Polyphosphates from <i>Mycobacterium bovis</i>– potent inhibitors of class III adenylate cyclases

Guo, Ying; Mayer, Hermann A.; Vollmer, Waldemar; Dittrich, Dorothea; Sander, Peter; Schultz, Anita; Schultz, Joachim E.

doi:10.1111/j.1742-4658.2008.06852.x

Cited by 11 publications

(8 citation statements)

References 54 publications

(71 reference statements)

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“…While, the trigger(s) of sudden changes in expression of ACs and subsequent cellular cAMP levels at late growth stages of Mtb is yet to identify, the intracellular polyphosphates may be an important determinant of cellular cAMP levels [42]. Polyphosphates, generated by the activity of an enzyme known as polyphosphate kinase, is highly accumulated at the stationary phase as well as under different stress conditions in Mtb [43], and are known to inhibit the activity of ACs [42]. These information warrant further studies to analyze the effect of polyphosphates on intracellular cAMP levels.…”

Section: Discussionmentioning

confidence: 99%

Expression of a Subset of Heat Stress Induced Genes of Mycobacterium tuberculosis Is Regulated by 3',5'-Cyclic AMP

2014

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Mycobacterium tuberculosis (Mtb) secretes excess of a second messenger molecule, 3',5'-cyclic AMP (cAMP), which plays a critical role in the survival of Mtb in host macrophages. Although Mtb produces cAMP in abundance, its exact role in the physiology of mycobacteria is elusive. In this study we have analyzed the expression of 16 adenylate cyclases (ACs) and kinetics of intracellular cAMP levels in Mtb during in vitro growth under the regular culture conditions, and after exposure to different stress agents. We observed a distinct expression pattern of these ACs which is correlated with intracellular cAMP levels. Interestingly cAMP levels are significantly elevated in Mtb following heat stress, whereas other stress conditions such as oxidative, nitrosative or low pH do not affect intracellular cAMP pool in vitro. A significant increase in expression by >2-fold of five ACs namely Rv1647, Rv2212, Rv1625c, Rv2488c and Rv0386 after heat stress further suggested that cAMP plays an important role in controlling Mtb response to heat stress. In the light of these observations, effect of exogenous cAMP on global gene expression profile was examined by using microarrays. The microarray gene expression analysis demonstrated that cAMP regulates expression of a subset of heat stress-induced genes comprising of dnaK, grpE, dnaJ, and Rv2025c. Further we performed electrophoretic mobility shift assay by using cAMP-receptor protein of Mtb (CRPM), which demonstrated that CRPM specifically recognizes a sequence −301 AGCGACCGTCAGCACG −286 in 5'-untranslated region of dnaK.

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Section: Discussionmentioning

confidence: 99%

Expression of a Subset of Heat Stress Induced Genes of Mycobacterium tuberculosis Is Regulated by 3',5'-Cyclic AMP

2014

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“…adenylyl cyclases and E. coli formate hydrogen lyase transcriptional activator. Bacterial peptidoglycan and muramyl dipeptides activate AC from Candida albicans (Xu et al ., ) and polyphosphates are potent inhibitors of different ACs from Mycobacterium tuberculosis but do not affect the AC from E. coli (Guo et al ., ).…”

Section: Adenylyl Cyclasesmentioning

confidence: 97%

Biological roles of cAMP: variations on a theme in the different kingdoms of life

2013

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Cyclic AMP (cAMP) plays a key regulatory role in most types of cells; however, the pathways controlled by cAMP may present important differences between organisms and between tissues within a specific organism. Changes in cAMP levels are caused by multiple triggers, most affecting adenylyl cyclases, the enzymes that synthesize cAMP. Adenylyl cyclases form a large and diverse family including soluble forms and others with one or more transmembrane domains. Regulatory mechanisms for the soluble adenylyl cyclases involve either interaction with diverse proteins, as happens in Escherichia coli or yeasts, or with calcium or bicarbonate ions, as occurs in mammalian cells. The transmembrane cyclases can be regulated by a variety of proteins, among which the α subunit and the βγ complex from G proteins coupled to membrane receptors are prominent. cAMP levels also are controlled by the activity of phosphodiesterases, enzymes that hydrolyze cAMP. Phosphodiesterases can be regulated by cAMP, cGMP or calcium‐calmodulin or by phosphorylation by different protein kinases. Regulation through cAMP depends on its binding to diverse proteins, its proximal targets, this in turn causing changes in a variety of distal targets. Specifically, binding of cAMP to regulatory subunits of cAMP‐dependent protein kinases (PKAs) affects the activity of substrates of PKA, binding to exchange proteins directly activated by cAMP (Epac) regulates small GTPases, binding to transcription factors such as the cAMP receptor protein (CRP) or the virulence factor regulator (Vfr) modifies the rate of transcription of certain genes, while cAMP binding to ion channels modulates their activity directly. Further studies on cAMP signalling will have important implications, not only for advancing fundamental knowledge but also for identifying targets for the development of new therapeutic agents.

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“…Recent reports have shown that altered miRNA levels are also associated with the phenotypical changes of HSC during the myofibroblastic transition process including the induction of ECM proteins (Guo et al, 2009a; Ji et al, 2009) (Table 1). …”

Section: Dysregulation Of Mirna In Liver Fibrosismentioning

confidence: 99%

microRNA are Central Players in Anti- and Profibrotic Gene Regulation during Liver Fibrosis

Noetel¹,

Kwiecinski²,

Elfimova³

et al. 2012

Front. Physio.

133

112

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MicroRNA (miRNA) are small non-coding RNA molecules that posttranscriptionally effect mRNA stability and translation by targeting the 3′-untranslated region (3′-UTR) of various transcripts. Thus, dysregulation of miRNA affects a wide range of cellular processes such as cell proliferation and differentiation involved in organ remodeling processes. Divergent miRNA patterns were observed during chronic liver diseases of various etiologies. Chronic liver diseases result in uncontrolled scar formation ending up in liver fibrosis or even cirrhosis. Since it has been shown that miR-29 dysregulation is involved in synthesis of extracellular matrix proteins, miR-29 is of special interest. The importance of miR-29 in hepatic collagen homeostasis is underlined by in vivo data showing that experimental severe fibrosis is associated with a prominent miR-29 decrease. The loss of miR-29 is due to the response of hepatic stellate cells to exposure to the profibrogenic mediators TGF-β and PDGF-BB. Several putative binding sites for the Smad proteins and the Ap1 complex are located in the miR-29 promoter, which are suggested to mediate miR-29 decrease in fibrosis. Other miRNA are highly increased after profibrogenic stimulation, such as miR-21. miR-21 is transcriptionally upregulated in response to Smad-3 rather than Smad-2 activation after TGF-β stimulation. In addition, TGF-β promotes miR-21 expression by formation of a microprocessor complex containing Smad proteins. Elevated miR-21 may then act as a profibrogenic miRNA by its repression of the TGF-β inhibitory Smad-7 protein.

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Polyphosphates from Mycobacterium bovis– potent inhibitors of class III adenylate cyclases

Cited by 11 publications

References 54 publications

Expression of a Subset of Heat Stress Induced Genes of Mycobacterium tuberculosis Is Regulated by 3',5'-Cyclic AMP

Expression of a Subset of Heat Stress Induced Genes of Mycobacterium tuberculosis Is Regulated by 3',5'-Cyclic AMP

Biological roles of cAMP: variations on a theme in the different kingdoms of life

microRNA are Central Players in Anti- and Profibrotic Gene Regulation during Liver Fibrosis

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