Latent infection of Homo sapiens with Mycobacterium tuberculosis (Homo sapiens)

From WikiPathways

Jump to: navigation, search
6, 13, 28, 2914, 2331241733278231588231116, 2285202421823321033130211318819, 259, 26cytosolHost cellBacterialphagocytic vesicle lumencytosolBacterialcell wallHost cell cystosolSec complexH2OOppB GlbN LTF Fe3+ MscR:Zn2+H2OO2G6PH2O2L-Glutamyl aminoacidSecA2 NAD+NADP+O2F420(ox.)CO3(2-) TrxB H+NADP+PeroxynitritePeptide-Methionine (R)-Sulfoxide SodBKatG dimerTpxPeptide methioninesulfoxideCu2+ Carboxymycobactin CO3(2-) nitrosomycothiolZn2+ TrxAOppC F420(red.)TrxB1 Fe3+ TrxA(ox.)MscR H+H2OGSNOLTF Carboxymycobactinheme NOMsrB GlbN:Heme dimerH2OLTF:2xFe3+:2xCO3(2-)BfrB complexH+dlaTTrxA/B1 (ox.)2xCarboxymycobactin:2xFe3+:LTF:2xCO3(2-)Mycobactin Fe2+S-Nitroso-L-cysteinylglycineMSNONAD+IrtB MSHUnsaturated lipidAmino AcidOppD TrxA/B1heme BfrA complexPeptide-MethionineNADPHSecD AhpD(ox.)Tpx D-Glucono-1,5-lactone 6-phosphateAhpC hexamerLTF:2xCO3(2-)FAD GlbN AhpDSodBPeroxynitriteSodC AhpD AhpC(ox.)OligopeptideimporterCarboxymycobactin NOFe3+ Peptide-Methionine (S)-Sulfoxide CO3(2-) Lpd dimerMycobactin:Fe3+Mycobactin Carboxymycobactin heme SodB Lipid-OHAhpE dimer (red.)PeroxynitriteSecA1 GSHH2OH+BfrB BfrA KatG NitriteCarboxymycobactin:Fe3+NO2NO3-CO3(2-) Rv2895c SecF MsrA Fgd1Fe2+ AhpC hexamerLTF OppA H+TrxA FeHM NH3IrtAB:Rv2895cAhpE NADHAhpD trimerNADHTrxA(ox.) SodC dimerSecE FAD O2MycobactinH2O2H+MSSM2xCarboxymycobactin:LTF:2xFe3+:2xCO3(2-)LTF SecG AhpE dimer (ox.)Tpx dimerAhpC H2OAhpC(ox.)ROS, RNS productionin phagocytesGgtAO2Fe3+ TrxB dimerLpd Fe3+ SecY Mycobactin:Fe3+Tpx(ox.)Lipid-OOHH2OIrtA AhpCFe3+H+NO+TrxB1(ox.) Fe3+ CarboxymycobactinSodB tetramerAhpE (ox.) GlbN:Ferriheme dimerMycobactinH2ONADPHdlaT(ox.)AhpC AhpCGSHMsrA/BO2.-7, 12


Infection by Mycobacterium tuberculosis (Mtb) is soon countered by the host's immune system, the organism is however almost never eradicated; ten per cent of infections will develop into "open tuberculosis", while the other ninety per cent become "latent", a state that can persist for decades until loss of immune control. A third of the world's population is estimated to harbour latent tuberculosis. Latent infection involves the bacterium being internalized by macrophages where it stops and counters the innate immune answer (Russell 2011, Russell et al. 2010). When a status-quo is reached, Mtb enters a non-replicating persistent state (Barry et al. 2009, Boshoff & Barry 2005). View original pathway at:Reactome.


Pathway is converted from Reactome ID: 1222352
Reactome version: 66
Reactome Author 
Reactome Author: Stephan, Ralf

Quality Tags

Ontology Terms



View all...
  1. Guimarães BG, Souchon H, Honoré N, Saint-Joanis B, Brosch R, Shepard W, Cole ST, Alzari PM.; ''Structure and mechanism of the alkyl hydroperoxidase AhpC, a key element of the Mycobacterium tuberculosis defense system against oxidative stress.''; PubMed Europe PMC Scholia
  2. Chauhan R, Mande SC.; ''Characterization of the Mycobacterium tuberculosis H37Rv alkyl hydroperoxidase AhpC points to the importance of ionic interactions in oligomerization and activity.''; PubMed Europe PMC Scholia
  3. Farhana A, Kumar S, Rathore SS, Ghosh PC, Ehtesham NZ, Tyagi AK, Hasnain SE.; ''Mechanistic insights into a novel exporter-importer system of Mycobacterium tuberculosis unravel its role in trafficking of iron.''; PubMed Europe PMC Scholia
  4. Braunstein M, Espinosa BJ, Chan J, Belisle JT, Jacobs WR.; ''SecA2 functions in the secretion of superoxide dismutase A and in the virulence of Mycobacterium tuberculosis.''; PubMed Europe PMC Scholia
  5. Wu CH, Tsai-Wu JJ, Huang YT, Lin CY, Lioua GG, Lee FJ.; ''Identification and subcellular localization of a novel Cu,Zn superoxide dismutase of Mycobacterium tuberculosis.''; PubMed Europe PMC Scholia
  6. Russell DG.; ''Mycobacterium tuberculosis and the intimate discourse of a chronic infection.''; PubMed Europe PMC Scholia
  7. Yang Y, Bazhin AV, Werner J, Karakhanova S.; ''Reactive oxygen species in the immune system.''; PubMed Europe PMC Scholia
  8. Madigan CA, Cheng TY, Layre E, Young DC, McConnell MJ, Debono CA, Murry JP, Wei JR, Barry CE, Rodriguez GM, Matsunaga I, Rubin EJ, Moody DB.; ''Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis.''; PubMed Europe PMC Scholia
  9. Pathania R, Navani NK, Gardner AM, Gardner PR, Dikshit KL.; ''Nitric oxide scavenging and detoxification by the Mycobacterium tuberculosis haemoglobin, HbN in Escherichia coli.''; PubMed Europe PMC Scholia
  10. Purwantini E, Mukhopadhyay B.; ''Conversion of NO2 to NO by reduced coenzyme F420 protects mycobacteria from nitrosative damage.''; PubMed Europe PMC Scholia
  11. Venugopal A, Bryk R, Shi S, Rhee K, Rath P, Schnappinger D, Ehrt S, Nathan C.; ''Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes.''; PubMed Europe PMC Scholia
