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Article ; Online: Unveiling the activation dynamics of a fold-switch bacterial glycosyltransferase by

Liebau, Jobst / Tersa, Montse / Trastoy, Beatriz / Patrick, Joan / Rodrigo-Unzueta, Ane / Corzana, Francisco / Sparrman, Tobias / Guerin, Marcelo E / Mäler, Lena

The Journal of biological chemistry

2020 Volume 295, Issue 29, Page(s) 9868–9878

Abstract: Fold-switch pathways remodel the secondary structure topology of proteins in response to the cellular environment. It is a major challenge to understand the dynamics of these folding processes. Here, we conducted an in-depth analysis of the α-helix-to-β- ... ...

Abstract	Fold-switch pathways remodel the secondary structure topology of proteins in response to the cellular environment. It is a major challenge to understand the dynamics of these folding processes. Here, we conducted an in-depth analysis of the α-helix-to-β-strand and β-strand-to-α-helix transitions and domain motions displayed by the essential mannosyltransferase PimA from mycobacteria. Using
MeSH term(s)	Bacterial Proteins/chemistry ; Mannosyltransferases/chemistry ; Molecular Dynamics Simulation ; Mycobacterium smegmatis/enzymology ; Nuclear Magnetic Resonance, Biomolecular ; Protein Folding
Chemical Substances	Bacterial Proteins ; Mannosyltransferases (EC 2.4.1.-) ; phosphatidyl-myo-inositol mannosyltransferase PimA, Mycobacterium smegmatis (EC 2.4.1.-)
Language	English
Publishing date	2020-05-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.RA120.014162
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Article ; Online: The Molecular Mechanism of Substrate Recognition and Catalysis of the Membrane Acyltransferase PatA from Mycobacteria.

Tersa, Montse / Raich, Lluís / Albesa-Jové, David / Trastoy, Beatriz / Prandi, Jacques / Gilleron, Martine / Rovira, Carme / Guerin, Marcelo E

ACS chemical biology

2018 Volume 13, Issue 1, Page(s) 131–140

Abstract: Glycolipids play a central role in a variety of important biological processes in all living organisms. PatA is a membrane acyltransferase involved in the biosynthesis of phosphatidyl-myo-inositol mannosides (PIMs), key structural elements, and virulence ...

Abstract	Glycolipids play a central role in a variety of important biological processes in all living organisms. PatA is a membrane acyltransferase involved in the biosynthesis of phosphatidyl-myo-inositol mannosides (PIMs), key structural elements, and virulence factors of Mycobacterium tuberculosis. PatA catalyzes the transfer of a palmitoyl moiety from palmitoyl-CoA to the 6-position of the mannose ring linked to the 2-position of inositol in PIM
MeSH term(s)	Acyltransferases/chemistry ; Acyltransferases/genetics ; Acyltransferases/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Binding Sites ; Catalysis ; Crystallography, X-Ray ; Mannosides/pharmacology ; Models, Molecular ; Mycobacterium smegmatis/enzymology ; Mycobacterium smegmatis/metabolism ; Protein Conformation ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
Chemical Substances	Bacterial Proteins ; Mannosides ; Recombinant Proteins ; Acyltransferases (EC 2.3.-)
Language	English
Publishing date	2018--19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.7b00578
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Article ; Online: Identification of the first structurally validated covalent ligands of the small GTPase RAB27A.

Jamshidiha, Mostafa / Lanyon-Hogg, Thomas / Sutherell, Charlotte L / Craven, Gregory B / Tersa, Montse / De Vita, Elena / Brustur, Delia / Pérez-Dorado, Inmaculada / Hassan, Sarah / Petracca, Rita / Morgan, Rhodri M / Sanz-Hernández, Máximo / Norman, Jim C / Armstrong, Alan / Mann, David J / Cota, Ernesto / Tate, Edward W

RSC medicinal chemistry

2021 Volume 13, Issue 2, Page(s) 150–155

Abstract: Rab27A is a small GTPase, which mediates transport and docking of secretory vesicles at the plasma ... ...

Abstract	Rab27A is a small GTPase, which mediates transport and docking of secretory vesicles at the plasma membrane
Language	English
Publishing date	2021-12-16
Publishing country	England
Document type	Journal Article
ISSN	2632-8682
ISSN (online)	2632-8682
DOI	10.1039/d1md00225b
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Article ; Online: Molecular ruler mechanism and interfacial catalysis of the integral membrane acyltransferase PatA.

