Molecule Information

General Information of the Molecule (ID: Mol00981)

• Name: Isocitrate lyase 2 (ICL2) ,Mycobacterium tuberculosis
• Synonyms: ICL2; Isocitrase; Isocitratase; aceA-2; MT1966
• Molecule Type: Protein
• Gene Name: icl2
• Sequence:
  MAIAETDTEVHTPFEQDFEKDVAATQRYFDSSRFAGIIRLYTARQVVEQRGTIPVDHIVA
  REAAGAFYERLRELFAARKSITTFGPYSPGQAVSMKRMGIEAIYLGGWATSAKGSSTEDP
  GPDLASYPLSQVPDDAAVLVRALLTADRNQHYLRLQMSERQRAATPAYDFRPFIIADADT
  GHGGDPHVRNLIRRFVEVGVPGYHIEDQRPGTKKCGHQGGKVLVPSDEQIKRLNAARFQL
  DIMRVPGIIVARTDAEAANLIDSRADERDQPFLLGATKLDVPSYKSCFLAMVRRFYELGV
  KELNGHLLYALGDSEYAAAGGWLERQGIFGLVSDAVNAWREDGQQSIDGIFDQVESRFVA
  AWEDDAGLMTYGEAVADVLEFGQSEGEPIGMAPEEWRAFAARASLHAARAKAKELGADPP
  WDCELAKTPEGYYQIRGGIPYAIAKSLAAAPFADILWMETKTADLADARQFAEAIHAEFP
  DQMLAYNLSPSFNWDTTGMTDEEMRRFPEELGKMGFVFNFITYGGHQIDGVAAEEFATAL
  RQDGMLALARLQRKMRLVESPYRTPQTLVGGPRSDAALAASSGRTATTKAMGKGSTQHQH
  LVQTEVPRKLLEEWLAMWSGHYQLKDKLRVQLRPQRAGSEVLELGIHGESDDKLANVIFQ
  PIQDRRGRTILLVRDQNTFGAELRQKRLMTLIHLWLVHRFKAQAVHYVTPTDDNLYQTSK
  MKSHGIFTEVNQEVGEIIVAEVNHPRIAELLTPDRVALRKLITKEA
• Function: Involved in the persistence and virulence of M.tuberculosis. Catalyzes the reversible formation of succinate and glyoxylate from isocitrate, a key step of the glyoxylate cycle, which operates as an anaplerotic route for replenishing the tricarboxylic acid cycle during growth on fatty acid substrates.
• Uniprot ID: ACEA2_MYCTO

Kingdom: N.A.
Phylum: Actinobacteria
Class: Actinomycetia
Order: Corynebacteriales
Family: Mycobacteriaceae
Genus: Mycobacterium
Species: Mycobacterium tuberculosis

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Isoniazid

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HIV-infected patients with tuberculosis [1]

• Resistant Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Resistant Drug: Isoniazid
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strains; 1773
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: HIV-infected patients with tuberculosis [1]

• Sensitive Disease: HIV-infected patients with tuberculosis [ICD-11: 1C60.0]
• Sensitive Drug: Isoniazid
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Mycobacterium tuberculosis strains; 1773
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MIC assay
• Mechanism Description: Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb's isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant.

References

• Ref 1: Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis. Nat Commun. 2014 Jun 30;5:4306. doi: 10.1038/ncomms5306.