  12. Flannagan RS, Cosío G, Grinstein S.; ''Antimicrobial mechanisms of phagocytes and bacterial evasion strategies.''; PubMed Europe PMC Scholia
  13. Barry CE, Boshoff HI, Dartois V, Dick T, Ehrt S, Flynn J, Schnappinger D, Wilkinson RJ, Young D.; ''The spectrum of latent tuberculosis: rethinking the biology and intervention strategies.''; PubMed Europe PMC Scholia
  14. Rho BS, Hung LW, Holton JM, Vigil D, Kim SI, Park MS, Terwilliger TC, Pédelacq JD.; ''Functional and structural characterization of a thiol peroxidase from Mycobacterium tuberculosis.''; PubMed Europe PMC Scholia
  15. Nagy JM, Cass AE, Brown KA.; ''Purification and characterization of recombinant catalase-peroxidase, which confers isoniazid sensitivity in Mycobacterium tuberculosis.''; PubMed Europe PMC Scholia
  16. Lee WL, Gold B, Darby C, Brot N, Jiang X, de Carvalho LP, Wellner D, St John G, Jacobs WR, Nathan C.; ''Mycobacterium tuberculosis expresses methionine sulphoxide reductases A and B that protect from killing by nitrite and hypochlorite.''; PubMed Europe PMC Scholia
  17. Reddy PV, Puri RV, Khera A, Tyagi AK.; ''Iron storage proteins are essential for the survival and pathogenesis of Mycobacterium tuberculosis in THP-1 macrophages and the guinea pig model of infection.''; PubMed Europe PMC Scholia
  18. Zhang Y, Lathigra R, Garbe T, Catty D, Young D.; ''Genetic analysis of superoxide dismutase, the 23 kilodalton antigen of Mycobacterium tuberculosis.''; PubMed Europe PMC Scholia
  19. Harrison PM, Arosio P.; ''The ferritins: molecular properties, iron storage function and cellular regulation.''; PubMed Europe PMC Scholia
  20. Dasgupta A, Sureka K, Mitra D, Saha B, Sanyal S, Das AK, Chakrabarti P, Jackson M, Gicquel B, Kundu M, Basu J.; ''An oligopeptide transporter of Mycobacterium tuberculosis regulates cytokine release and apoptosis of infected macrophages.''; PubMed Europe PMC Scholia
  21. Dayaram YK, Talaue MT, Connell ND, Venketaraman V.; ''Characterization of a glutathione metabolic mutant of Mycobacterium tuberculosis and its resistance to glutathione and nitrosoglutathione.''; PubMed Europe PMC Scholia
  22. St John G, Brot N, Ruan J, Erdjument-Bromage H, Tempst P, Weissbach H, Nathan C.; ''Peptide methionine sulfoxide reductase from Escherichia coli and Mycobacterium tuberculosis protects bacteria against oxidative damage from reactive nitrogen intermediates.''; PubMed Europe PMC Scholia
  23. Jaeger T, Budde H, Flohé L, Menge U, Singh M, Trujillo M, Radi R.; ''Multiple thioredoxin-mediated routes to detoxify hydroperoxides in Mycobacterium tuberculosis.''; PubMed Europe PMC Scholia
  24. Hugo M, Turell L, Manta B, Botti H, Monteiro G, Netto LE, Alvarez B, Radi R, Trujillo M.; ''Thiol and sulfenic acid oxidation of AhpE, the one-cysteine peroxiredoxin from Mycobacterium tuberculosis: kinetics, acidity constants, and conformational dynamics.''; PubMed Europe PMC Scholia
  25. Khare G, Gupta V, Nangpal P, Gupta RK, Sauter NK, Tyagi AK.; ''Ferritin structure from Mycobacterium tuberculosis: comparative study with homologues identifies extended C-terminus involved in ferroxidase activity.''; PubMed Europe PMC Scholia
  26. Ouellet H, Ouellet Y, Richard C, Labarre M, Wittenberg B, Wittenberg J, Guertin M.; ''Truncated hemoglobin HbN protects Mycobacterium bovis from nitric oxide.''; PubMed Europe PMC Scholia
  27. Bashiri G, Squire CJ, Moreland NJ, Baker EN.; ''Crystal structures of F420-dependent glucose-6-phosphate dehydrogenase FGD1 involved in the activation of the anti-tuberculosis drug candidate PA-824 reveal the basis of coenzyme and substrate binding.''; PubMed Europe PMC Scholia
  28. Boshoff HI, Barry CE.; ''Tuberculosis - metabolism and respiration in the absence of growth.''; PubMed Europe PMC Scholia
  29. Russell DG, Barry CE, Flynn JL.; ''Tuberculosis: what we don't know can, and does, hurt us.''; PubMed Europe PMC Scholia
  30. Miller CC, Rawat M, Johnson T, Av-Gay Y.; ''Innate protection of Mycobacterium smegmatis against the antimicrobial activity of nitric oxide is provided by mycothiol.''; PubMed Europe PMC Scholia
  31. Bryk R, Lima CD, Erdjument-Bromage H, Tempst P, Nathan C.; ''Metabolic enzymes of mycobacteria linked to antioxidant defense by a thioredoxin-like protein.''; PubMed Europe PMC Scholia
  32. Ryndak MB, Wang S, Smith I, Rodriguez GM.; ''The Mycobacterium tuberculosis high-affinity iron importer, IrtA, contains an FAD-binding domain.''; PubMed Europe PMC Scholia
  33. Vogt RN, Steenkamp DJ, Zheng R, Blanchard JS.; ''The metabolism of nitrosothiols in the Mycobacteria: identification and characterization of S-nitrosomycothiol reductase.''; PubMed Europe PMC Scholia


View all...
