrate dehydrogenase (ICDH) activity) and we sought to better understand the regulation at this junction...
March 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28217856/molecular-characterization-of-a-new-gene-cluster-for-steroid-degradation-in-mycobacterium-smegmatis
#6
Lorena Fernández-Cabezón, Esther García-Fernández, Beatriz Galán, José L García
The C-19 steroids 4-androstene-3,17-dione (AD), 1,4-androstadiene-3,17-dione (ADD) or 9α-hydroxy-4-androstene-3,17-dione (9OH-AD), which have been postulated as intermediates of the cholesterol catabolic pathway in Mycobacterium smegmatis, cannot be used as sole carbon and energy sources by this bacterium. Only the ΔkstR mutant which constitutively expresses the genes repressed by the KstR regulator can metabolize AD and ADD with severe difficulties but still cannot metabolize 9OH-AD, suggesting that these compounds are not true intermediates but side products of the cholesterol pathway...
February 20, 2017: Environmental Microbiology
https://www.readbyqxmd.com/read/28002883/cholesterol-metabolism-a-potential-therapeutic-target-in-mycobacteria
#7
REVIEW
Areej Abuhammad
Tuberculosis (TB), although a curable disease, is still one of the most difficult infections to treat. Mycobacterium tuberculosis infects 10 million people worldwide and kills 1.5 million people each year. Reactivation of a latent infection is the major cause of TB. Cholesterol is a critical carbon source during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into lipid virulence factors. The M. tuberculosis genome contains a large regulon of cholesterol catabolic genes suggesting that the microorganism can utilize host sterol for infection and persistence...
July 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/27856345/drug-targeting-of-heme-proteins-in-mycobacterium-tuberculosis
#8
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
#9
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
#10
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...
January 2017: Microbial Biotechnology
https://www.readbyqxmd.com/read/27718364/uptake-and-metabolism-of-fluorescent-steroids-by-mycobacterial-cells
#11
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...
January 2017: Steroids
https://www.readbyqxmd.com/read/27677638/discovery-and-biophysical-evaluation-of-first-low-nanomolar-hits-targeting-cyp125-of-m-%C3%A2-tuberculosis
#12
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
#13
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
#14
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...
May 7, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27155346/immune-oxysterols-role-in-mycobacterial-infection-and-inflammation
#15
REVIEW
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 signalling 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 signalling to regulate the dynamics of cholesterol synthesis and homeostasis...
May 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/26544033/chewing-the-fat-lipid-metabolism-and-homeostasis-during-m-tuberculosis-infection
#16
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
#17
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
#18
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
#19
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
#20
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
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