Glutamate mediated metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis

Lee, J.J., Lim, J., Gao, S., Lawson, C.P., Odell, M., Raheem, S., Woo, J., Kang, S-H., Kang, S-S., Jeon, B-Y. and Eoh, H. 2018. Glutamate mediated metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis. Scientific Reports. 8.

TitleGlutamate mediated metabolic neutralization mitigates propionate toxicity in intracellular Mycobacterium tuberculosis
AuthorsLee, J.J., Lim, J., Gao, S., Lawson, C.P., Odell, M., Raheem, S., Woo, J., Kang, S-H., Kang, S-S., Jeon, B-Y. and Eoh, H.
Abstract

Metabolic networks in biological systems are interconnected, such that malfunctioning parts can be corrected by other parts within the network, a process termed adaptive metabolism. Unlike Bacillus Calmette-Guérin (BCG), Mycobacterium tuberculosis (Mtb) better manages its intracellular lifestyle by executing adaptive metabolism. Here, we used metabolomics and identified glutamate synthase (GltB/D) that converts glutamine to glutamate (Q → E) as a metabolic effort used to neutralize cytoplasmic pH that is acidified while consuming host propionate carbon through the methylcitrate cycle (MCC). Methylisocitrate lyase, the last step of the MCC, is intrinsically downregulated in BCG, leading to obstruction of carbon flux toward central carbon metabolism, accumulation of MCC intermediates, and interference with GltB/D mediated neutralizing activity against propionate toxicity. Indeed, vitamin B12 mediated bypass MCC and additional supplement of glutamate led to selectively correct the phenotypic attenuation in BCG and restore the adaptive capacity of BCG to the similar level of Mtb phenotype. Collectively, a defective crosstalk between MCC and Q → E contributes to attenuation of intracellular BCG. Furthermore, GltB/D inhibition enhances the level of propionate toxicity in Mtb. Thus, these findings revealed a new adaptive metabolism and propose GltB/D as a synergistic target to improve the antimicrobial outcomes of MCC inhibition in Mtb.

KeywordsBacteriology, Infection
JournalScientific Reports
Journal citation8
ISSN2045-2322
Year2018
PublisherSpringer
Publisher's versions41598-018-26950-z.pdf
Digital Object Identifier (DOI)doi:10.1038/s41598-018-26950-z
Publication dates
Published31 May 2018
LicenseCC BY 4.0

Related outputs

Signatures of anthocyanin metabolites identified in humans inhibit biomarkers of vascular inflammation in human endothelial cells
Warner, E.F., Smith, M.J., Zhang, Q., Raheem, S., O’Hagan, D., O'Connell, M.A. and Kay, C.D. 2017. Signatures of anthocyanin metabolites identified in humans inhibit biomarkers of vascular inflammation in human endothelial cells. Molecular Nutrition & Food Research. 61 (9), p. 1600053.

Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance
Warhurst, D., Craig, J.C. and Raheem, S. 2016. Influence of LAR and VAR on Para-Aminopyridine Antimalarials Targetting Haematin in Chloroquine-Resistance. PLoS ONE. 11 (8), p. e0160091.

Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells
Warner, E.F., Zhang, Q., Raheem, S., O’Hagan, D., O’Connell, M.A. and Kay, C.D. 2016. Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells. Journal of Nutrition. 146 (3), pp. 465-473.

Effects of Fluconazole on the Metabolomic Profile of Candida albicans
Katragkou, A., Alexander, E.L., Eoh, H., Raheem, S., Roilides, E. and Walsh, T.J. 2016. Effects of Fluconazole on the Metabolomic Profile of Candida albicans. Journal of Antimicrobial Chemotherapy. 71 (3), pp. 635-640.

Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytes.
di Gesso, J.L., Kerr, J.S., Zhang, Q., Raheem, S., Yalamanchili, S.K., O’Hagan, D., Kay, C.D. and O'Connell, M.A. 2015. Flavonoid metabolites reduce tumor necrosis factor-α secretion to a greater extent than their precursor compounds in human THP-1 monocytes. Molecular Nutrition & Food Research. 59 (6), pp. 1143-1154.