Anso, Itxaso / Basso, Luis G M / Wang, Lei / Marina, Alberto / Páez-Pérez, Edgar D / Jäger, Christian / Gavotto, Floriane / Tersa, Montse / Perrone, Sebastián / Contreras, F-Xabier / Prandi, Jacques / Gilleron, Martine / Linster, Carole L / Corzana, Francisco / Lowary, Todd L / Trastoy, Beatriz / Guerin, Marcelo E

Science advances

2021 Volume 7, Issue 42, Page(s) eabj4565

Abstract: Glycolipids are prominent components of bacterial membranes that play critical roles not only in maintaining the structural integrity of the cell but also in modulating host-pathogen interactions. PatA is an essential acyltransferase involved in the ... ...

Abstract	Glycolipids are prominent components of bacterial membranes that play critical roles not only in maintaining the structural integrity of the cell but also in modulating host-pathogen interactions. PatA is an essential acyltransferase involved in the biosynthesis of phosphatidyl-
Language	English
Publishing date	2021-10-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abj4565
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Article ; Online: Dissecting the Structural and Chemical Determinants of the "Open-to-Closed" Motion in the Mannosyltransferase PimA from Mycobacteria.

Rodrigo-Unzueta, Ane / Ghirardello, Mattia / Urresti, Saioa / Delso, Ignacio / Giganti, David / Anso, Itxaso / Trastoy, Beatriz / Comino, Natalia / Tersa, Montse / D'Angelo, Cecilia / Cifuente, Javier O / Marina, Alberto / Liebau, Jobst / Mäler, Lena / Chenal, Alexandre / Albesa-Jové, David / Merino, Pedro / Guerin, Marcelo E

Biochemistry

2020 Volume 59, Issue 32, Page(s) 2934–2945

Abstract: The phosphatidyl- ...

Abstract	The phosphatidyl-
MeSH term(s)	Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Mannose/metabolism ; Mannosyltransferases/chemistry ; Mannosyltransferases/metabolism ; Models, Molecular ; Movement ; Protein Conformation
Chemical Substances	Bacterial Proteins ; Mannosyltransferases (EC 2.4.1.-) ; phosphatidyl-myo-inositol mannosyltransferase PimA, Mycobacterium smegmatis (EC 2.4.1.-) ; Mannose (PHA4727WTP)
Language	English
Publishing date	2020-08-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.0c00376
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Article: Dissecting the Structural and Chemical Determinants of the “Open-to-Closed” Motion in the Mannosyltransferase PimA from Mycobacteria

Rodrigo-Unzueta, Ane / Ghirardello, Mattia / Urresti, Saioa / Delso, Ignacio / Giganti, David / Anso, Itxaso / Trastoy, Beatriz / Comino, Natalia / Tersa, Montse / D’Angelo, Cecilia / Cifuente, Javier O / Marina, Alberto / Liebau, Jobst / Mäler, Lena / Chenal, Alexandre / Albesa-Jové, David / Merino, Pedro / Guerin, Marcelo E

Biochemistry. 2020 July 28, v. 59, no. 32

2020

Abstract: The phosphatidyl-myo-inositol mannosyltransferase A (PimA) is an essential peripheral membrane glycosyltransferase that initiates the biosynthetic pathway of phosphatidyl-myo-inositol mannosides (PIMs), key structural elements and virulence factors of ... ...

Abstract	The phosphatidyl-myo-inositol mannosyltransferase A (PimA) is an essential peripheral membrane glycosyltransferase that initiates the biosynthetic pathway of phosphatidyl-myo-inositol mannosides (PIMs), key structural elements and virulence factors of Mycobacterium tuberculosis. PimA undergoes functionally important conformational changes, including (i) α-helix-to-β-strand and β-strand-to-α-helix transitions and (ii) an “open-to-closed” motion between the two Rossmann-fold domains, a conformational change that is necessary to generate a catalytically competent active site. In previous work, we established that GDP-Man and GDP stabilize the enzyme and facilitate the switch to a more compact active state. To determine the structural contribution of the mannose ring in such an activation mechanism, we analyzed a series of chemical derivatives, including mannose phosphate (Man-P) and mannose pyrophosphate-ribose (Man-PP-RIB), and additional GDP derivatives, such as pyrophosphate ribose (PP-RIB) and GMP, by the combined use of X-ray crystallography, limited proteolysis, circular dichroism, isothermal titration calorimetry, and small angle X-ray scattering methods. Although the β-phosphate is present, we found that the mannose ring, covalently attached to neither phosphate (Man-P) nor PP-RIB (Man-PP-RIB), does promote the switch to the active compact form of the enzyme. Therefore, the nucleotide moiety of GDP-Man, and not the sugar ring, facilitates the “open-to-closed” motion, with the β-phosphate group providing the high-affinity binding to PimA. Altogether, the experimental data contribute to a better understanding of the structural determinants involved in the “open-to-closed” motion not only observed in PimA but also visualized and/or predicted in other glycosyltransfeases. In addition, the experimental data might prove to be useful for the discovery and/or development of PimA and/or glycosyltransferase inhibitors.
Keywords	Mycobacterium tuberculosis ; X-ray diffraction ; active sites ; biochemical pathways ; calorimetry ; chemical bonding ; chemical derivatives ; chemical elements ; circular dichroism spectroscopy ; mannose ; mannosyltransferases ; moieties ; phosphates ; proteolysis ; ribose ; small-angle X-ray scattering ; titration ; virulence
Language	English
Dates of publication	2020-0728
Size	p. 2934-2945.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-light
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.0c00376
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: The Redox State Regulates the Conformation of Rv2466c to Activate the Antitubercular Prodrug TP053.

