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Information on EC 2.6.1.42 - branched-chain-amino-acid transaminase and Organism(s) Mycobacterium tuberculosis and UniProt Accession P9WQ75
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EC Tree
2.6.1.42 branched-chain-amino-acid transaminaseIUBMB Comments
Also acts on L-isoleucine and L-valine, and thereby differs from EC 2.6.1.6, leucine transaminase, which does not. It also differs from EC 2.6.1.66, valine---pyruvate transaminase.
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Word Map
- 2.6.1.42
-
bcats
- isoleucine
-
transamination
- aminotransferases
- pyridoxal
-
ketoacids
- alpha-ketoisocaproate
- transaminases
- l-valine
-
isomeroreductase
- gabapentin
-
acetohydroxy
- alpha-ketoacids
- nutrition
- synthesis
-
acetohydroxyacid
- medicine
- drug development
- analysis
The taxonomic range for the selected organisms is: Mycobacterium tuberculosis
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
bcat1, bcatm, branched-chain aminotransferase, bcatc, bcat2, branched-chain amino acid aminotransferase, branched chain aminotransferase, hbcat, hbcatm, branched-chain amino acid transaminase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Rv2210c
branched-chain amino acid aminotransferase
-
-
-
-
branched-chain amino acid-glutamate transaminase
-
-
-
-
branched-chain aminotransferase
glutamate-branched-chain amino acid transaminase
-
-
-
-
L-branched chain amino acid aminotransferase
-
-
-
-
transaminase B
-
-
-
-
branched-chain aminotransferase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
L-leucine + 2-oxoglutarate = 4-methyl-2-oxopentanoate + L-glutamate
MtIlvE displays a ping-pong kinetic mechanism. The phosphate ester of the PLP cofactor, and the alpha-amino group from L-glutamate and the active site Lys204, play roles in acid-base catalysis and binding, respectively. An intrinsic primary kinetic isotope effect is identified for the alpha-C-H bond cleavage of L-glutamate. Large solvent kinetic isotope effect values for the ping and pong half-reactions are also identified
L-leucine + 2-oxoglutarate = 4-methyl-2-oxopentanoate + L-glutamate
reaction mechanism of aminotransferases via external aldimine, quinonoid intermediate, ketimine, and carbinolamine, overview
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
amino group transfer
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
-
-, -, -, -, -, -, -, -, -, -, -, -, -, -, -, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
branched-chain-amino-acid:2-oxoglutarate aminotransferase
Also acts on L-isoleucine and L-valine, and thereby differs from EC 2.6.1.6, leucine transaminase, which does not. It also differs from EC 2.6.1.66, valine---pyruvate transaminase.
CAS REGISTRY NUMBER
COMMENTARY
9054-65-3
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3-methyl-2-oxobutanoate + L-glutamate
L-valine + 2-oxoglutarate
-
-
-
r
3-methyl-2-oxopentanoate + L-glutamate
L-isoleucine + 2-oxoglutarate
high activity
-
-
r
4-methyl-2-oxopentanoate + L-glutamate
L-leucine + 2-oxoglutarate
-
-
-
r
4-methylsulfanyl-2-oxobutanoate + L-glutamate
L-methionine + 2-oxoglutarate
-
-
-
r
beta-phenylpyruvate + L-glutamate
L-phenylalanine + 2-oxoglutarate
-
-
-
r
L-glutamate + 2-oxoglutarate
2-oxoglutarate + L-glutamate
-
-
-
r
L-phenylalanine + 2-oxoglutarate
beta-phenylpyruvate + L-glutamate
-
-
-
r
L-phenylalanine + 2-oxoglutarate
phenylpyruvate + L-glutamate
-
-
-
r
L-glutamate + 4-methylthio-2-oxo-butanoate
2-oxoglutarate + L-methionine
-
-
-
-
?
L-isoleucine + 2-oxoglutarate
3-methyl-2-oxopentanoate + L-glutamate
-
-
-
-
?
L-isoleucine + 2-oxoglutarate
3-methyl-2-oxopentanoic acid + L-glutamate
-
-
-
-
r
L-isoleucine + 4-methylthio-2-oxo-butanoate
3-methyl-2-oxopentanoate + L-methionine
-
-
-
-
?