Anthocyanins and their physiologically relevant metabolites alter the expression of IL-6 and VCAM-1 in CD40L and oxidized LDL challenged vascular endothelial cells
Amin, H.P., Czank, C., Raheem, S., Zhang, Q., Botting, N.P., Cassidy, A. and Kay, C.D. 2015. Anthocyanins and their physiologically relevant metabolites alter the expression of IL-6 and VCAM-1 in CD40L and oxidized LDL challenged vascular endothelial cells. Molecular Nutrition & Food Research. 59 (6), pp. 1095-1106.

Methods for Isolating, Identifying, and Quantifying Anthocyanin Metabolites in Clinical Samples
de Ferrars, R.M., Czank, C., Saha, S., Needs, P.W., Zhang, Q., Raheem, S., Botting, N.P., Kroon, P.A. and Kay, C.D. 2014. Methods for Isolating, Identifying, and Quantifying Anthocyanin Metabolites in Clinical Samples. Analytical Chemistry. 86 (20), pp. 10052-10058.

Arabidopsis AtPARK13, which confers thermotolerance, targets misfolded proteins
Basak, I., Pal, R., Patil, K.S., Dunne, A., Ho, H.P., Lee, S., Peiris, D., Maple-Grødem, J., Odell, M., Chang, E.J., Larsen, J.P. and Møller, S. 2014. Arabidopsis AtPARK13, which confers thermotolerance, targets misfolded proteins. Journal of Biological Chemistry. 289, pp. 14458-14469.

ROS-mediated DJ-1 monomerization modulates intracellular trafficking involving Karyopherin-2
Bjørkblom, B., Maple-Grødem, J., Puno, M.R., Odell, M., Larsen, J.P. and Møller, S. 2014. ROS-mediated DJ-1 monomerization modulates intracellular trafficking involving Karyopherin-2. Molecular and Cellular Biology. 34 (16), pp. 3024-3040.

Arabidopsis AtPARK13, which confers thermotolerance, targets misfolded proteins
Basak, I., Pal, R., Patil, K.S., Dunne, A., Ho, H.P., Lee, S., Peiris, D., Maple-Grødem, J., Odell, M., Chang, E.J., Larsen, J.P. and Møller, S. 2014. Arabidopsis AtPARK13, which confers thermotolerance, targets misfolded proteins. Journal of Biological Chemistry. 289 (21), pp. 14458-69.

Proteomics analysis of Bacillus licheniformis in response to oligosaccharides elicitors
Reffatti, P.F., Roy, I., Odell, M. and Keshavarz, T. 2014. Proteomics analysis of Bacillus licheniformis in response to oligosaccharides elicitors. Enzyme Microb Technol. . 61-62, pp. 61-66.

Evidence for the involvement of intracellular Ca 2+ ions in the elicitation mechanism of Bacillus Licheniformis
Reffatti, P., Roy, I., Odell, M. and Keshavarz, T. 2013. Evidence for the involvement of intracellular Ca 2+ ions in the elicitation mechanism of Bacillus Licheniformis. Journal of Molecular Microbiology and Biotechnology. OnlineFirst.

The neuroprotective role of catalase overexpression in SH-SY5Y cells against beta-amyloid and H2O2 toxicity
Chilumuri, A., Odell, M. and Milton, N.G.N. 2013. The neuroprotective role of catalase overexpression in SH-SY5Y cells against beta-amyloid and H2O2 toxicity. Alzheimer's & Dementia. 9 (4), p. P361.