101483view11:34, 1 November 2018ReactomeTeamreactome version 66
101020view21:14, 31 October 2018ReactomeTeamreactome version 65
100555view19:48, 31 October 2018ReactomeTeamreactome version 64
100103view16:33, 31 October 2018ReactomeTeamreactome version 63
99653view15:04, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99255view12:45, 31 October 2018ReactomeTeamreactome version 62
93855view13:41, 16 August 2017ReactomeTeamreactome version 61
93417view11:23, 9 August 2017ReactomeTeamreactome version 61
87759view09:57, 25 July 2016RyanmillerOntology Term : 'Mycobacterium tuberculosis infection pathway' added !
87739view09:44, 25 July 2016RyanmillerOntology Term : 'disease pathway' added !
87737view09:44, 25 July 2016RyanmillerOntology Term : 'bacterial infectious disease' added !
86506view09:19, 11 July 2016ReactomeTeamreactome version 56
83102view09:58, 18 November 2015ReactomeTeamVersion54
81435view12:57, 21 August 2015ReactomeTeamVersion53
76907view08:17, 17 July 2014ReactomeTeamFixed remaining interactions
76612view11:58, 16 July 2014ReactomeTeamFixed remaining interactions
75943view10:00, 11 June 2014ReactomeTeamRe-fixing comment source
75645view10:53, 10 June 2014ReactomeTeamReactome 48 Update
75000view13:51, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74644view08:42, 30 April 2014ReactomeTeamNew pathway

External references


View all...
NameTypeDatabase referenceComment
2xCarboxymycobactin:2xFe3+:LTF:2xCO3(2-)ComplexR-HSA-8951553 (Reactome)
2xCarboxymycobactin:LTF:2xFe3+:2xCO3(2-)ComplexR-HSA-8951548 (Reactome)
AhpC ProteinP9WQB7 (Uniprot-TrEMBL)
AhpC hexamerComplexR-MTU-1222632 (Reactome)
AhpC(ox.)ProteinP9WQB7 (Uniprot-TrEMBL)
AhpCProteinP9WQB7 (Uniprot-TrEMBL)
AhpD ProteinP9WQB5 (Uniprot-TrEMBL)
AhpD trimerComplexR-MTU-1222514 (Reactome)
AhpD(ox.)ProteinP9WQB5 (Uniprot-TrEMBL)
AhpDProteinP9WQB5 (Uniprot-TrEMBL)
AhpE (ox.) ProteinP9WIE3 (Uniprot-TrEMBL)
AhpE ProteinP9WIE3 (Uniprot-TrEMBL)
AhpE dimer (ox.)ComplexR-MTU-1500809 (Reactome)
AhpE dimer (red.)ComplexR-MTU-1500773 (Reactome)
Amino AcidR-ALL-2103117 (Reactome)
BfrA ProteinP9WPQ9 (Uniprot-TrEMBL)
BfrA complexComplexR-MTU-1562615 (Reactome)
BfrB ProteinP9WNE5 (Uniprot-TrEMBL)
BfrB complexComplexR-MTU-1562601 (Reactome)
CO3(2-) MetaboliteCHEBI:41609 (ChEBI)
Carboxymycobactin MetaboliteCHEBI:62579 (ChEBI)
Carboxymycobactin:Fe3+ComplexR-ALL-5607576 (Reactome)
CarboxymycobactinMetaboliteCHEBI:62579 (ChEBI)
Cu2+ MetaboliteCHEBI:29036 (ChEBI)
D-Glucono-1,5-lactone 6-phosphateMetaboliteCHEBI:16938 (ChEBI)
F420(ox.)MetaboliteCHEBI:141634 (ChEBI)
F420(red.)MetaboliteCHEBI:141635 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
Fe2+ MetaboliteCHEBI:18248 (ChEBI)
Fe2+MetaboliteCHEBI:18248 (ChEBI)
Fe3+ MetaboliteCHEBI:29034 (ChEBI)
Fe3+MetaboliteCHEBI:29034 (ChEBI)
FeHM MetaboliteCHEBI:36144 (ChEBI)
Fgd1ProteinP9WNE1 (Uniprot-TrEMBL)
G6PMetaboliteCHEBI:17665 (ChEBI)
GSHMetaboliteCHEBI:16856 (ChEBI)
GSNOMetaboliteCHEBI:50091 (ChEBI)
GgtAProteinP71828 (Uniprot-TrEMBL)
GlbN ProteinP9WN25 (Uniprot-TrEMBL)
GlbN:Ferriheme dimerComplexR-MTU-1222369 (Reactome)
GlbN:Heme dimerComplexR-MTU-1222294 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
IrtA ProteinP9WQJ9 (Uniprot-TrEMBL)
IrtAB:Rv2895cComplexR-MTU-1222486 (Reactome)
IrtB ProteinP9WQJ7 (Uniprot-TrEMBL)
KatG ProteinP9WIE5 (Uniprot-TrEMBL)
KatG dimerComplexR-MTU-1222385 (Reactome)
L-Glutamyl amino acidMetaboliteCHEBI:15857 (ChEBI)
LTF ProteinP02788 (Uniprot-TrEMBL)
LTF:2xCO3(2-)ComplexR-HSA-8951550 (Reactome)
LTF:2xFe3+:2xCO3(2-)ComplexR-HSA-1222432 (Reactome)
Lipid-OHR-ALL-1222348 (Reactome)
Lipid-OOHR-ALL-1222300 (Reactome)
Lpd ProteinP9WHH9 (Uniprot-TrEMBL)
Lpd dimerComplexR-MTU-1222635 (Reactome)
MSHMetaboliteCHEBI:16768 (ChEBI)
MSNOMetaboliteCHEBI:59637 (ChEBI)
MSSMMetaboliteCHEBI:16086 (ChEBI)
MscR ProteinO53533 (Uniprot-TrEMBL)
MscR:Zn2+ComplexR-MTU-1222283 (Reactome)
