Mycobacterial Enzymes

Receptor Guanylyl Cyclase C cGMP Phosphodiesterase Mycobacterial Enzymes

Nucleotide cyclases are proteins capable of generating cyclic nucleotide second messengers and have been classified into six classes based on their primary amino acid sequences. Eukaryotic adenylyl and guanylyl cyclases as well as several bacterial adenylyl cyclases are members of the Class III (or Universal Class) of enzymes.

Our analysis of the genome of Mycobacterium tuberculosis indicates the presence of at least 16 putative Class III cyclases, raising the importance of this family of enzymes in the biology of M. tuberculosis and possibly in disease. We have  initiated systematic biochemical and structural analysis of all Class III cyclases from M. tuberculosis.

We have analysed of the genomes of bacteria and archae with particular interest to the Class III cyclases. Using the existing structural and biochemical information on their eukaryotic counterparts, we have attempted to predict the status (whether active or not) and the substrate specificity (ATP vs GTP) of these proteins. In addition the association of the cyclase domain with several other protein domains points out the versatility of the cyclase domain.

Our biochemical, mutational studies on Rv0805 from M. tuberculosis are the first on cyclic nucleotide phosphodiesterases from mycobacteria.  We have also recently identified for the first time, a novel cyclic AMP binding protein in these organisms which regulates portein lysine acetylation.

Our recent in silico analysis has shown the presence of Class III cyclic nucleotide phosphodiesterases in bacteria, archae as well as eukaryotes. It is therefore likely that Class III phosphodiesterases may be involved in eukaryotic cyclic nucleotide signaling in addition to the widely studied Class I enzymes.  Recently we have extensively characterized a novel mammalian metallophosphoesterase that is associated with the locus involved in the WAGR syndrome in humans.

 

T

 

 

 

 

 

 

 

                                                                                                                                                                     

Relevant publications:

 

Singhal A, Arora G, Virmani R, Kundu P, Khanna T, Sajid A, Misra R, Joshi J, Yadav V, Samanta S, Saini N, Pandey AK, Visweswariah SS, Hentschker C, Becher D, Gerth U, Singh Y.

Systematic analysis of mycobacterial acylation reveals first example of acylation-mediated regulation of enzyme activity of a bacterial phosphatase.

 

Visweswariah SS, Busby SJ.

Evolution of bacterial transcription factors: how proteins take on new tasks, but do not always stop doing the old ones.

 

Müller T, Rasool I, Heinz-Erian P, Mildenberger E, Hülstrunk C, Müller A, Michaud L, Koot BG, Ballauff A, Vodopiutz J, Rosipal S, Petersen BS, Franke A, Fuchs I, Witt H, Zoller H, Janecke AR, Visweswariah SS.

Congenital secretory diarrhoea caused by activating germline mutations in GUCY2C.

Banerjee A, Adolph RS, Gopalakrishnapai J, Kleinboelting S, Emmerich C, Steegborn C, Visweswariah SS.

A Universal Stress Protein (USP) in Mycobacteria Binds cAMP.

 

Biswas KH, Badireddy S, Rajendran A, Anand GS, Visweswariah

Cyclic nucleotide binding and structural changes in the isolated GAF domain of Anabaena adenylyl cyclase, CyaB2.

 

Barathy DV, Bharambe NG, Syed W, Zaveri A, Visweswariah SS, Colaco M, Misquith S, Suguna K.

Autoinhibitory mechanism and activity-related structural changes in a mycobacterial adenylyl cyclase.

 

Matange N, Podobnik M, Visweswariah SS.

Metallophosphoesterases: structural fidelity with functional promiscuity.

Kumar S, Matange N, Umapathy S, Visweswariah SS.

Linking carbon metabolism to carotenoid production in mycobacteria using Raman spectroscopy.

 

Sharma R, Zaveri A, Gopalakrishnapai J, Srinath T, Varshney U, Visweswariah SS.

Paralogous cAMP receptor proteins in Mycobacterium smegmatis show biochemical and functional divergence.

 

Sharma S, Zaveri A, Visweswariah SS, Krishnan Y.

A fluorescent nucleic acid nanodevice quantitatively images elevated cyclic adenosine monophosphate in membrane-bound compartments.

 

Pedroza-Roldán C, Aceves-Sánchez Mde J, Zaveri A, Charles-Nińo C, Elizondo-Quiroga DE, Hernández-Gutiérrez R, Allen K, Visweswariah SS, Flores-Valdez MA.

The adenylyl cyclase Rv2212 modifies the proteome and infectivity of Mycobacterium bovis BCG.

 

Matange N, Podobnik M, Visweswariah SS.

The non-catalytic "cap domain" of a mycobacterial metallophosphoesterase regulates its expression and localization in the cell.

 

Kahramanoglou C, Cortes T, Matange N, Hunt DM, Visweswariah SS, Young DB, Buxton RS.

Genomic mapping of cAMP receptor protein (CRP Mt) in Mycobacterium tuberculosis: relation to transcriptional start sites and the role of CRPMt as a transcription factor.

Nucleic Acids Res. 2014 Jul;42(13):8320-9.

 

Podobnik M, Siddiqui N, Rebolj K, Nambi S, Merzel F, Visweswariah SS.