Structure of Cu(I)-bound DJ-1 reveals a biscysteinate metal binding site at the homodimer interface: insights into mutational inactivation of DJ-1 in parkinsonism
Puno, M.R., Patel, N.A., Møller, S.G., Robinson, C.V., Moody, P.C.E. and Odell, M. 2013. Structure of Cu(I)-bound DJ-1 reveals a biscysteinate metal binding site at the homodimer interface: insights into mutational inactivation of DJ-1 in parkinsonism. Journal of the American Chemical Society. 135 (43), p. 15974–15977.

Benzothiazole aniline-tetra(ethylene glycol) and 3-amino-1,2,4-triazole inhibit neuroprotection against amyloid peptides by catalase overexpression in vitro
Chilumuri, A., Odell, M. and Milton, N.G.N. 2013. Benzothiazole aniline-tetra(ethylene glycol) and 3-amino-1,2,4-triazole inhibit neuroprotection against amyloid peptides by catalase overexpression in vitro. ACS chemical neuroscience. 4 (11), pp. 1501-1512.

Is quorum sensing involved in lovastatin production in the filamentous fungus Aspergillus terreus?
Raina, S., De Vizio, D., Palonen, E.K., Odell, M., Brandt, A.M., Soini, J.T. and Keshavarz, T. 2012. Is quorum sensing involved in lovastatin production in the filamentous fungus Aspergillus terreus? Process Biochemistry. 47 (5), pp. 843-852.

Flavonoid metabolism: the synthesis of phenolic glucuronides and sulfates as candidate metabolites for bioactivity studies of dietary flavonoids
Zhang, Q., Raheem, S., Botting, N.P., Slawin, A.M.Z., Kay, C.D. and O’Hagan, D. 2012. Flavonoid metabolism: the synthesis of phenolic glucuronides and sulfates as candidate metabolites for bioactivity studies of dietary flavonoids. Tetrahedron. 68, pp. 4194-4201.

Identification, cloning and characterization of two N-acetylgalactosamine binding lectins from the albumen gland of Helix pomatia
Markiv, A., Peiris, D., Curley, G.P., Odell, M. and Dwek, M. 2011. Identification, cloning and characterization of two N-acetylgalactosamine binding lectins from the albumen gland of Helix pomatia. Journal of Biological Chemistry. 286 (23), pp. 20260-20266.

Total synthesis of 3,5-O-dicaffeoylquinic acid and its derivatives
Raheem, S., Botting, Nigel P., Williamson, G. and Barron, D. 2011. Total synthesis of 3,5-O-dicaffeoylquinic acid and its derivatives. Tetrahedron Letters. 52 (52), p. 7175.

Quorum sensing as a method for improving sclerotiorin production in Penicillium sclerotiorum
Raina, S., Odell, M. and Keshavarz, T. 2010. Quorum sensing as a method for improving sclerotiorin production in Penicillium sclerotiorum. Journal of Biotechnology. 148 (2-3), pp. 91-98.

Cancer prognostication using a recombinant form of the lectin from Helix pomatia agglutinin
Dwek, M., Markiv, A. and Odell, M. 2009. Cancer prognostication using a recombinant form of the lectin from Helix pomatia agglutinin. Glycobiology. 19 (11), p. 1318.

Microbial quorum sensing: a tool or a target for antimicrobial therapy?
Raina, S., De Vizio, D., Odell, M., Clements, M.O., Vanhulle, S. and Keshavarz, T. 2009. Microbial quorum sensing: a tool or a target for antimicrobial therapy? Biotechnology and Applied Biochemistry. 54 (2), pp. 65-84.

Polyhydroxyalkanoate synthase in Bacillus cereus SPV, a class IV PHA synthase
Philip, S.E., Odell, M., Keshavarz, T. and Roy, I. 2008. Polyhydroxyalkanoate synthase in Bacillus cereus SPV, a class IV PHA synthase. 11th International Symposium on Biodegradable Polyesters. Massey University in Auckland, New Zealand 23 - 26 Nov 2008

Structural basis for nick recognition by a minimal pluripotent DNA ligase
Nair, P.A., Nandakumar, J., Smith, P., Odell, M., Lima, C.D. and Shuman, S. 2007. Structural basis for nick recognition by a minimal pluripotent DNA ligase. Nature Structural and Molecular Biology. 14 (8), pp. 770-778.