MsrA ProteinP9WJM5 (Uniprot-TrEMBL)
MsrA/BComplexR-MTU-1243099 (Reactome)
MsrB ProteinP71971 (Uniprot-TrEMBL)
Mycobactin MetaboliteCHEBI:61168 (ChEBI)
Mycobactin:Fe3+ComplexR-ALL-5607578 (Reactome)
Mycobactin:Fe3+ComplexR-ALL-5607579 (Reactome)
MycobactinMetaboliteCHEBI:61168 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
NO+MetaboliteCHEBI:29120 (ChEBI)
NO2MetaboliteCHEBI:33101 (ChEBI)
NO3-MetaboliteCHEBI:17632 (ChEBI)
NOMetaboliteCHEBI:16480 (ChEBI)
NitriteMetaboliteCHEBI:16301 (ChEBI)
O2.-MetaboliteCHEBI:18421 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
Oligopeptide importerComplexR-MTU-1500757 (Reactome)
OppA ProteinP9WGU5 (Uniprot-TrEMBL)
OppB ProteinP9WQJ5 (Uniprot-TrEMBL)
OppC ProteinP9WFZ9 (Uniprot-TrEMBL)
OppD ProteinP9WFZ7 (Uniprot-TrEMBL)
Peptide methionine sulfoxideComplexR-ALL-2201256 (Reactome)
Peptide-Methionine (R)-Sulfoxide R-ALL-1641509 (Reactome)
Peptide-Methionine (S)-Sulfoxide R-ALL-1222452 (Reactome)
Peptide-MethionineR-ALL-1222500 (Reactome)
PeroxynitriteMetaboliteCHEBI:25941 (ChEBI)
ROS, RNS production in phagocytesPathwayR-HSA-1222556 (Reactome) The first line of defense against infectious agents involves an active recruitment of phagocytes to the site of infection. Recruited cells include polymorhonuclear (PMN) leukocytes (i.e., neutrophils) and monocytes/macrophages, which function together as innate immunity sentinels (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). Dendritic cells are also present, serving as important players in antigen presentation for ensuing adaptive responses (Savina A & Amigorena S 2007). These cell types are able to bind and engulf invading microbes into a membrane-enclosed vacuole - the phagosome, in a process termed phagocytosis. Phagocytosis can be defined as the receptor-mediated engulfment of particles greater than 0.5 micron in diameter. It is initiated by the cross-linking of host cell membrane receptors following engagement with their cognate ligands on the target surface (Underhill DM & Ozinsky A 2002; Stuart LM & Ezekowitz RA 2005; Flannagan RS et al. 2012). When engulfed by phagocytes, microorganisms are exposed to a number of host defense microbicidal events within the resulting phagosome. These include the production of reactive oxygen and nitrogen species (ROS and RNS, RONS) by specialized enzymes (Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013). NADPH oxidase (NOX) complex consume oxygen to produce superoxide radical anion (O2.-) and hydrogen peroxide (H2O2) (Robinson et al. 2004). Induced NO synthase (iNOS) is involved in the production of NO, which is the primary source of all RNS in biological systems (Evans TG et al. 1996). The NADPH phagocyte oxidase and iNOS are expressed in both PMN and mononuclear phagocytes and both cell types have the capacity for phagosomal burst activity. However, the magnitude of ROS generation in neutrophils far exceeds that observed in macrophages (VanderVen BC et al. 2009). Macrophages are thought to produce considerably more RNS than neutrophils (Fang FC et al. 2004; Nathan & Shiloh 2000).

The presence of RONS characterized by a relatively low reactivity, such as H2O2, O2˙− or NO, has no deleterious effect on biological environment (Attia SM 2010; Weidinger A & and Kozlov AV 2015) Their activity is controlled by endogenous antioxidants (both enzymatic and non-enzymatic) that are induced by oxidative stress. However the relatively low reactive species can initiate a cascade of reactions to generate more damaging “secondary� species such as hydroxyl radical (•OH), singlet oxygen or peroxinitrite (Robinson JM 2008; Fang FC et al. 2004). These "secondary" RONS are extremely toxic causing irreversible damage to all classes of biomolecules (Weidinger A & and Kozlov AV 2015; Fang FC et al. 2004; Kohchi C et al. 2009; Gostner JM et al. 2013; Vatansever F et al. 2013).

