scholarly journals A Survey of Nucleotide Cyclases in Actinobacteria: Unique Domain Organization and Expansion of the Class III Cyclase Family inMycobacterium tuberculosis

2004 ◽  
Vol 5 (1) ◽  
pp. 17-38 ◽  
Author(s):  
Avinash R. Shenoy ◽  
K. Sivakumar ◽  
A. Krupa ◽  
N. Srinivasan ◽  
Sandhya S. Visweswariah
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Cyclic Nucleotides ◽  
Metabolic Pathways ◽  
Second Messengers ◽  
Class Iii ◽  
Genome Sequences ◽  
Important Group ◽  
Unique Domain ◽  
First Time

Cyclic nucleotides are well-known second messengers involved in the regulation of important metabolic pathways or virulence factors. There are six different classes of nucleotide cyclases that can accomplish the task of generating cAMP, and four of these are restricted to the prokaryotes. The role of cAMP has been implicated in the virulence and regulation of secondary metabolites in the phylum Actinobacteria, which contains important pathogens, such asMycobacterium tuberculosis, M. leprae, M. bovisandCorynebacterium, and industrial organisms from the genusStreptomyces. We have analysed the actinobacterial genome sequences found in current databases for the presence of different classes of nucleotide cyclases, and find that only class III cyclases are present in these organisms. Importantly, prominent members such asM. tuberculosisandM. lepraehave 17 and 4 class III cyclases, respectively, encoded in their genomes, some of which display interesting domain fusions seen for the first time. In addition, a pseudogene corresponding to a cyclase fromM. aviumhas been identified as the only cyclase pseudogene inM. tuberculosisandM. bovis. TheCorynebacteriumandStreptomycesgenomes encode only a single adenylyl cyclase each, both of which have corresponding orthologues inM. tuberculosis. A clustering of the cyclase domains in Actinobacteria reveals the presence of typical eukaryote-like, fungi-like and other bacteria-like class III cyclase sequences within this phylum, suggesting that these proteins may have significant roles to play in this important group of organisms.

Rapid kinetics of second messenger production in bitter taste

1996 ◽  
Vol 270 (3) ◽  
pp. C926-C931 ◽  
Author(s):  
A. I. Spielman ◽  
H. Nagai ◽  
G. Sunavala ◽  
M. Dasso ◽  
H. Breer ◽  
...  
Keyword(s):  
Bitter Taste ◽  
Second Messengers ◽  
Second Messenger ◽  
Mouse Strains ◽  
Protective Mechanism ◽  
Transient Nature ◽  
Sucrose Octaacetate ◽  
Rapid Kinetics ◽  
First Time

The tasting of bitter compounds may have evolved as a protective mechanism against ingestion of potentially harmful substances. We have identified second messengers involved in bitter taste and show here for the first time that they are rapid and transient. Using a quench-flow system, we have studied bitter taste signal transduction in a pair of mouse strains that differ in their ability to taste the bitter stimulus sucrose octaacetate (SOA); however, both strains taste the bitter agent denatonium. In both strains of mice, denatonium (10 mM) induced a transient and rapid increase in levels of the second messenger inositol 1,4,5-trisphosphate (IP3) with a maximal production near 75-100 ms after stimulation. In contrast, SOA (100 microM) brought about a similar increase in IP3 only in SOA-taster mice. The response to SOA was potentiated in the presence of GTP (1 microM). The GTP-enhanced SOA-response supports a G protein-mediated response for this bitter compound. The rapid kinetics, transient nature, and specificity of the bitter taste stimulus-induced IP3 formation are consistent with the role of IP3 as a second messenger in the chemoelectrical transduction of bitter taste.

scholarly journals Phosphodiesterase Activities in the Eye of Old and Young Rats in Normoxic, Hypoxic and Hyperoxic Atmospheres

2003 ◽  
Vol 1 (1) ◽  
pp. 25-32 ◽  
Author(s):  
G. Spoto ◽  
A. Contento ◽  
M. Di Nicola ◽  
G. Bianchi ◽  
C. Di Giulio ◽  
...  
Keyword(s):  
Cyclic Nucleotides ◽  
Biological Effects ◽  
Atmospheric Oxygen ◽  
Second Messengers ◽  
Camp Phosphodiesterase ◽  
Young Rats ◽  
Physiological Processes ◽  
Adaptive Processes ◽  
Old Rats

