Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition
Abstract
Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb’s cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.
- Authors:
- more »
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institute of Allergy and Infectious Diseases (NIAID); Abby and Howard P. Milstein Program in Chemical Biology and Translational Medicine; Welch Foundation; TB Structural Genomics; Bill and Melinda Gates Foundation; National Cancer Institute (NCI); William Randolph Hearst Foundation
- OSTI Identifier:
- 1504971
- Grant/Contract Number:
- AC02-06CH11357; U19AI-111143; A-0015; P01AI095208; P30 CA008748
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Science
- Additional Journal Information:
- Journal Volume: 363; Journal Issue: 6426; Journal ID: ISSN 0036-8075
- Publisher:
- AAAS
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Ballinger, Elaine, Mosior, John, Hartman, Travis, Burns-Huang, Kristin, Gold, Ben, Morris, Roxanne, Goullieux, Laurent, Blanc, Isabelle, Vaubourgeix, Julien, Lagrange, Sophie, Fraisse, Laurent, Sans, Stéphanie, Couturier, Cedric, Bacqué, Eric, Rhee, Kyu, Scarry, Sarah M., Aubé, Jeffrey, Yang, Guangbin, Ouerfelli, Ouathek, Schnappinger, Dirk, Ioerger, Thomas R., Engelhart, Curtis A., McConnell, Jennifer A., McAulay, Kathrine, Fay, Allison, Roubert, Christine, Sacchettini, James, and Nathan, Carl. Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition. United States: N. p., 2019.
Web. doi:10.1126/science.aau8959.
Ballinger, Elaine, Mosior, John, Hartman, Travis, Burns-Huang, Kristin, Gold, Ben, Morris, Roxanne, Goullieux, Laurent, Blanc, Isabelle, Vaubourgeix, Julien, Lagrange, Sophie, Fraisse, Laurent, Sans, Stéphanie, Couturier, Cedric, Bacqué, Eric, Rhee, Kyu, Scarry, Sarah M., Aubé, Jeffrey, Yang, Guangbin, Ouerfelli, Ouathek, Schnappinger, Dirk, Ioerger, Thomas R., Engelhart, Curtis A., McConnell, Jennifer A., McAulay, Kathrine, Fay, Allison, Roubert, Christine, Sacchettini, James, & Nathan, Carl. Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition. United States. https://doi.org/10.1126/science.aau8959
Ballinger, Elaine, Mosior, John, Hartman, Travis, Burns-Huang, Kristin, Gold, Ben, Morris, Roxanne, Goullieux, Laurent, Blanc, Isabelle, Vaubourgeix, Julien, Lagrange, Sophie, Fraisse, Laurent, Sans, Stéphanie, Couturier, Cedric, Bacqué, Eric, Rhee, Kyu, Scarry, Sarah M., Aubé, Jeffrey, Yang, Guangbin, Ouerfelli, Ouathek, Schnappinger, Dirk, Ioerger, Thomas R., Engelhart, Curtis A., McConnell, Jennifer A., McAulay, Kathrine, Fay, Allison, Roubert, Christine, Sacchettini, James, and Nathan, Carl. Fri .
"Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition". United States. https://doi.org/10.1126/science.aau8959. https://www.osti.gov/servlets/purl/1504971.
@article{osti_1504971,
title = {Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition},
author = {Ballinger, Elaine and Mosior, John and Hartman, Travis and Burns-Huang, Kristin and Gold, Ben and Morris, Roxanne and Goullieux, Laurent and Blanc, Isabelle and Vaubourgeix, Julien and Lagrange, Sophie and Fraisse, Laurent and Sans, Stéphanie and Couturier, Cedric and Bacqué, Eric and Rhee, Kyu and Scarry, Sarah M. and Aubé, Jeffrey and Yang, Guangbin and Ouerfelli, Ouathek and Schnappinger, Dirk and Ioerger, Thomas R. and Engelhart, Curtis A. and McConnell, Jennifer A. and McAulay, Kathrine and Fay, Allison and Roubert, Christine and Sacchettini, James and Nathan, Carl},
abstractNote = {Mycobacterium tuberculosis (Mtb) is the leading infectious cause of death in humans. Synthesis of lipids critical for Mtb’s cell wall and virulence depends on phosphopantetheinyl transferase (PptT), an enzyme that transfers 4'-phosphopantetheine (Ppt) from coenzyme A (CoA) to diverse acyl carrier proteins. We identified a compound that kills Mtb by binding and partially inhibiting PptT. Killing of Mtb by the compound is potentiated by another enzyme encoded in the same operon, Ppt hydrolase (PptH), that undoes the PptT reaction. Thus, loss-of-function mutants of PptH displayed antimicrobial resistance. Our PptT-inhibitor cocrystal structure may aid further development of antimycobacterial agents against this long-sought target. The opposing reactions of PptT and PptH uncover a regulatory pathway in CoA physiology.},
doi = {10.1126/science.aau8959},
journal = {Science},
number = 6426,
volume = 363,
place = {United States},
year = {Fri Feb 01 00:00:00 EST 2019},
month = {Fri Feb 01 00:00:00 EST 2019}
}
Web of Science
Works referenced in this record:
Novel Cephalosporins Selectively Active on Nonreplicating Mycobacterium tuberculosis
journal, June 2016
- Gold, Ben; Smith, Robert; Nguyen, Quyen
- Journal of Medicinal Chemistry, Vol. 59, Issue 13
Phaser.MRage: automated molecular replacement.