Albesa-Jové, David / Comino, Natalia / Tersa, Montse / Mohorko, Elisabeth / Urresti, Saioa / Dainese, Elisa / Chiarelli, Laurent R / Pasca, Maria Rosalia / Manganelli, Riccardo / Makarov, Vadim / Riccardi, Giovanna / Svergun, Dmitri I / Glockshuber, Rudi / Guerin, Marcelo E

The Journal of biological chemistry

2015 Volume 290, Issue 52, Page(s) 31077–31089

Abstract: Rv2466c is a key oxidoreductase that mediates the reductive activation of TP053, a thienopyrimidine derivative that kills replicating and non-replicating Mycobacterium tuberculosis, but whose mode of action remains enigmatic. Rv2466c is a homodimer in ... ...

Abstract	Rv2466c is a key oxidoreductase that mediates the reductive activation of TP053, a thienopyrimidine derivative that kills replicating and non-replicating Mycobacterium tuberculosis, but whose mode of action remains enigmatic. Rv2466c is a homodimer in which each subunit displays a modular architecture comprising a canonical thioredoxin-fold with a Cys(19)-Pro(20)-Trp(21)-Cys(22) motif, and an insertion consisting of a four α-helical bundle and a short α-helical hairpin. Strong evidence is provided for dramatic conformational changes during the Rv2466c redox cycle, which are essential for TP053 activity. Strikingly, a new crystal structure of the reduced form of Rv2466c revealed the binding of a C-terminal extension in α-helical conformation to a pocket next to the active site cysteine pair at the interface between the thioredoxin domain and the helical insertion domain. The ab initio low-resolution envelopes obtained from small angle x-ray scattering showed that the fully reduced form of Rv2466c adopts a "closed" compact conformation in solution, similar to that observed in the crystal structure. In contrast, the oxidized form of Rv2466c displays an "open" conformation, where tertiary structural changes in the α-helical subdomain suffice to account for the observed conformational transitions. Altogether our structural, biochemical, and biophysical data strongly support a model in which the formation of the catalytic disulfide bond upon TP053 reduction triggers local structural changes that open the substrate binding site of Rv2466c allowing the release of the activated, reduced form of TP053. Our studies suggest that similar structural changes might have a functional role in other members of the thioredoxin-fold superfamily.
MeSH term(s)	Antitubercular Agents/chemistry ; Bacterial Proteins/chemistry ; Bacterial Proteins/genetics ; Crystallography, X-Ray ; Models, Molecular ; Mycobacterium tuberculosis/chemistry ; Mycobacterium tuberculosis/genetics ; Oxidation-Reduction ; Prodrugs/chemistry ; Protein Binding ; Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary
Chemical Substances	Antitubercular Agents ; Bacterial Proteins ; Prodrugs
Language	English
Publishing date	2015-11-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M115.677039
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Article ; Online: Structural basis for selective recognition of acyl chains by the membrane-associated acyltransferase PatA.

Albesa-Jové, David / Svetlíková, Zuzana / Tersa, Montse / Sancho-Vaello, Enea / Carreras-González, Ana / Bonnet, Pascal / Arrasate, Pedro / Eguskiza, Ander / Angala, Shiva K / Cifuente, Javier O / Korduláková, Jana / Jackson, Mary / Mikušová, Katarína / Guerin, Marcelo E

Nature communications

2016 Volume 7, Page(s) 10906

Abstract: The biosynthesis of phospholipids and glycolipids are critical pathways for virtually all cell membranes. PatA is an essential membrane associated acyltransferase involved in the biosynthesis of mycobacterial phosphatidyl-myo-inositol mannosides (PIMs). ... ...