L-leucine + 2-oxoglutarate
4-methyl-2-oxopentanoic acid + L-glutamate
-
-
-
-
r
L-leucine + 4-methylthio-2-oxo-butanoate
4-methyl-2-oxopentanoate + L-methionine
-
-
-
-
?
L-phenylalanine + 4-methylthio-2-oxo-butanoate
phenylpyruvate + L-methionine
-
-
-
-
?
L-valine + 2-oxoglutarate
3-methyl-2-oxobutanoic acid + L-glutamate
-
-
-
-
r
L-valine + 4-methylthio-2-oxo-butanoate
2-oxoisopentanoate + L-methionine
-
-
-
-
?
L-isoleucine + 2-oxoglutarate
3-methyl-2-oxopentanoate + L-glutamate
-
-
-
r
L-isoleucine + 2-oxoglutarate
3-methyl-2-oxopentanoate + L-glutamate
-
-
-
-
r
L-isoleucine + 2-oxoglutarate
3-methyl-2-oxopentanoate + L-glutamate
high activity
-
-
r
L-leucine + 2-oxoglutarate
4-methyl-2-oxopentanoate + L-glutamate
-
-
-
r
L-leucine + 2-oxoglutarate
4-methyl-2-oxopentanoate + L-glutamate
-
-
-
-
r
L-valine + 2-oxoglutarate
3-methyl-2-oxobutanoate + L-glutamate
-
-
-
r
L-valine + 2-oxoglutarate
3-methyl-2-oxobutanoate + L-glutamate
-
-
-
-
r
additional information
?
-
a broad substrate specificity is displayed by MtIlvE. But the enzyme is extremely specific for L-glutamate as the amino donor in the direction of branched-chain amino acid synthesis, and L-aspartate has no activity with the enzyme. 2-Oxo-phenylpyruvate is a 20fold poorer substrate, as is 2-oxo-3-methylthiobutyrate, which exhibits a very high Km value but a very robust V value, equivalent to those of the best branched-chain 2-oxo acid substrates
-
-
-
additional information
?
-
-
a broad substrate specificity is displayed by MtIlvE. But the enzyme is extremely specific for L-glutamate as the amino donor in the direction of branched-chain amino acid synthesis, and L-aspartate has no activity with the enzyme. 2-Oxo-phenylpyruvate is a 20fold poorer substrate, as is 2-oxo-3-methylthiobutyrate, which exhibits a very high Km value but a very robust V value, equivalent to those of the best branched-chain 2-oxo acid substrates
-
-
-
additional information
?
-
MtIlvE is an L-amino acid aminotransferase
-
-
-
additional information
?
-
-
MtIlvE is an L-amino acid aminotransferase
-
-
-
additional information
?
-
the substrate preference of 2-oxoacids is 3-methyl-2-oxovalerate > 4-methyl-2-oxovalerate > 2-oxoisovalerate >> beta-phenylpyruvate > 4-methylthio-2-oxobutyrate, and for amino acids it is L-Ile = L-Leu = L-Val > L-Phe
-
-
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
L-isoleucine + 2-oxoglutarate
3-methyl-2-oxopentanoate + L-glutamate
-
-
-
r
L-isoleucine + 2-oxoglutarate
3-methyl-2-oxopentanoate + L-glutamate
-
-
-
-
r
L-leucine + 2-oxoglutarate
4-methyl-2-oxopentanoate + L-glutamate
-
-
-
r
L-leucine + 2-oxoglutarate
4-methyl-2-oxopentanoate + L-glutamate
-
-
-
-
r
L-valine + 2-oxoglutarate
3-methyl-2-oxobutanoate + L-glutamate
-
-
-
r
L-valine + 2-oxoglutarate
3-methyl-2-oxobutanoate + L-glutamate
-
-
-
-
r
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
D-cycloserine
DCS, mechanism-based inhibition of the Mycobacterium tuberculosis branched-chain aminotransferase by D-cycloserine, mechanism and enzyme-bound three-dimensional structure with a role of residue C196, overview. Time and concentration-dependent inactivation. The structure of the covalent D-cycloserine-PMP adduct bound to MtIlvE reveals that the D-cycloserine ring is planar and aromatic
L-Cycloserine
LCS, mechanism-based inhibition of the Mycobacterium tuberculosis branched-chain aminotransferase by L-cycloserine, mchanism overview, time and concentration-dependent inactivation
carboxymethoxylamine
-
mixed-type inhibition, acts also as growth inhibitor of organism
O-(t-butyl)hydroxylamine
-
mixed-type inhibition, acts also as growth inhibitor of organism
O-allylhydroxylamine
-
mixed-type inhibition, acts also as growth inhibitor of organism
O-Benzylhydroxylamine
-
mixed-type inhibition, acts also as growth inhibitor of organism
additional information