Although macrophages and neutrophils use similar mechanisms for the internalization of targets, there are differences in how they perform phagocytosis and in the final outcome of the process (Tapper H & Grinstein S 1997; Vierira OV et al. 2002). Once formed, the phagosome undergoes an extensive maturation process whereby it develops into a microbicidal organelle able to eliminate the invading pathogen. Maturation involves re-modeling both the membrane of the phagosome and its luminal contents (Vierira OV et al. 2002). In macrophages, phagosome formation and maturation follows a series of strictly coordinated membrane fission/fusion events between the phagosome and compartments of the endo/lysosomal network gradually transforming the nascent phagosome into a phagolysosome, a degradative organelle endowed with potent microbicidal properties (Zimmerli S et al. 1996; Vierira OV et al. 2002). Neutrophils instead contain a large number of preformed granules such as azurophilic and specific granules that can rapidly fuse with phagosomes delivering antimicrobial substances (Karlsson A & Dahlgren C 2002; Naucler C et al. 2002; Nordenfelt P and Tapper H 2011). Phagosomal pH dynamics may also contribute to the maturation process by regulating membrane traffic events. The microbicidal activity of macrophages is characterized by progressive acidification of the lumen (down to pH 4–5) by the proton pumping vATPase. A low pH is a prerequisite for optimal enzymatic activity of most late endosomal/lysosomal hydrolases reported in macrophages. Neutrophil phagosome pH regulation differs significantly from what is observed in macrophages (Nordenfelt P and Tapper H 2011; Winterbourn CC et al. 2016). The massive activation of the oxidative burst is thought to result in early alkalization of neutrophil phagosomes which is linked to proton consumption during the generation of hydrogen peroxide (Segal AW et al. 1981; Levine AP et al. 2015). Other studies showed that neutrophil phagosome maintained neutral pH values before the pH gradually decreased (Jankowski A et al. 2002). Neutrophil phagosomes also exhibited a high proton leak, which was initiated upon activation of the NADPH oxidase, and this activation counteracted phagosomal acidification (Jankowski A et al. 2002).

The Reactome module describes ROS and RNS production by phagocytic cells. The module includes cell-type specific events, for example, myeloperoxidase (MPO)-mediated production of hypochlorous acid in neutrophils. It also highlights differences between phagosomal pH dynamics in neutrophils and macrophages. The module describes microbicidal activity of selective RONS such as hydroxyl radical or peroxynitrite however the mechanisms by which reactive oxygen/nitrogen species kill pathogens is still a matter of debate.

Rv2895c ProteinP9WL31 (Uniprot-TrEMBL)
S-Nitroso-L-cysteinylglycineMetaboliteCHEBI:61088 (ChEBI)
Sec complexComplexR-MTU-1222323 (Reactome)
SecA1 ProteinP9WGP5 (Uniprot-TrEMBL)
SecA2 ProteinP9WGP3 (Uniprot-TrEMBL)
SecD ProteinP9WGP1 (Uniprot-TrEMBL)
SecE ProteinP9WGN7 (Uniprot-TrEMBL)
SecF ProteinP9WGN9 (Uniprot-TrEMBL)
SecG ProteinP9WGN5 (Uniprot-TrEMBL)
SecY ProteinP9WGN3 (Uniprot-TrEMBL)
SodB ProteinP9WGE7 (Uniprot-TrEMBL)
SodB tetramerComplexR-MTU-1222672 (Reactome)
SodBProteinP9WGE7 (Uniprot-TrEMBL)
SodC ProteinP9WGE9 (Uniprot-TrEMBL)
SodC dimerComplexR-MTU-1222313 (Reactome)
Tpx ProteinP9WG35 (Uniprot-TrEMBL)
Tpx dimerComplexR-MTU-1222584 (Reactome)
Tpx(ox.)ProteinP9WG35 (Uniprot-TrEMBL)
TpxProteinP9WG35 (Uniprot-TrEMBL)
TrxA ProteinP9WG67 (Uniprot-TrEMBL)
TrxA(ox.) ProteinP9WG67 (Uniprot-TrEMBL)
TrxA(ox.)ProteinP9WG67 (Uniprot-TrEMBL)
TrxA/B1 (ox.)ComplexR-MTU-1243098 (Reactome)
TrxA/B1ComplexR-MTU-1243096 (Reactome)
TrxAProteinP9WG67 (Uniprot-TrEMBL)
TrxB ProteinP9WHH1 (Uniprot-TrEMBL)
TrxB dimerComplexR-MTU-1222425 (Reactome)
TrxB1 ProteinQ7D8E1 (Uniprot-TrEMBL)
TrxB1(ox.) ProteinQ7D8E1 (Uniprot-TrEMBL)
Unsaturated lipidR-ALL-1222455 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
dlaT(ox.)ProteinP9WIS7 (Uniprot-TrEMBL)
dlaTProteinP9WIS7 (Uniprot-TrEMBL)
heme MetaboliteCHEBI:17627 (ChEBI)
nitrosomycothiolMetaboliteCHEBI:59637 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2xCarboxymycobactin:2xFe3+:LTF:2xCO3(2-)ArrowR-HSA-8951549 (Reactome)
2xCarboxymycobactin:2xFe3+:LTF:2xCO3(2-)R-HSA-8951552 (Reactome)
2xCarboxymycobactin:LTF:2xFe3+:2xCO3(2-)ArrowR-HSA-1222641 (Reactome)
2xCarboxymycobactin:LTF:2xFe3+:2xCO3(2-)R-HSA-8951549 (Reactome)
AhpC hexamermim-catalysisR-HSA-1222346 (Reactome)
AhpC hexamermim-catalysisR-HSA-1222431 (Reactome)
AhpC hexamermim-catalysisR-HSA-1222526 (Reactome)
AhpC(ox.)ArrowR-HSA-1222346 (Reactome)
AhpC(ox.)ArrowR-HSA-1222431 (Reactome)
AhpC(ox.)ArrowR-HSA-1222526 (Reactome)