Abstract	The biosynthesis of phospholipids and glycolipids are critical pathways for virtually all cell membranes. PatA is an essential membrane associated acyltransferase involved in the biosynthesis of mycobacterial phosphatidyl-myo-inositol mannosides (PIMs). The enzyme transfers a palmitoyl moiety from palmitoyl-CoA to the 6-position of the mannose ring linked to 2-position of inositol in PIM1/PIM2. We report here the crystal structures of PatA from Mycobacterium smegmatis in the presence of its naturally occurring acyl donor palmitate and a nonhydrolyzable palmitoyl-CoA analog. The structures reveal an α/β architecture, with the acyl chain deeply buried into a hydrophobic pocket that runs perpendicular to a long groove where the active site is located. Enzyme catalysis is mediated by an unprecedented charge relay system, which markedly diverges from the canonical HX4D motif. Our studies establish the mechanistic basis of substrate/membrane recognition and catalysis for an important family of acyltransferases, providing exciting possibilities for inhibitor design.
MeSH term(s)	Acyltransferases/chemistry ; Acyltransferases/metabolism ; Catalysis ; Catalytic Domain ; Cell Membrane/metabolism ; Crystallography, X-Ray ; Mannosides/biosynthesis ; Mycobacterium smegmatis/chemistry ; Mycobacterium smegmatis/metabolism ; Palmitates/metabolism ; Palmitoyl Coenzyme A/metabolism ; Phosphatidylinositols/biosynthesis ; Protein Structure, Secondary ; Protein Structure, Tertiary
Chemical Substances	Mannosides ; Palmitates ; Phosphatidylinositols ; Palmitoyl Coenzyme A (1763-10-6) ; Acyltransferases (EC 2.3.-)
Language	English
Publishing date	2016-03-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2041-1723
ISSN (online)	2041-1723
DOI	10.1038/ncomms10906
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Article ; Online: Rv2466c mediates the activation of TP053 to kill replicating and non-replicating Mycobacterium tuberculosis.

Albesa-Jové, David / Chiarelli, Laurent R / Makarov, Vadim / Pasca, Maria Rosalia / Urresti, Saioa / Mori, Giorgia / Salina, Elena / Vocat, Anthony / Comino, Natalia / Mohorko, Elisabeth / Ryabova, Svetlana / Pfieiffer, Bernhard / Lopes Ribeiro, Ana Luisa de Jesus / Rodrigo-Unzueta, Ane / Tersa, Montse / Zanoni, Giuseppe / Buroni, Silvia / Altmann, Karl-Heinz / Hartkoorn, Ruben C /

Glockshuber, Rudi / Cole, Stewart T / Riccardi, Giovanna / Guerin, Marcelo E

ACS chemical biology

2014 Volume 9, Issue 7, Page(s) 1567–1575

Abstract: The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis highlights the need to discover new antitubercular agents. Here we describe the synthesis and characterization of a new series of thienopyrimidine (TP) ... ...

Abstract	The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis highlights the need to discover new antitubercular agents. Here we describe the synthesis and characterization of a new series of thienopyrimidine (TP) compounds that kill both replicating and non-replicating M. tuberculosis. The strategy to determine the mechanism of action of these TP derivatives was to generate resistant mutants to the most effective compound TP053 and to isolate the genetic mutation responsible for this phenotype. The only non-synonymous mutation found was a g83c transition in the Rv2466c gene, resulting in the replacement of tryptophan 28 by a serine. The Rv2466c overexpression increased the sensitivity of M. tuberculosis wild-type and resistant mutant strains to TP053, indicating that TP053 is a prodrug activated by Rv2466c. Biochemical studies performed with purified Rv2466c demonstrated that only the reduced form of Rv2466c can activate TP053. The 1.7 Å resolution crystal structure of the reduced form of Rv2466c, a protein whose expression is transcriptionally regulated during the oxidative stress response, revealed a unique homodimer in which a β-strand is swapped between the thioredoxin domains of each subunit. A pronounced groove harboring the unusual active-site motif CPWC might account for the uncommon reactivity profile of the protein. The mutation of Trp28Ser clearly predicts structural defects in the thioredoxin fold, including the destabilization of the dimerization core and the CPWC motif, likely impairing the activity of Rv2466c against TP053. Altogether our experimental data provide insights into the molecular mechanism underlying the anti-mycobacterial activity of TP-based compounds, paving the way for future drug development programmes.
MeSH term(s)	Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacology ; Drug Design ; Drug Resistance, Multiple, Bacterial ; Genes, Bacterial ; Humans ; Microbial Sensitivity Tests ; Models, Molecular ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/growth & development ; Pyrimidines/chemistry ; Pyrimidines/pharmacology ; Tuberculosis/drug therapy
Chemical Substances	Antitubercular Agents ; Pyrimidines ; thienopyrimidine
Language	English
Publishing date	2014-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/cb500149m
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