Allostery and conformational dynamics in cAMP-binding acyltransferases.

J Biol Chem. 2014 Jun 6;289(23):16588-600.

 

Matange N, Hunt DM, Buxton RS, Visweswariah SS.

Overexpression of the Rv0805 phosphodiesterase elicits a cAMP-independent transcriptional response.

 

Nambi S, Gupta K, Bhattacharyya M, Ramakrishnan P, Ravikumar V, Siddiqui N, Thomas AT, Visweswariah SS.

Cyclic AMP-dependent protein lysine acylation in mycobacteria regulates fatty acid and propionate metabolism.

 J Biol Chem. 2013 May 17;288(20):14114-24.

 

Nambi S, BadiReddy S, Visweswariah SS, Anand GS.

Cyclic AMP-induced conformational changes in mycobacterial protein acetyltransferases.

J Biol Chem. 2012 May 25;287(22): 18115-29.

 

Chakraborti PK, Matange N, Nandicoori VK, Singh Y, Tyagi JS, Visweswariah SS.

Signalling mechanisms in mycobacteria.

Tuberculosis 2011 Sepl91(5):432-40.

 

Nambi S, Basu N, Visweswariah SS.

cAMP-regulated protein lysine acetylases in mycobacteria.

J. Biol Chem. 2010 Aug 6;285(32):24313-23.

 

Podobnik M, Tyagi R, Matange N, Dermol U, Gupta AK, Mattoo R, Seshadri K, Visweswariah SS.

A mycobacterial cyclic AMP phosphodiesterase that moonlights as a modifier of cell wall permeability.

J. Biol. Chem. 2009 Nov 20;284(47):32846-57.

 

Dass BK, Sharma R, Shenoy AR, Mattoo R, Visweswariah SS.

Cyclic AMP in mycobacteria: characterization and functional role of the Rv1647 ortholog in Mycobacterium smegmatis.

J Bacteriol. 2008 Jun;190(11):3824-34.

 

Shenoy AR, Visweswariah SS.

New messages from old messengers: cAMP and mycobacteria.

Trends Microbiol. 2006 Dec;14(12):543-50.

 

Shenoy AR, Visweswariah SS.

Mycobacterial adenylyl cyclases: biochemical diversity and structural plasticity.

FEBS Lett. 2006 Jun 12;580(14):3344-52.

Ketkar AD, Shenoy AR, Ramagopal UA, Visweswariah SS, Suguna K.
A Structural Basis for the Role of Nucleotide Specifying Residues in Regulating the Oligomerization of the Rv1625c Adenylyl Cyclase from M.tuberculosis.
J Mol Biol. 2006 Mar 3;356(4):904-16.

Shenoy AR, Sreenath NP, Podobnik M, Kovacevic M, Visweswariah SS.
The Rv0805 gene from Mycobacterium tuberculosis encodes a 3’, 5’-cyclic nucleotide phosphodiesterase: biochemical and mutational analysis.
Biochemistry. 2005 Dec 6;44(48):15695-704.

Shenoy AR, Srinivas A, Mahalingam M, Visweswariah SS.
An adenylyl cyclase pseudogene in Mycobacterium tuberculosis has a functional ortholog in Mycobacterium avium.
Biochimie. 2005;87:557-63.

Shenoy AR, Sreenath NP, Mahalingam M, Visweswariah SS.
Characterization of phylogenetically distant members of the adenylate cyclase family from mycobacteria: Rv1647 from Mycobacterium tuberculosis and its orthologue ML1399 from M. leprae.
Biochem J. 2005;387:541-51.

Shenoy AR, Visweswariah SS.
Class III nucleotide cyclases in bacteria and archaebacteria: lineage specific expansion of adenylyl cyclases and a dearth of guanylyl cyclases.
FEBS Lett. 2004;561:11-21.

Ketkar AD, Shenoy AR, Kesavulu MM, Visweswariah SS and Suguna K.
Purification, crystallization and preliminary X-ray diffraction analysis of the catalytic domain of adenylyl cyclase Rv1625c from Mycobacterium tuberculosis.
Acta Crystallogr D Biol Crystallogr. 2004 Feb;60(Pt 2):371-3.

Shenoy AR, Shivakumar K, Krupa A, Srinivasan N, Visweswariah SS.
A survey of nucleotide cyclases in Actinobacteria: unique domain organization and expansion of the class III cyclase family in Mycobacterium tuberculosis.
Comp. Fuct. Genomics 2004;5:17-38.

Shenoy AR, Srinivasan N, Subramaniam M, Visweswariah SS.
Mutational analysis of the Mycobacterium tuberculosis Rv1625c adenylyl cyclase: residues that confer nucleotide specificity contribute to dimerization.
FEBS Lett. 2003 Jun 19;545(2-3):253-9.

Shenoy AR, Srinivasan N, Visweswariah SS.
The ascent of nucleotide cyclases: conservation and evolution of a theme.
J Biosci. 2002 Mar;27(2):85-91.

 

 
Receptor Guanylyl Cyclase C cGMP Phosphodiesterase Mycobacterial Enzymes

 

Home Research Activities Lab Members Publications Collaborators

Indian Institute of Science • Dept. of MRDG