Polyhydroxy-alkanoates - the biodegradable polymers
Philip, S.E., Odell, M., Keshavarz, T. and Roy, I. 2007. Polyhydroxy-alkanoates - the biodegradable polymers. International Conference on Biodegradable Polymers: their production, characterisation and application. SCI, London 10 Dec 2007

Circadian orchestration of the hepatic proteome
Reddy, A.B., Karp, N.A., Maywood, E.S., Sage, E.A., Deery, M., O'Neill, J.S., Wong, G.K.Y., Chesham, J., Odell, M., Lilley, K.S., Kyriacou, C.P. and Hastings, M.H. 2006. Circadian orchestration of the hepatic proteome. Current Biology. 16 (11), pp. 1107-1115.

Polyhydroxyalkanoate synthases: the enzymes involved in biodegradable polymer synthesis
Valappil, S.P., Philip, S.E., Odell, M., Keshavarz, T. and Roy, I. 2005. Polyhydroxyalkanoate synthases: the enzymes involved in biodegradable polymer synthesis. Proceedings of Frontiers in Chemical Biology: Mechanistic Enzymology and Biocatalysis. Exeter, UK 31 Aug - 02 Sep 2005

DNA Ligases: Stuctures
Odell, M. 2004. DNA Ligases: Stuctures. in: Lennarz, W.J. and Lane, M.D. (ed.) Encyclopedia of biological chemistry Amsterdam, Netherlands Elsevier.

No ARM in it? (reply to Kippert and Gerloff)
Kyriacou, C.P. and Odell, M. 2004. No ARM in it? (reply to Kippert and Gerloff). Current Biology. 14 (16), pp. R652-R653.

Analysis of the DNA joining repertoire of Chlorella virus DNA ligase and a new crystal structure of the ligase-adenylate intermediate
Odell, M., Malinina, L., Sriskanda, V., Teplova, M. and Shuman, S. 2003. Analysis of the DNA joining repertoire of Chlorella virus DNA ligase and a new crystal structure of the ligase-adenylate intermediate. Nucleic Acids Research. 31 (17), pp. 5090-5100.

The Drosophila clock protein Timeless is a member of the Arm/HEAT family
Vodovar, N., Clayton, J., Costa, R., Odell, M. and Kyriacou, C.P. 2002. The Drosophila clock protein Timeless is a member of the Arm/HEAT family. Current Biology. 12 (18), pp. R610-R611.

Structure-based experimental confirmation of biochemical function to a methyltransferase, MJ0882, from hyperthermophile Methanococcus jannaschii
Huang, L., Hung, L., Odell, M., Yokota, H., Kim, R. and Kim, S.H. 2002. Structure-based experimental confirmation of biochemical function to a methyltransferase, MJ0882, from hyperthermophile Methanococcus jannaschii. Journal of Structural and Functional Genomics. 2 (3), pp. 121-127.

Crystal structure of eukaryotic DNA ligase–adenylate illuminates the mechanism of nick sensing and strand joining
Odell, M., Sriskanda, V., Shuman, S. and Nikolov, D.B. 2000. Crystal structure of eukaryotic DNA ligase–adenylate illuminates the mechanism of nick sensing and strand joining. Molecular Cell. 6 (5), pp. 1183-1193.

Footprinting of Chlorella virus DNA ligase bound at a nick in duplex DNA
Odell, M. and Shuman, S. 1999. Footprinting of Chlorella virus DNA ligase bound at a nick in duplex DNA. Journal of Biological Chemistry. 274 (20), pp. 14032-14039.

Permalink - https://westminsterresearch.westminster.ac.uk/item/q5532/glutamate-mediated-metabolic-neutralization-mitigates-propionate-toxicity-in-intracellular-mycobacterium-tuberculosis


Share this
Tweet
Email