L-cycloserine is a 10fold better inhibitor of Mycobacterium tuberculosis growth than D-cycloserine. Both the D-cycloserine and L-cycloserine-PMP complexes have the same mass, and are likely to be the same aromatized, isoxazole product, but the kinetics of formation of the MtIlvE D-cycloserine-PMP and MtIlvE L-cycloserine-PMP adducts are quite different. While the kinetics of the formation of the MtIlvE D-cycloserine-PMP complex can be fit to a single exponential, the formation of the MtIlvE L-cycloserine-PMP complex occurs in two steps. No inhibition of the enzyme by propargylglycine (an inhibitor of cystathionine gamma-synthase), by gabaculine (an inhibitor of GABA aminotransferase and ornithine decarboxylase) or by difluoromethylornithine (DFMO, the inhibitor of ornithine decarboxylase). Also gabapentin, a potent inhibitor of the cytosolic isozyme hBCATc, has no effect on the activity of MtIlvE
-
additional information
-
L-cycloserine is a 10fold better inhibitor of Mycobacterium tuberculosis growth than D-cycloserine. Both the D-cycloserine and L-cycloserine-PMP complexes have the same mass, and are likely to be the same aromatized, isoxazole product, but the kinetics of formation of the MtIlvE D-cycloserine-PMP and MtIlvE L-cycloserine-PMP adducts are quite different. While the kinetics of the formation of the MtIlvE D-cycloserine-PMP complex can be fit to a single exponential, the formation of the MtIlvE L-cycloserine-PMP complex occurs in two steps. No inhibition of the enzyme by propargylglycine (an inhibitor of cystathionine gamma-synthase), by gabaculine (an inhibitor of GABA aminotransferase and ornithine decarboxylase) or by difluoromethylornithine (DFMO, the inhibitor of ornithine decarboxylase). Also gabapentin, a potent inhibitor of the cytosolic isozyme hBCATc, has no effect on the activity of MtIlvE
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4.2
4-methylthio-2-oxo-butanoate
-
cosubstrate leucine, pH 7.4, 37°C
9.53
L-glutamate
-
cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
7.44
L-phenylalanine
-
cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
2.85
L-isoleucine
-
cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
2.5
L-leucine
-
cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
1.77
L-valine
-
cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
additional information
additional information
MtIlvE displays a ping-pong kinetic mechanism. Analysis of steady-state and pre-steady-state kinetic isotope effects. Michaelis-Menten kinetics
-
additional information
additional information
-
MtIlvE displays a ping-pong kinetic mechanism. Analysis of steady-state and pre-steady-state kinetic isotope effects. Michaelis-Menten kinetics
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.01424
carboxymethoxylamine
-
uncompetitive component of mixed-type inhibition, pH 7.4, 37°C
0.0209
carboxymethoxylamine
-
competitive component of mixed-type inhibition, pH 7.4, 37°C
0.011
O-(t-butyl)hydroxylamine
-
competitive component of mixed-type inhibition, pH 7.4, 37°C
0.0856
O-(t-butyl)hydroxylamine
-
uncompetitive component of mixed-type inhibition, pH 7.4, 37°C
0.0216
O-allylhydroxylamine
-
competitive component of mixed-type inhibition, pH 7.4, 37°C
0.2
O-allylhydroxylamine
-
or higher, uncompetitive component of mixed-type inhibition, pH 7.4, 37°C
0.0082
O-Benzylhydroxylamine
-
competitive component of mixed-type inhibition, pH 7.4, 37°C
0.0841
O-Benzylhydroxylamine
-
uncompetitive component of mixed-type inhibition, pH 7.4, 37°C
additional information
additional information
inhibition kinetics of L- and D-cyclserine, the inactivation follows pseudo-first-order kinetics, at least one molar equivalent of inhibitor binds to one molecule of enzyme for inactivation. Rapid inactivation by L-cycloserine with the second-order rate constant of inactivation kinact/KI_LCS of 7.32 M/s being greater than kinact/KI_DCS of 0.12 M/s
-
additional information
additional information
-
inhibition kinetics of L- and D-cyclserine, the inactivation follows pseudo-first-order kinetics, at least one molar equivalent of inhibitor binds to one molecule of enzyme for inactivation. Rapid inactivation by L-cycloserine with the second-order rate constant of inactivation kinact/KI_LCS of 7.32 M/s being greater than kinact/KI_DCS of 0.12 M/s
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
11.82
-
substrate L-valine, cosubstrate 2-oxoglutarate, pH 7.4, 37°C