text, January 2013
- Bunkóczi, Gábor; Echols, Nathaniel; McCoy, Airlie
- Apollo - University of Cambridge Repository
Chemoenzymatic exchange of phosphopantetheine on protein and peptide
journal, January 2014
- Kosa, Nicolas M.; Pham, Kevin M.; Burkart, Michael D.
- Chem. Sci., Vol. 5, Issue 3
Structure, function, and biogenesis of the cell wall of Mycobacterium tuberculosis
journal, February 2003
- Brennan, P. J.
- Tuberculosis, Vol. 83, Issue 1-3
A Droplet-Based, Composite PDMS/Glass Capillary Microfluidic System for Evaluating Protein Crystallization Conditions by Microbatch and Vapor-Diffusion Methods with On-Chip X-Ray Diffraction
journal, May 2004
- Zheng, Bo; Tice, Joshua D.; Roach, L. Spencer
- Angewandte Chemie, Vol. 116, Issue 19
Enzyme kinetics: partial and complete non-competitive inhibition
journal, January 1999
- Whiteley, Chris G.
- Biochemical Education, Vol. 27, Issue 1
Kunkel Lecture: Fundamental immunodeficiency and its correction
journal, July 2017
- Nathan, Carl
- The Journal of Experimental Medicine, Vol. 214, Issue 8
I-TASSER: a unified platform for automated protein structure and function prediction
journal, March 2010
- Roy, Ambrish; Kucukural, Alper; Zhang, Yang
- Nature Protocols, Vol. 5, Issue 4
Comprehensive Essentiality Analysis of the Mycobacterium tuberculosis Genome via Saturating Transposon Mutagenesis
journal, January 2017
- DeJesus, Michael A.; Gerrick, Elias R.; Xu, Weizhen
- mBio, Vol. 8, Issue 1
Investigations on Pantothenic Acid and Its Related Compounds: X. Biochemical Studies (5).* Purification and Substrate Specificity of Phosphopantothenoylcysteine Decarboxylase from Rat Liver**
journal, March 1967
- Abiko, Yasushi
- The Journal of Biochemistry, Vol. 61, Issue 3
Protein inactivation in mycobacteria by controlled proteolysis and its application to deplete the beta subunit of RNA polymerase
journal, November 2010
- Kim, Jee-Hyun; Wei, Jun-Rong; Wallach, Joshua B.
- Nucleic Acids Research, Vol. 39, Issue 6
Interactive XCMS Online: Simplifying Advanced Metabolomic Data Processing and Subsequent Statistical Analyses
journal, June 2014
- Gowda, Harsha; Ivanisevic, Julijana; Johnson, Caroline H.
- Analytical Chemistry, Vol. 86, Issue 14
Biochemistry and molecular genetics of cell‐wall lipid biosynthesis in mycobacteria
journal, April 1997
- Kolattukudy, P. E.; Fernandes, Norvin D.; Azad, A. K.
- Molecular Microbiology, Vol. 24, Issue 2
Coenzyme A biosynthesis: an antimicrobial drug target
journal, January 2008
- Spry, Christina; Kirk, Kiaran; Saliba, Kevin J.
- FEMS Microbiology Reviews, Vol. 32, Issue 1
Metabolite damage and its repair or pre-emption
journal, January 2013
- Linster, Carole L.; Van Schaftingen, Emile; Hanson, Andrew D.
