BRENDA - Enzyme Database

Methylcitrate cycle defines the bactericidal essentiality of isocitrate lyase for survival of Mycobacterium tuberculosis on fatty acids

Eoh, H.; Rhee, K.Y.; Proc. Natl. Acad. Sci. USA 111, 4976-4981 (2014)

Data extracted from this reference:

Inhibitors
EC Number
Inhibitors
Commentary
Organism
Structure
4.1.3.1
Itaconic acid
itaconic acid specifically inhibits growth of wild-type cells on acetate and propionate, but not dextrose, in an ICL-dependent manner, and elicited metabolomic changes similar to those observed with ICL-deficient cells. Enzyme ICL inhibition by itaconic acid results in a specific decrease in intrabacterial pH from pH 7.3 to pH 6.4 in propionate-grown cells, not in acetate-grown cells
Mycobacterium tuberculosis
4.1.3.30
Itaconic acid
itaconic acid specifically inhibits growth of wild-type cells on acetate and propionate, but not dextrose, in an ICL-dependent manner, and elicited metabolomic changes similar to those observed with ICL-deficient cells. Enzyme ICL inhibition by itaconic acid results in a specific decrease in intrabacterial pH from pH 7.3 to pH 6.4 in propionat-grown cells, not in acetate-grown cells
Mycobacterium tuberculosis
Natural Substrates/ Products (Substrates)
EC Number
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
4.1.3.1
isocitrate
Mycobacterium tuberculosis
-
succinate + glyoxylate
-
-
?
4.1.3.1
additional information
Mycobacterium tuberculosis
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
?
-
-
-
4.1.3.30
(2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate
Mycobacterium tuberculosis
-
succinate + pyruvate
-
-
?
4.1.3.30
additional information
Mycobacterium tuberculosis
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
?
-
-
-
Organism
EC Number
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
4.1.3.1
Mycobacterium tuberculosis
-
-
-
4.1.3.30
Mycobacterium tuberculosis
-
-
-
Substrates and Products (Substrate)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
4.1.3.1
isocitrate
-
728701
Mycobacterium tuberculosis
succinate + glyoxylate
-
-
-
?
4.1.3.1
additional information
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
728701
Mycobacterium tuberculosis
?
-
-
-
-
4.1.3.30
(2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate
-
728701
Mycobacterium tuberculosis
succinate + pyruvate
-
-
-
?
4.1.3.30
additional information
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
728701
Mycobacterium tuberculosis
?
-
-
-
-
Inhibitors (protein specific)
EC Number
Inhibitors
Commentary
Organism
Structure
4.1.3.1
Itaconic acid
itaconic acid specifically inhibits growth of wild-type cells on acetate and propionate, but not dextrose, in an ICL-dependent manner, and elicited metabolomic changes similar to those observed with ICL-deficient cells. Enzyme ICL inhibition by itaconic acid results in a specific decrease in intrabacterial pH from pH 7.3 to pH 6.4 in propionate-grown cells, not in acetate-grown cells
Mycobacterium tuberculosis
4.1.3.30
Itaconic acid
itaconic acid specifically inhibits growth of wild-type cells on acetate and propionate, but not dextrose, in an ICL-dependent manner, and elicited metabolomic changes similar to those observed with ICL-deficient cells. Enzyme ICL inhibition by itaconic acid results in a specific decrease in intrabacterial pH from pH 7.3 to pH 6.4 in propionat-grown cells, not in acetate-grown cells
Mycobacterium tuberculosis
Natural Substrates/ Products (Substrates) (protein specific)
EC Number
Natural Substrates
Organism
Commentary (Nat. Sub.)
Natural Products
Commentary (Nat. Pro.)
Organism (Nat. Pro.)
Reversibility
4.1.3.1
isocitrate
Mycobacterium tuberculosis
-
succinate + glyoxylate
-
-
?
4.1.3.1
additional information
Mycobacterium tuberculosis
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
?
-
-
-
4.1.3.30
(2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate
Mycobacterium tuberculosis
-
succinate + pyruvate
-
-
?
4.1.3.30
additional information
Mycobacterium tuberculosis
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
?
-
-
-
Substrates and Products (Substrate) (protein specific)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
4.1.3.1
isocitrate
-
728701
Mycobacterium tuberculosis
succinate + glyoxylate
-
-
-
?
4.1.3.1
additional information
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
728701
Mycobacterium tuberculosis
?
-
-
-
-
4.1.3.30
(2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate
-
728701
Mycobacterium tuberculosis
succinate + pyruvate
-
-
-
?
4.1.3.30
additional information
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
728701
Mycobacterium tuberculosis
?
-
-
-
-
General Information
EC Number
General Information
Commentary
Organism
4.1.3.1
malfunction
enzyme-deficient cells undergo a progressive depletion of TCA cycle intermediates and accumulation of propionyl-CoA when metabolizing fatty acid substrates, phenotype, overview. Enzyme-deficient cells are unable to metabolize both even- and odd-chain fatty acids because of the dead-end depletion of TCA cycle intermediates by a constitutively active, but broken, methylcitrate cycle. Addition of cobalamin is sufficient to selectively protect ICL-deficient cells from the bactericidal effects of acetate and propionate, and this attenuation is accompanied by a dose-dependent restoration of TCA cycle activity and propionyl-CoA levels
Mycobacterium tuberculosis
4.1.3.1
physiological function
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids
Mycobacterium tuberculosis
4.1.3.30
malfunction
absence of MCL activity results in the accumulation of methylisocitrate as a metabolic dead end product arising from the stoichiometric consumption of oxaloacetate by propionyl-CoA, phenotype, overview. Isocitrate lyases are essential for survival on both acetate and propionate because of its methylisocitrate lyase activity. Lack of methylisocitrate lyase activity converts the cell methylcitrate cycle into a dead end pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH
Mycobacterium tuberculosis
4.1.3.30
physiological function
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids
Mycobacterium tuberculosis
General Information (protein specific)
EC Number
General Information
Commentary
Organism
4.1.3.1
malfunction
enzyme-deficient cells undergo a progressive depletion of TCA cycle intermediates and accumulation of propionyl-CoA when metabolizing fatty acid substrates, phenotype, overview. Enzyme-deficient cells are unable to metabolize both even- and odd-chain fatty acids because of the dead-end depletion of TCA cycle intermediates by a constitutively active, but broken, methylcitrate cycle. Addition of cobalamin is sufficient to selectively protect ICL-deficient cells from the bactericidal effects of acetate and propionate, and this attenuation is accompanied by a dose-dependent restoration of TCA cycle activity and propionyl-CoA levels
Mycobacterium tuberculosis
4.1.3.1
physiological function
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids
Mycobacterium tuberculosis
4.1.3.30
malfunction
absence of MCL activity results in the accumulation of methylisocitrate as a metabolic dead end product arising from the stoichiometric consumption of oxaloacetate by propionyl-CoA, phenotype, overview. Isocitrate lyases are essential for survival on both acetate and propionate because of its methylisocitrate lyase activity. Lack of methylisocitrate lyase activity converts the cell methylcitrate cycle into a dead end pathway that sequesters tricarboxylic acid (TCA) cycle intermediates into methylcitrate cycle intermediates, depletes gluconeogenic precursors, and results in defects of membrane potential and intrabacterial pH
Mycobacterium tuberculosis
4.1.3.30
physiological function
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids
Mycobacterium tuberculosis