Phosphodiesterase activity was tested on homogenized eyes of young and old rats kept in hypoxic and hyperoxic conditions, with the aim of correlating any difference in PDE activity with aging and variations in atmospheric oxygen contents. The activities of the two enzymes, cAMP phosphodiesterase (cAMP-PDE) and cGMP phosphodiesterase (cGMP-PDE), were tested. Phosphodiesterases seem to be particularly susceptible to variations in oxygen tension, suggesting an important role of cyclic nucleotides in cellular adaptive processes. Particularly, cAMP-PDE activity increases lightly both in hypoxic and hyperoxic conditions in young and old rats. For cGMP-PDE activity of young rats, a similar behaviour to cAMP-PDE activity is observed with a similar increase in hypoxic and hyperoxic conditions respect to the control rats. Instead old rats seem to be quite insensible to hypoxia, while they show a fair increase in cGMP-PDE activity in the case of hyperoxia. The second messengers cAMP and cGMP play important roles in mediating the biological effects of a wide variety of first messengers. The intracellular levels of cyclic nucleotides depend upon rates of synthesis and degradation, actuated, respectively, by cyclases and phosphodiesterases (PDEs). Therefore, PDEs seem to play an important role in a wide variety of physiological processes.

scholarly journals Cording Mycobacterium tuberculosis Bacilli Have a Key Role in the Progression towards Active Tuberculosis, Which is Stopped by Previous Immune Response

2020 ◽  
Vol 8 (2) ◽  
pp. 228 ◽  
Author(s):  
Lilibeth Arias ◽  
Paula Cardona ◽  
Martí Català ◽  
Víctor Campo-Pérez ◽  
Clara Prats ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Early Stage ◽  
Microscopic Analysis ◽  
Neutrophil Infiltration ◽  
Active Tuberculosis ◽  
Bcg Vaccination ◽  
H37rv Strain ◽  
First Time

Cording was the first virulence factor identified in Mycobacterium tuberculosis (Mtb). We aimed to ascertain its role in the induction of active tuberculosis (TB) in the mouse strain C3HeB/FeJ by testing the immunopathogenic capacity of the H37Rv strain. We have obtained two batches of the same strain by stopping their growth in Proskauer Beck liquid medium once the mid-log phase was reached, in the noncording Mtb (NCMtb) batch, and two days later in the cording Mtb (CMtb) batch, when cording could be detected by microscopic analysis. Mice were challenged with each batch intravenously and followed-up for 24 days. CMtb caused a significant increase in the bacillary load at an early stage post-challenge (day 17), when a granulomatous response started, generating exudative lesions characterized by neutrophilic infiltration, which promoted extracellular bacillary growth together with cording formation, as shown for the first time in vivo. In contrast, NCMtb experienced slight or no bacillary growth and lesions could barely be detected. Previous Bacillus Calmette-Guérin (BCG) vaccination or low dose aerosol (LDA) Mtb infection were able to delay the progression towards active TB after CMtb challenge. While BCG vaccination also reduced bacillary load when NCMtb was challenged, LDA did not, and its proliferative lesions experienced neutrophil infiltration. Analysis of lung cytokine and chemokine profiles points to their capacity to block the production of CXCL-1 and further amplification of IL-1β, IL-17 and neutrophilic extracellular trap formation, all of which are essential for TB progression. These data highlight the key role of cording formation in the induction of active TB.

scholarly journals Functional Role of the PE Domain and Immunogenicity of the Mycobacterium tuberculosis Triacylglycerol Hydrolase LipY

2007 ◽  
Vol 76 (1) ◽  
pp. 127-140 ◽  
Author(s):  
Kanhu C. Mishra ◽  
Chantal de Chastellier ◽  
Yeddula Narayana ◽  
Pablo Bifani ◽  
Alistair K. Brown ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Humoral Response ◽  
Host Immune System ◽  
Functional Roles ◽  
Triacylglycerol Hydrolase ◽  
Immunodominant Antigen ◽  
Surface Localization ◽  
A Cell ◽  
First Time