- Nature Chemical Biology, Vol. 9, Issue 2
Novel Insights into the Mechanism of Inhibition of MmpL3, a Target of Multiple Pharmacophores in Mycobacterium tuberculosis
journal, August 2014
- Li, Wei; Upadhyay, Ashutosh; Fontes, Fabio L.
- Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 11
A genetic strategy to identify targets for the development of drugs that prevent bacterial persistence
journal, November 2013
- Kim, J. -H.; O'Brien, K. M.; Sharma, R.
- Proceedings of the National Academy of Sciences, Vol. 110, Issue 47
A Droplet-Based, Composite PDMS/Glass Capillary Microfluidic System for Evaluating Protein Crystallization Conditions by Microbatch and Vapor-Diffusion Methods with On-Chip X-Ray Diffraction
journal, May 2004
- Zheng, Bo; Tice, Joshua D.; Roach, L. Spencer
- Angewandte Chemie International Edition, Vol. 43, Issue 19
Mycobacterium tuberculosis acyl carrier protein synthase adopts two different pH-dependent structural conformations
journal, June 2011
- Gokulan, Kuppan; Aggarwal, Anup; Shipman, Lance
- Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 7
Recent advances in targeting coenzyme A biosynthesis and utilization for antimicrobial drug development
journal, August 2014
- Moolman, Wessel J. A.; de Villiers, Marianne; Strauss, Erick
- Biochemical Society Transactions, Vol. 42, Issue 4
Sparse matrix sampling: a screening method for crystallization of proteins
journal, August 1991
- Jancarik, J.; Kim, S. H.
- Journal of Applied Crystallography, Vol. 24, Issue 4
The I-TASSER Suite: protein structure and function prediction
journal, December 2014
- Yang, Jianyi; Yan, Renxiang; Roy, Ambrish
- Nature Methods, Vol. 12, Issue 1
I-TASSER server for protein 3D structure prediction
journal, January 2008
- Zhang, Yang
- BMC Bioinformatics, Vol. 9, Issue 1
A Comparative Lipidomics Platform for Chemotaxonomic Analysis of Mycobacterium tuberculosis
journal, December 2011
- Layre, Emilie; Sweet, Lindsay; Hong, Sunhee
- Chemistry & Biology, Vol. 18, Issue 12
A sensitive single-enzyme assay system using the non-ribosomal peptide synthetase BpsA for measurement of L-glutamine in biological samples
journal, January 2017
- Brown, Alistair S.; Robins, Katherine J.; Ackerley, David F.
- Scientific Reports, Vol. 7, Issue 1
Metabolomic data streaming for biology-dependent data acquisition
journal, June 2014
- Rinehart, Duane; Johnson, Caroline H.; Nguyen, Thomas
- Nature Biotechnology, Vol. 32, Issue 6
Unambiguous Synthesis and Prophylactic Antimalarial Activities of Imidazolidinedione Derivatives
journal, October 2005
- Zhang, Quan; Guan, Jian; Sacci, John
- Journal of Medicinal Chemistry, Vol. 48, Issue 20
Molecular mechanisms that confer antibacterial drug resistance
journal, August 2000
- Walsh, Christopher
- Nature, Vol. 406, Issue 6797
Expression, purification and characterization of the acyl carrier protein phosphodiesterase from Pseudomonas Aeruginosa
journal, June 2010
- Murugan, Elavazhagan; Kong, Rong; Sun, Huihua
- Protein Expression and Purification, Vol. 71, Issue 2
Pathway-Selective Sensitization of Mycobacterium tuberculosis for Target-Based Whole-Cell Screening
journal, July 2012
- Abrahams, Garth L.; Kumar, Anuradha; Savvi, Suzana
- Chemistry & Biology, Vol. 19, Issue 7
A View from Above: Cloud Plots to Visualize Global Metabolomic Data
journal, December 2012
- Patti, Gary J.; Tautenhahn, Ralf; Rinehart, Duane
- Analytical Chemistry, Vol. 85, Issue 2
A Novel Small-Molecule Inhibitor of the Mycobacterium tuberculosis Demethylmenaquinone Methyltransferase MenG Is Bactericidal to Both Growing and Nutritionally Deprived Persister Cells
journal, February 2017
- Sukheja, Paridhi; Kumar, Pradeep; Mittal, Nisha
- mBio, Vol. 8, Issue 1
Acyl Carrier Protein Phosphodiesterase (AcpH) of Escherichia coli Is a Non-Canonical Member of the HD Phosphatase/Phosphodiesterase Family †
journal, January 2007
- Thomas, Jacob; Rigden, Daniel J.; Cronan, John E.