12.8
-
substrate 2-oxoglutarate, cosubstrate L-leucine, pH 7.4, 37°C
13.44
-
substrate L-leucine, cosubstrate 2-oxoglutarate, pH 7.4, 37°C
14.35
-
substrate L-isoleucine, cosubstrate 2-oxoglutarate, pH 7.4, 37°C
2.17
-
substrate L-phenylalanine, cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
2.58
-
substrate L-valine, cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
3.65
-
substrate L-leucine, cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
4.22
-
substrate 4-methylthio-2-oxo-butanoate, cosubstrate leucine, pH 7.4, 37°C
4.28
-
substrate L-isoleucine, cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
5.7
-
substrate L-glutamate, cosubstrate 4-methylthio-2-oxo-butanoate, pH 7.4, 37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
branched-chain amino acid aminotransferases (BCATs) differ from other (S)-selective transaminases (TAs) in 3D-structure and organization of the PLP-binding domain. Unlike other (S)-selective TAs, BCATs belong to the PLP fold type IV and are characterized by the proton transfer on the re-face of PLP, in contrast to the si-specificity of proton transfer in fold type I (S)-selective TAs. Moreover, BCATs are the only (S)-selective enzymes within fold type IV TAs. Dual substrate recognition in BCATs is implemented via the lock and key mechanism without side-chain rearrangements of the active site residues. Another feature of the active site organization in BCATs is the binding of the substrate alpha-COOH group on the P-side of the active site near the PLP phosphate group. Close localization of two charged groups seems to increase the effectiveness of external aldimine formation in BCAT catalysis
metabolism
physiological function
additional information
structure-function analysis and substrate specificity, comparisons, overview
metabolism
BCAT are the key enzymes of BCAA metabolism in all organisms
metabolism
the biosynthetic pathway of the branched-chain amino acids is essential for Mycobacterium tuberculosis growth and survival. The pyridoxal 5'-phosphate (PLP)-dependent branched-chain aminotransferase, IlvE. This enzyme is responsible for the final step of the synthesis of the branched-chain amino acids isoleucine, leucine, and valine. Enzyme MtIlvE is involved in the last step of the methionine salvage pathway, where it catalyzes the transfer of an amino group from any of the BCAAs to 2-oxo-3-methylthiobutyrate
physiological function
branched-chain amino acid aminotransferases (BCATs) catalyze reversible stereoselective transamination of branched-chain amino acids (BCAAs) L-leucine, L-isoleucine, and L-valine. The catalysis proceeds through the ping-pong mechanism with the assistance of the cofactor pyridoxal 5'-phosphate (PLP)
physiological function
the branched-chain aminotransferase is a pyridoxal 5'-phosphate (PLP)-dependent enzyme responsible for the final step in the biosynthesis of all three branched-chain amino acids, L-leucine, L-isoleucine, and L-valine, in bacteria
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
40000
2 * 40000, the biologically active form of IlvE is a homodimer, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
homodimer
additional information
homodimer
2 * 40000, the biologically active form of IlvE is a homodimer, SDS-PAGE
additional information
the three-dimensional structure reveals that each monomer is tethered by a substrate specificity loop to its partner molecule
additional information
-
the three-dimensional structure reveals that each monomer is tethered by a substrate specificity loop to its partner molecule
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop vapor diffusion method, using 1% (w/v) tryptone, 50 mM HEPES pH 7.0, and 12% (w/v) polyethylene glycol 3350
purified recombinant enzyme MtIlvE bound by inhibitor D-cycloserine and pyridoxamine (PMP), X-ray diffraction structure determination and analysis at 1.7 A resolution
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
immobilized metal ion affinity chromatography (Ni2+), gel filtration
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Venos, E.S.; Knodel, M.H.; Radford, C.L.; Berger, B.J.