AhpC(ox.)R-HSA-1222417 (Reactome)
AhpC(ox.)R-HSA-1222655 (Reactome)
AhpCArrowR-HSA-1222417 (Reactome)
AhpCArrowR-HSA-1222655 (Reactome)
AhpCR-HSA-1222346 (Reactome)
AhpCR-HSA-1222431 (Reactome)
AhpCR-HSA-1222526 (Reactome)
AhpD trimermim-catalysisR-HSA-1222655 (Reactome)
AhpD(ox.)ArrowR-HSA-1222655 (Reactome)
AhpD(ox.)R-HSA-1222690 (Reactome)
AhpDArrowR-HSA-1222690 (Reactome)
AhpDR-HSA-1222655 (Reactome)
AhpE dimer (ox.)ArrowR-HSA-1500804 (Reactome)
AhpE dimer (red.)R-HSA-1500804 (Reactome)
AhpE dimer (red.)mim-catalysisR-HSA-1500804 (Reactome)
Amino AcidR-HSA-1222712 (Reactome)
BfrA complexmim-catalysisR-HSA-1562604 (Reactome)
BfrB complexmim-catalysisR-HSA-1562603 (Reactome)
Carboxymycobactin:Fe3+ArrowR-HSA-8951552 (Reactome)
Carboxymycobactin:Fe3+R-HSA-1222325 (Reactome)
CarboxymycobactinArrowR-HSA-1222325 (Reactome)
CarboxymycobactinArrowR-HSA-1222738 (Reactome)
CarboxymycobactinR-HSA-1222641 (Reactome)
CarboxymycobactinR-HSA-1222738 (Reactome)
D-Glucono-1,5-lactone 6-phosphateArrowR-HSA-1500781 (Reactome)
F420(ox.)ArrowR-HSA-1500761 (Reactome)
F420(ox.)R-HSA-1500781 (Reactome)
F420(red.)ArrowR-HSA-1500781 (Reactome)
F420(red.)R-HSA-1500761 (Reactome)
Fe2+ArrowR-HSA-1222399 (Reactome)
Fe2+R-HSA-1562603 (Reactome)
Fe2+R-HSA-1562604 (Reactome)
Fe3+ArrowR-HSA-1562603 (Reactome)
Fe3+ArrowR-HSA-1562604 (Reactome)
Fgd1mim-catalysisR-HSA-1500781 (Reactome)
G6PR-HSA-1500781 (Reactome)
GSHArrowR-HSA-1500817 (Reactome)
GSHR-HSA-1500817 (Reactome)
GSNOR-HSA-1222712 (Reactome)
GgtAmim-catalysisR-HSA-1222712 (Reactome)
GlbN:Ferriheme dimerArrowR-HSA-1222723 (Reactome)
GlbN:Heme dimerR-HSA-1222723 (Reactome)
GlbN:Heme dimermim-catalysisR-HSA-1222723 (Reactome)
H+ArrowR-HSA-1222399 (Reactome)
H+ArrowR-HSA-1222594 (Reactome)
H+R-HSA-1222412 (Reactome)
H+R-HSA-1222462 (Reactome)
H+R-HSA-1222469 (Reactome)
H+R-HSA-1222485 (Reactome)
H+R-HSA-1222583 (Reactome)
H+R-HSA-1562603 (Reactome)
H+R-HSA-1562604 (Reactome)
H2O2ArrowR-HSA-1222462 (Reactome)
H2O2ArrowR-HSA-1222469 (Reactome)
H2O2R-HSA-1222341 (Reactome)
H2O2R-HSA-1222346 (Reactome)
H2O2R-HSA-1222704 (Reactome)
H2OArrowR-HSA-1222346 (Reactome)
H2OArrowR-HSA-1222431 (Reactome)
H2OArrowR-HSA-1222526 (Reactome)
H2OArrowR-HSA-1222583 (Reactome)
H2OArrowR-HSA-1222704 (Reactome)
H2OArrowR-HSA-1222755 (Reactome)
H2OArrowR-HSA-1500761 (Reactome)
H2OArrowR-HSA-1500804 (Reactome)
H2OArrowR-HSA-1562603 (Reactome)
H2OArrowR-HSA-1562604 (Reactome)
IrtAB:Rv2895cmim-catalysisR-HSA-1222399 (Reactome)
IrtAB:Rv2895cmim-catalysisR-HSA-1222597 (Reactome)
KatG dimermim-catalysisR-HSA-1222704 (Reactome)
L-Glutamyl amino acidArrowR-HSA-1222712 (Reactome)
LTF:2xCO3(2-)ArrowR-HSA-8951552 (Reactome)
LTF:2xFe3+:2xCO3(2-)R-HSA-1222641 (Reactome)
Lipid-OHArrowR-HSA-1222526 (Reactome)
Lipid-OOHArrowR-HSA-1222341 (Reactome)
Lipid-OOHR-HSA-1222526 (Reactome)
Lpd dimermim-catalysisR-HSA-1222412 (Reactome)
MSHR-HSA-1222583 (Reactome)
MSHR-HSA-1222594 (Reactome)
MSNOArrowR-HSA-1222594 (Reactome)
MSSMArrowR-HSA-1222583 (Reactome)
MscR:Zn2+mim-catalysisR-HSA-1222583 (Reactome)
MsrA/Bmim-catalysisR-HSA-1222363 (Reactome)
Mycobactin:Fe3+ArrowR-HSA-1222325 (Reactome)
Mycobactin:Fe3+ArrowR-HSA-1222597 (Reactome)
Mycobactin:Fe3+R-HSA-1222399 (Reactome)
Mycobactin:Fe3+R-HSA-1222597 (Reactome)
MycobactinArrowR-HSA-1222399 (Reactome)
MycobactinArrowR-HSA-1222722 (Reactome)
MycobactinR-HSA-1222325 (Reactome)
MycobactinR-HSA-1222722 (Reactome)
NAD+ArrowR-HSA-1222412 (Reactome)
NAD+ArrowR-HSA-1222583 (Reactome)
NADHR-HSA-1222412 (Reactome)
NADHR-HSA-1222583 (Reactome)
NADP+ArrowR-HSA-1222399 (Reactome)
NADP+ArrowR-HSA-1222485 (Reactome)
NADPHR-HSA-1222399 (Reactome)
NADPHR-HSA-1222485 (Reactome)
NH3ArrowR-HSA-1222583 (Reactome)
NO+R-HSA-1222594 (Reactome)
NO+R-HSA-1222723 (Reactome)
NO2R-HSA-1500761 (Reactome)
NO3-ArrowR-HSA-1222723 (Reactome)
NOArrowR-HSA-1500761 (Reactome)
NitriteArrowR-HSA-1222431 (Reactome)
NitriteArrowR-HSA-1222755 (Reactome)
NitriteArrowR-HSA-1500804 (Reactome)
O2.-R-HSA-1222462 (Reactome)
O2.-R-HSA-1222469 (Reactome)
O2ArrowR-HSA-1222462 (Reactome)
O2ArrowR-HSA-1222469 (Reactome)
O2ArrowR-HSA-1222704 (Reactome)
O2R-HSA-1222723 (Reactome)
O2R-HSA-1562603 (Reactome)
O2R-HSA-1562604 (Reactome)
Oligopeptide importermim-catalysisR-HSA-1500817 (Reactome)
Peptide methionine sulfoxideR-HSA-1222363 (Reactome)
Peptide-MethionineArrowR-HSA-1222363 (Reactome)
PeroxynitriteR-HSA-1222431 (Reactome)
PeroxynitriteR-HSA-1222755 (Reactome)
PeroxynitriteR-HSA-1500804 (Reactome)
R-HSA-1222325 (Reactome) Carboxymycobactin and mycobactin exchange their iron loads. This interplay between polar and nonpolar siderophore is unique to Mtb. However, mycobactin can gather iron from nonpolar regions of the host cell by itself too (Madigan et al. 2012).