ABSTRACT PE and PPE proteins appear to be important for virulence and immunopathogenicity in mycobacteria, yet the functions of the PE/PPE domains remain an enigma. To decipher the role of these domains, we have characterized the triacylglycerol (TAG) hydrolase LipY from Mycobacterium tuberculosis, which is the only known PE protein expressing an enzymatic activity. The overproduction of LipY in mycobacteria resulted in a significant reduction in the pool of TAGs, consistent with the lipase activity of this enzyme. Unexpectedly, this reduction was more pronounced in mycobacteria overexpressing LipY lacking the PE domain [LipY(ΔPE)], suggesting that the PE domain participates in the modulation of LipY activity. Interestingly, Mycobacterium marinum contains a protein homologous to LipY, termed LipYmar, in which the PE domain is substituted by a PPE domain. As for LipY, overexpression of LipYmar in Mycobacterium smegmatis significantly reduced the TAG pool, and this was further pronounced when the PPE domain of LipYmar was removed. Fractionation studies and Western blot analysis demonstrated that both LipY and LipY(ΔPE) were mainly present in the cell wall, indicating that the PE domain was not required for translocation to this site. Furthermore, electron microscopy immunolabeling of LipY(ΔPE) clearly showed a cell surface localization, thereby suggesting that the lipase may interact with the host immune system. Accordingly, a strong humoral response against LipY and LipY(ΔPE) was observed in tuberculosis patients. Together, our results suggest for the first time that both PE and PPE domains can share similar functional roles and that LipY represents a novel immunodominant antigen.

scholarly journals Deciphering the function of the CNGB1b subunit in olfactory CNG channels

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Vasilica Nache ◽  
Nisa Wongsamitkul ◽  
Jana Kusch ◽  
Thomas Zimmer ◽  
Frank Schwede ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Cyclic Nucleotides ◽  
Second Messengers ◽  
Receptor Potential ◽  
Similar Extent ◽  
Exact Role ◽  
Channel Activation ◽  
Signal Transduction Cascade ◽  
Camp And Cgmp

Abstract Olfactory cyclic nucleotide-gated (CNG) ion channels are key players in the signal transduction cascade of olfactory sensory neurons. The second messengers cAMP and cGMP directly activate these channels, generating a depolarizing receptor potential. Olfactory CNG channels are composed of two CNGA2 subunits and two modulatory subunits, CNGA4, and CNGB1b. So far the exact role of the modulatory subunits for channel activation is not fully understood. By measuring ligand binding and channel activation simultaneously, we show that in functional heterotetrameric channels not only the CNGA2 subunits and the CNGA4 subunit but also the CNGB1b subunit binds cyclic nucleotides and, moreover, also alone translates this signal to open the pore. In addition, we show that the CNGB1b subunit is the most sensitive subunit in a heterotetrameric channel to cyclic nucleotides and that it accelerates deactivation to a similar extent as does the CNGA4 subunit. In conclusion, the CNGB1b subunit participates in ligand-gated activation of olfactory CNG channels and, particularly, contributes to rapid termination of odorant signal in an olfactory sensory neuron.

scholarly journals EP300 (p300) mediated histone butyrylation is critical for adipogenesis

2021 ◽  
Author(s):  
Tapas K. Kundu ◽  
Aditya Bhattacharya ◽  
Sourav Chatteerjee ◽  
Utsa Bhaduri ◽  
Akash Kumar Singh ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
High Fat Diet ◽  
Specific Inhibitor ◽  
Synthetic Derivative ◽  
Small Molecule Modulator ◽  
Lysine Acetyltransferase ◽  
Targeted Inhibition ◽  
Mice Liver ◽  
First Time