Branched-chain amino acid aminotransferase and methionine formation in Mycobacterium tuberculosis
BMC Microbiol.
4
39
2004
Mycobacterium tuberculosis
Tremblay, L.W.; Blanchard, J.S.
The 1.9 A structure of the branched-chain amino-acid transaminase (IlvE) from Mycobacterium tuberculosis
Acta Crystallogr. Sect. F
65
1071-1077
2009
Mycobacterium tuberculosis (P9WQ75), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WQ75)
Castell, A.; Mille, C.; Unge, T.
Structural analysis of mycobacterial branched-chain aminotransferase: implications for inhibitor design
Acta Crystallogr. Sect. D
66
549-557
2010
Mycobacterium tuberculosis, Mycolicibacterium smegmatis (A0R066), Mycolicibacterium smegmatis
Amorim Franco, T.M.; Favrot, L.; Vergnolle, O.; Blanchard, J.S.
Mechanism-based inhibition of the Mycobacterium tuberculosis branched-chain aminotransferase by D- and L-cycloserine
ACS Chem. Biol.
12
1235-1244
2017
Mycobacterium tuberculosis (P9WQ75), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WQ75)
Bezsudnova, E.Y.; Boyko, K.M.; Popov, V.O.
Properties of bacterial and archaeal branched-chain amino acid aminotransferases
Biochemistry (Moscow)
82
1572-1591
2017
Brevibacillus brevis (A0A2Z4MEX9), Escherichia coli (P0AB80), Gluconobacter oxydans (Q5FTR3), Gluconobacter oxydans 621H (Q5FTR3), Helicobacter pylori (O26004), Helicobacter pylori 26695 (O26004), Helicobacter pylori ATCC 700392 (O26004), Lacticaseibacillus paracasei (A0A5Q8BPF5), Lactococcus lactis, Methanococcus aeolicus (A6UWA0), Methanococcus aeolicus ATCC BAA-1280 (A6UWA0), Methanococcus aeolicus DSM 17508 (A6UWA0), Methanococcus aeolicus Nankai-3 (A6UWA0), Methanococcus aeolicus OCM 812 (A6UWA0), Mycobacterium tuberculosis (P9WQ75), Mycobacterium tuberculosis ATCC 25618 (P9WQ75), Mycobacterium tuberculosis H37Rv (P9WQ75), Pseudomonas aeruginosa (O86428), Pseudomonas aeruginosa 1C (O86428), Pseudomonas aeruginosa ATCC 15692 (O86428), Pseudomonas aeruginosa CIP 104116 (O86428), Pseudomonas aeruginosa DSM 22644 (O86428), Pseudomonas aeruginosa JCM 14847 (O86428), Pseudomonas aeruginosa LMG 12228 (O86428), Pseudomonas aeruginosa PRS 101 (O86428), Pseudomonas sp., Thermococcus sp. CKU-1, Thermoproteus uzoniensis (F2L0W0), Thermoproteus uzoniensis 768-20 (F2L0W0), Vulcanisaeta moutnovskia (F0QW25), Vulcanisaeta moutnovskia 768-28 (F0QW25)
Amorim Franco, T.M.; Hegde, S.; Blanchard, J.S.
Chemical mechanism of the branched-chain aminotransferase IlvE from Mycobacterium tuberculosis
Biochemistry
55
6295-6303
2016
Mycobacterium tuberculosis (P9WQ75), Mycobacterium tuberculosis, Mycobacterium tuberculosis H37Rv (P9WQ75), Mycobacterium tuberculosis ATCC 25618 (P9WQ75)
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