R-HSA-1222341 (Reactome) Due to their abundance in Mycobacteria, lipids fulfill a buffering role in the tolerance of antioxidants. Lipid production is triggered by oxidative stress. The peroxidated lipid can be reduced by AhpC (Chauhan & Mande 2001).
R-HSA-1222346 (Reactome) The versatile AhpC reduces hydrogen peroxide to water (Bryk et al. 2002).
R-HSA-1222363 (Reactome) MsrA and MsrB are enzymes that can both reduce the S- and R-stereoisomers of (peptidyl-) methionine sulfoxide. The exact nature of the accompanying thioredoxin is not settled, but it is predicted to be TrxA. The whole methionine-MsrA/B-thioredoxin-and-reductase system is an important part of NO detoxification in Mtb (St John et al. 2001, Lee et al. 2009).
R-HSA-1222399 (Reactome) The IrtA transporter has a flavin reductase domain very much like Fre from E.coli that can probably act as ferrisiderophore reductase to relieve incoming loaded mycobactin from its Fe3+ by reducing it to Fe2+. Furthermore Rv2895c, which co-precipitates with IrtB and therefore is probably part of the transporter complex, has such a domain as well (Farhana et al. 2008).
R-HSA-1222412 (Reactome) Peroxiredoxin AhpC gets its reducing equivalents through a cascade of proteins via AhpD, a disulfide reductase, DlaT, a lipoylated disulfide reductase, and, finally, from Lpd, the NADH-dependent dihydrolipoyl reductase. The latter two are also part of the pyruvate dehydrogenase complex (Venugopal et al. 2011).
R-HSA-1222417 (Reactome) The peroxiredoxin AhpC can be alternatively reactivated by TrxA (Jaeger et al. 2004).
R-HSA-1222431 (Reactome) AhpC is an unusual peroxiredoxin - it has three cysteine residues that participate in the reduction of toxic peroxynitrite to nitrite. In a second step, another thioredoxin or the reductase chain AhpD/DlaT/Lpd is needed for reactivation (Guimaraes et al. 2005).
R-HSA-1222462 (Reactome) Iron-containing superoxide dismutase is localized both within and without the bacterium where it catalyzes the reduction of superoxide (Zhang et al. 1991).
R-HSA-1222469 (Reactome) Copper-containing superoxide dismutase is localized in the plasma membrane of the bacterium where it catalyzes the reduction of superoxide (Wu et al. 1998).
R-HSA-1222485 (Reactome) TrxB is an NADPH-dependent thioredoxin reductase that reactivates TrxA (Jaeger et al. 2006).
R-HSA-1222523 (Reactome) Superoxide dismutase SodB is secreted via the Sec transport complex (Braunstein et al. 2003).
R-HSA-1222526 (Reactome) Reduction of peroxidated lipids depends on reduced AhpC, the only alkyl hydoperoxidase in Mtb (Chauhan & Mande 2001).
R-HSA-1222583 (Reactome) MscR is an alcohol dehydrogenase that can probably reduce nitrosomycothiol with the help of NADH/H+ reducing equivalents to the sulfinamide which then presumably decomposes to the thione and ammonia (Vogt et al. 2003).
R-HSA-1222594 (Reactome) Nitrosyl is scavenged by mycothiol (MSH), which is functionally analogous to glutathione, which mycobacteria do not possess (Miller et al. 2007).
R-HSA-1222597 (Reactome) The ABC-type transporter IrtA, probably complexed with IrtB and ViuB (Rv2895c), specifically transports iron-loaded mycobactin into the cytosol (Ryndak et al. 2009).
R-HSA-1222641 (Reactome) Since bacterial siderophores bind iron with much greater affinity, they can scavenge iron ions from loaded lactoferrin (Madigan et al. 2012).
R-HSA-1222644 (Reactome) The Tpx peroxiredoxin is reactivated by either TrxA or TrxB1 (Jaeger et al. 2006).
R-HSA-1222655 (Reactome) Peroxiredoxin AhpC gets its reducing equivalents through a cascade of proteins via AhpD, a disulfide reductase, DlaT, a lipoylated disulfide reductase, and, finally, from Lpd, the NADH-dependent dihydrolipoyl reductase. The latter two are also part of the pyruvate dehydrogenase complex (Venugopal et al. 2011).