The master epigenetic enzyme EP300 (p300) besides having lysine acetyltransferase activity can also catalyse other acylation modifications (propionylation, butyrylation, crotonylation etc.), the physiological implications of which are yet to be established. Here we report that lysine butyrylation concomittantly increases during adipogenesis, along with increased butyryl CoA levels due to upregulated fatty acid metabolic pathways. To delineate the role of p300 catalysed butyrylation in adipogenesis, we have identified a semi-synthetic derivative (LTK-14A) of garcinol which specifically inhibited histone butyrylation without affecting acetylation. Treatment of 3T3L1 cells with LTK-14A significantly abolished adipogenesis by downregulation of genes related to adipogenesis presumably through the inhibition of H4K5 butyrylation. Administering the specific inhibitor to high fat diet fed C57BL6/J mice as well as genetically obese db/db mice led to an attenuation/decrease in their weight gain respectively. The reduced obesity could be at least partially attributed to the targeted inhibition of H4K5 butyrylation, as observed by immunofluorescence staining of the inhibitor treated mice liver sections and immunoblotting with histones extracted from epididymal fat pads. This report therefore not only for the first time causally links histone butyrylation with adipogenesis but also presents a novel small molecule modulator that could be developed for anti-obesity therapeutics.

scholarly journals Development of an In Vitro Membrane Model to Study the Function of EsxAB Heterodimer and Establish the Role of EsxB in Membrane Permeabilizing Activity of Mycobacterium tuberculosis

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1015
Author(s):  
Salvador Vazquez Reyes ◽  
Supriyo Ray ◽  
Javier Aguilera ◽  
Jianjun Sun
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Lipid Membranes ◽  
Effect Of Temperature ◽  
In Vitro Assays ◽  
Vitro Model ◽  
First Time ◽  
Dose Dependent Increase ◽  
Dose Dependent

EsxA and EsxB are secreted as a heterodimer and have been shown to play critical roles in phagosome rupture and translocation of Mycobacterium tuberculosis into the cytosol. Recent in vitro studies have suggested that the EsxAB heterodimer is dissociated upon acidification, which might allow EsxA insertion into lipid membranes. While the membrane permeabilizing activity (MPA) of EsxA has been well characterized in liposomes composed of di-oleoyl-phosphatidylcholine (DOPC), the MPA of EsxAB heterodimer has not been detected through in vitro assays due to its negligible activity with DOPC liposomes. In this study, we established a new in vitro membrane assay to test the MPA activity of N-terminal acetylated EsxA (N-EsxA). We established that a dose-dependent increase in anionic charged lipids enhances the MPA of N-EsxA. The MPA of both N-EsxA and EsxAB were significantly increased with this new liposome system and made it possible to characterize the MPA of EsxAB in more physiologically-relevant conditions. We tested, for the first time, the effect of temperature on the MPA of N-EsxA and EsxAB in this new system. Interestingly, the MPA of N-EsxA was lower at 37 °C than at RT, and on the contrary, the MPA of EsxAB was higher at 37 °C than at RT. Surprisingly, after incubation at 37 °C, the MPA of N-EsxA continuously decreased over time, while MPA of EsxAB remained stable, suggesting EsxB plays a key role in stabilizing N-EsxA to preserve its MPA at 37 °C. In summary, this study established a new in vitro model system that characterizes the MPA of EsxAB and the role of EsxB at physiological-relevant conditions.

scholarly journals The Role of Epigenetic Changes in the Progression of Alcoholic Steatohepatitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Hyeong Geug Kim ◽  
Jung-hyo Cho ◽  
Jeongkyu Kim ◽  
Seung-Jin Kim
Keyword(s):  
Metabolic Pathways ◽  
Histone Deacetylases ◽  
Current Knowledge ◽  
Lipid Homeostasis ◽  
Epigenetic Changes ◽  
Class Iii ◽  
Alcoholic Steatohepatitis ◽  
Common Causes ◽  
Severe Fatty Liver

Alcoholic steatohepatitis (ASH) is a progression hepatitis with severe fatty liver and its mortality rate for 30-days in patients are over 30%. Additionally, ASH is well known for one-fifth all alcoholic related liver diseases in the world. Excessive chronic alcohol consumption is one of the most common causes of the progression of ASH and is associated with poor prognosis and liver failure. Alcohol abuse dysregulates the lipid homeostasis and causes oxidative stress and inflammation in the liver. Consequently, metabolic pathways stimulating hepatic accumulation of excessive lipid droplets are induced. Recently, many studies have indicated a link between ASH and epigenetic changes, showing differential expression of alcohol-induced epigenetic genes in the liver. However, the specific mechanisms underlying the pathogenesis of ASH remain elusive. Thus, we here summarize the current knowledge about the roles of epigenetics in lipogenesis, inflammation, and apoptosis in the context of ASH pathophysiology. Especially, we highlight the latest findings on the roles of Sirtuins, a conserved family of class-III histone deacetylases, in ASH. Additionally, we discuss the involvement of DNA methylation, histone modifications, and miRNAs in ASH as well as the ongoing efforts for the clinical translation of the findings in ASH-related epigenetic changes.