- Biochemistry, Vol. 46, Issue 1
4′-Phosphopantetheinyl Transferase PptT, a New Drug Target Required for Mycobacterium tuberculosis Growth and Persistence In Vivo
journal, December 2012
- Leblanc, Cécile; Prudhomme, Thomas; Tabouret, Guillaume
- PLoS Pathogens, Vol. 8, Issue 12
Validation of CoaBC as a Bactericidal Target in the Coenzyme A Pathway of Mycobacterium tuberculosis
journal, October 2016
- Evans, Joanna C.; Trujillo, Carolina; Wang, Zhe
- ACS Infectious Diseases, Vol. 2, Issue 12
AcpM, the Meromycolate Extension Acyl Carrier Protein of Mycobacterium tuberculosis , Is Activated by the 4′-Phosphopantetheinyl Transferase PptT, a Potential Target of the Multistep Mycolic Acid Biosynthesis
journal, March 2015
- Zimhony, Oren; Schwarz, Alon; Raitses-Gurevich, Maria
- Biochemistry, Vol. 54, Issue 14
Rapid and flexible biochemical assays for evaluating 4′-phosphopantetheinyl transferase activity
journal, May 2011
- Owen, Jeremy G.; Copp, Janine N.; Ackerley, David F.
- Biochemical Journal, Vol. 436, Issue 3
Reaction intermediate analogues as bisubstrate inhibitors of pantothenate synthetase
journal, March 2014
- Xu, Zhixiang; Yin, Wei; Martinelli, Leonardo K.
- Bioorganic & Medicinal Chemistry, Vol. 22, Issue 5
Nonsteroidal anti-inflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials
journal, September 2012
- Gold, B.; Pingle, M.; Brickner, S. J.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 40
Exploiting the coenzyme A biosynthesis pathway for the identification of new antimalarial agents: the case for pantothenamides
journal, August 2014
- Saliba, Kevin J.; Spry, Christina
- Biochemical Society Transactions, Vol. 42, Issue 4
Structure, Biochemistry, and Inhibition of Essential 4′-Phosphopantetheinyl Transferases from Two Species of Mycobacteria
journal, July 2014
- Vickery, Christopher R.; Kosa, Nicolas M.; Casavant, Ellen P.
- ACS Chemical Biology, Vol. 9, Issue 9
Crystal structure of the essential Mycobacterium tuberculosis phosphopantetheinyl transferase PptT, solved as a fusion protein with maltose binding protein
journal, December 2014
- Jung, James; Bashiri, Ghader; Johnston, Jodie M.
- Journal of Structural Biology, Vol. 188, Issue 3
The Enigmatic Acyl Carrier Protein Phosphodiesterase of Escherichia coli : GENETIC AND ENZYMOLOGICAL CHARACTERIZATION
journal, August 2005
- Thomas, Jacob; Cronan, John E.
- Journal of Biological Chemistry, Vol. 280, Issue 41
Characterization of a Bacillus megaterium strain with metal bioremediation potential and in silico discovery of novel cadmium binding motifs in the regulator, CadC
journal, March 2021
- Kumari, Weerasingha Mudiyanselage Nilmini H.; Thiruchittampalam, Shalini; Weerasinghe, Mahinagoda Siril Samantha
- Applied Microbiology and Biotechnology, Vol. 105, Issue 6
Acyl Carrier Protein
journal, April 1967
- Vagelos, P. Roy; Larrabee, Allan R.
- Journal of Biological Chemistry, Vol. 242, Issue 8
Works referencing / citing this record:
Structural insights into phosphopantetheinyl hydrolase PptH from Mycobacterium tuberculosis
journal, January 2020
- Mosior, John; Bourland, Ronnie; Soma, Shivatheja
- Protein Science, Vol. 29, Issue 3
Drug-resistance in Mycobacterium tuberculosis : where we stand
journal, January 2019
- Mabhula, Amanda; Singh, Vinayak
- MedChemComm, Vol. 10, Issue 8
Harnessing Biological Insight to Accelerate Tuberculosis Drug Discovery
journal, July 2019
- de Wet, Timothy J.; Warner, Digby F.; Mizrahi, Valerie
- Accounts of Chemical Research, Vol. 52, Issue 8