R-HSA-1222690 (Reactome) Peroxiredoxin AhpC gets its reducing equivalents through a cascade of proteins via AhpD, a disulfide reductase, DlaT, a lipoylated disulfide reductase, and, finally, from Lpd, the NADH-dependent dihydrolipoyl reductase. The latter two are also part of the pyruvate dehydrogenase complex (Venugopal et al. 2011).
R-HSA-1222704 (Reactome) Another important antioxidant activity is the KatG catalase/peroxidase which also activates the anti-tuberculosis drug isoniazid (Nagy et al. 1997).
R-HSA-1222712 (Reactome) Most gamma-glutamyl transpeptidases (GGT) cleave both glutathione and glutathione conjugates. Mtb GGT cleaves nitrosoglutathione )GSNO) to Cys(NO)-Gly, thus making it soluble for transport into the cytosol (Dayaram et al. 2006).
R-HSA-1222722 (Reactome) Mycobactin is the lipophilic siderophore of Mtb. After export into the periplasmic space, it localizes to the bacterium's cell wall. The responsible transporter activity is still unknown (Madigan et al. 2012).
R-HSA-1222723 (Reactome) Heme proteins, especially the truncated globin GlbN in Mtb possess oxygen-dependent nitric oxide dioxygenase activity, where the heme that is oxidized to ferriheme in the process will need to be reduced in a second step to activate the protein again. The responsible heme protein reductase is unknown (Ouellet et al. 2002, Pathania et al. 2002).
R-HSA-1222738 (Reactome) Carboxymycobactin is the more polar siderophore of Mtb and it is localized, after its secretion, in the phagosomal lumen. The transporters for export and secretion of this molecule are still unknown (Madigan et al. 2012).
R-HSA-1222755 (Reactome) Tpx, like AhpC, is a peroxiredoxin with alkylhydroperoxidase, peroxidase, and peroxynitritase activities. Peroxynitrite is detoxified to nitrite (Jaeger et al. 2006, Rho et al. 2006).
R-HSA-1500761 (Reactome) The archaeal cofactor F420 reduces toxic nitrogen dioxide that can be produced when NO and oxygen combine. F420 itself is reduced by the enzyme Fgd (Purwantini & Mukhopadyay 2008).
R-HSA-1500781 (Reactome) The enzyme in Mtb known to reduce F420 is the glucose-6-phosphate dehydrogenase Fgd1 (Bashiri et al. 2008).
R-HSA-1500804 (Reactome) The peroxiredoxin AhpE participates in reducing peroxynitrite to nitrite, but how it is recycled back to the reduced form is still unknown (Hugo et al. 2009).
R-HSA-1500817 (Reactome) Glutathione is taken up by the bacterium by an ABC transporter called the oligopeptide importer. OppA determines substrate specificity (Dasgupta et al. 2010).
R-HSA-1562603 (Reactome) Mtb bacterioferritin BfrB oxidises Fe2+ to Fe3+, migrates them to its centre, and collects thousands of them as FeO(OH) in the central mineral core from which they can be later remobilised (Harrison & Arrosio 1996, Khare et al. 2011).
R-HSA-1562604 (Reactome) Mtb bacterioferritin BfrA oxidises Fe2+ to Fe3+, migrates them to its centre, and collects thousands of them as FeO(OH) in the central mineral core from which they can be later remobilised (Reddy et al. 2012).
R-HSA-8951549 (Reactome) Since bacterial siderophores bind iron with much greater affinity, they can scavenge iron ions from loaded lactoferrin (Madigan et al. 2012).
R-HSA-8951552 (Reactome) Since bacterial siderophores bind iron with much greater affinity, they can scavenge iron ions from loaded lactoferrin (Madigan et al. 2012).
S-Nitroso-L-cysteinylglycineArrowR-HSA-1222712 (Reactome)
Sec complexmim-catalysisR-HSA-1222523 (Reactome)
SodB tetramermim-catalysisR-HSA-1222462 (Reactome)
SodBArrowR-HSA-1222523 (Reactome)
SodBR-HSA-1222523 (Reactome)
SodC dimermim-catalysisR-HSA-1222469 (Reactome)
Tpx dimermim-catalysisR-HSA-1222755 (Reactome)
Tpx(ox.)ArrowR-HSA-1222755 (Reactome)
Tpx(ox.)R-HSA-1222644 (Reactome)
TpxArrowR-HSA-1222644 (Reactome)
TpxR-HSA-1222755 (Reactome)
TrxA(ox.)ArrowR-HSA-1222363 (Reactome)
TrxA(ox.)ArrowR-HSA-1222417 (Reactome)
TrxA(ox.)R-HSA-1222485 (Reactome)
TrxA/B1 (ox.)ArrowR-HSA-1222644 (Reactome)
TrxA/B1R-HSA-1222644 (Reactome)
TrxA/B1mim-catalysisR-HSA-1222644 (Reactome)
TrxAArrowR-HSA-1222485 (Reactome)
TrxAR-HSA-1222363 (Reactome)
TrxAR-HSA-1222417 (Reactome)
TrxAmim-catalysisR-HSA-1222417 (Reactome)
TrxB dimermim-catalysisR-HSA-1222485 (Reactome)
Unsaturated lipidR-HSA-1222341 (Reactome)
dlaT(ox.)ArrowR-HSA-1222690 (Reactome)
dlaT(ox.)R-HSA-1222412 (Reactome)
dlaTArrowR-HSA-1222412 (Reactome)
dlaTR-HSA-1222690 (Reactome)
dlaTmim-catalysisR-HSA-1222690 (Reactome)
nitrosomycothiolR-HSA-1222583 (Reactome)
Personal tools