scholarly journals A revised mechanism for (p)ppGpp synthesis by Rel proteins: The critical role of the 2′-OH of GTP

2020 ◽  
Vol 295 (37) ◽  
pp. 12851-12867
Author(s):  
Pratik Rajendra Patil ◽  
Neha Vithani ◽  
Virender Singh ◽  
Ashok Kumar ◽  
Balaji Prakash
Keyword(s):  
Active Site ◽  
Catalytic Mechanism ◽  
Rna World ◽  
Second Messengers ◽  
Critical Role ◽  
Catalytic Role ◽  
World Hypothesis ◽  
First Time ◽  
Selection Of

Bacterial Rel proteins synthesize hyperphosphorylated guanosine nucleotides, denoted as (p)ppGpp, which by inhibiting energy requiring molecular pathways help bacteria to overcome the depletion of nutrients in its surroundings. (p)ppGpp synthesis by Rel involves transferring a pyrophosphate from ATP to the oxygen of 3′-OH of GTP/GDP. Initially, a conserved glutamate at the active site was believed to generate the nucleophile necessary to accomplish the reaction. Later this role was alluded to a Mg2+ ion. However, no study has unequivocally established a catalytic mechanism for (p)ppGpp synthesis. Here we present a revised mechanism, wherein for the first time we explore a role for 2′-OH of GTP and show how it is important in generating the nucleophile. Through a careful comparison of substrate-bound structures of Rel, we illustrate that the active site does not discriminate GTP from dGTP, for a substrate. Using biochemical studies, we demonstrate that both GTP and dGTP bind to Rel, but only GTP (but not dGTP) can form the product. Reactions performed using GTP analogs substituted with different chemical moieties at the 2′ position suggest a clear role for 2′-OH in catalysis by providing an indispensable hydrogen bond; preliminary computational analysis further supports this view. This study elucidating a catalytic role for 2′-OH of GTP in (p)ppGpp synthesis allows us to propose different mechanistic possibilities by which it generates the nucleophile for the synthesis reaction. This study underscores the selection of ribose nucleotides as second messengers and finds its roots in the old RNA world hypothesis.

Psychological Resilience Provides No Independent Protection From Suicidal Risk

Crisis ◽  
2016 ◽  
Vol 37 (2) ◽  
pp. 130-139 ◽  
Author(s):  
Danica W. Y. Liu ◽  
A. Kate Fairweather-Schmidt ◽  
Richard Burns ◽  
Rachel M. Roberts ◽  
Kaarin J. Anstey
Keyword(s):  
Risk Factors ◽  
Well Being ◽  
Current Status ◽  
Psychological Resilience ◽  
Cross Sectional ◽  
Life Project ◽  
Resilience Factors ◽  
First Time

Abstract. Background: Little is known about the role of resilience in the likelihood of suicidal ideation (SI) over time. Aims: We examined the association between resilience and SI in a young-adult cohort over 4 years. Our objectives were to determine whether resilience was associated with SI at follow-up or, conversely, whether SI was associated with lowered resilience at follow-up. Method: Participants were selected from the Personality and Total Health (PATH) Through Life Project from Canberra and Queanbeyan, Australia, aged 28–32 years at the first time point and 32–36 at the second. Multinomial, linear, and binary regression analyses explored the association between resilience and SI over two time points. Models were adjusted for suicidality risk factors. Results: While unadjusted analyses identified associations between resilience and SI, these effects were fully explained by the inclusion of other suicidality risk factors. Conclusion: Despite strong cross-sectional associations, resilience and SI appear to be unrelated in a longitudinal context, once risk/resilience factors are controlled for. As independent indicators of psychological well-being, suicidality and resilience are essential if current status is to be captured. However, the addition of other factors (e.g., support, mastery) makes this association tenuous. Consequently, resilience per se may not be protective of SI.

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