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Literature summary extracted from

  • Makowska-Grzyska, M.; Kim, Y.; Gorla, S.K.; Wei, Y.; Mandapati, K.; Zhang, M.; Maltseva, N.; Modi, G.; Boshoff, H.I.; Gu, M.; Aldrich, C.; Cuny, G.D.; Hedstrom, L.; Joachimiak, A.
    Mycobacterium tuberculosis IMPDH in complexes with substrates, products and antitubercular compounds (2015), PLoS ONE, 10, e0138976.
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
1.1.1.205 drug development inosine 5'-monophosphate dehydrogenase 2 (IMPDH2) from Mycobacterium tuberculosis is an attractive drug target Mycobacterium tuberculosis

Cloned(Commentary)

EC Number Cloned (Comment) Organism
1.1.1.205 gene guaB2, recombinant expression of wild-type and mutant enzymes in Escherichia coli strain BL21(DE3) Mycobacterium tuberculosis

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
1.1.1.205 purified recombinant MtbIMPDH2DELTACBS enzyme mutant in apofomr or complexed with IMP/NAD+, or with inhibitors MAD1/IMP, P41/IMP, or Q67/IMP, the crystallization conditions are for the apoform mutant 0.1 M sodium/potassium phosphate, pH 6.2, 25% 1,2-propandiol, 10% glycerol, 16°C, for the MAD1/IMP-enzyme mutant complex 0.1 M sodium/potassium phosphate, pH 6.2, 25% 1,2-propandiol, 10% glycerol, 16°C, for the P41/IMP-enzyme mutant complex 0.3 M magnesium formate, 0.1 M Tris, pH 8.5, 16°C, for the Q67/IMP-enzyme mutant complex 0.1 M sodium/potassium phosphate, pH 6.2, 25% 1,2-propandiol, 10% glycerol, 16°C, and for the NAD+/IMP-enzyme mutant complex 0.4 M magnesium formate, 0.1M Tris-HCl, pH 8.5, 20% sucrose, 16°C, crystals are soaked with 200 mM ligand solutions, X-ray diffraction structure determination and analysis at 1.60-2.00 A resolution. Analysis of the crystal structure of the enzyme mutant in complex with XMP and NAD+, detailed overview Mycobacterium tuberculosis

Protein Variants

EC Number Protein Variants Comment Organism
1.1.1.205 additional information deletion of IMPDH CBS domain of MtbIMPDH2, residues E126-R252 are replaced with a GG linker. The MtbIMPDH2DELTACBS mutant shows significantly improved solubility and crystallizability properties compared to the wild-type enzyme, with the steady state kinetic parameters comparable to those reported for the wild-type enzyme Mycobacterium tuberculosis

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.1.1.205 (2R)-2-phenyl-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 (2S)-2-(2,3-dichlorophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 (2S)-2-(2,3-dichlorophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-6-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 (2S)-2-(2,3-dimethoxyphenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 (2S)-2-(2-chloro-3-nitrophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 (2S)-2-(2-chlorophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 2-(2,4-dichlorophenoxy)-N-[2-(pyridin-2-yl)-1,3-benzoxazol-5-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 2-(2-chlorophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 2-(4-methoxyphenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 2-chloro-5-[[(2-[3-[(1Z)-N-hydroxyethanimidoyl]phenyl]propan-2-yl)carbamoyl]amino]-N,N-dimethylbenzamide
-
 Mycobacterium tuberculosis
1.1.1.205 2-chloro-5-[[(2-[3-[(1Z)-N-hydroxyethanimidoyl]phenyl]propan-2-yl)carbamoyl]amino]benzamide
-
 Mycobacterium tuberculosis
1.1.1.205 2-chloro-N,N-diethyl-5-[[(2-[3-[(1Z)-N-hydroxyethanimidoyl]phenyl]propan-2-yl)carbamoyl]amino]benzamide
-
 Mycobacterium tuberculosis
1.1.1.205 2-chloro-N,N-dimethyl-5-[([2-[3-(prop-1-en-2-yl)phenyl]propan-2-yl]carbamoyl)amino]benzamide noncompetitive inhibitor, that has similar affinity to both E-IMP and E-XMP, enzyme binding structure analysis, overview Mycobacterium tuberculosis
1.1.1.205 2-phenoxy-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide
-
 Mycobacterium tuberculosis
1.1.1.205 5'-O-([1-[(2E)-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-methylbut-2-en-1-yl]-1H-1,2,3-triazol-4-yl]methyl)adenosine an uncompetitive inhibitor with a strong preference for the E-XMP reaction intermediate, enzyme binding structure analysis, overview Mycobacterium tuberculosis
1.1.1.205 additional information IMPDH has multiple active site states that can be targeted for inhibitor design, and both the IMP/XMP and cofactor binding sites are exploited for that purpose, inhibitor screening of compounds with antitubercular activity, overview. Mechanism of MtbIMPDH2DELTACBS enzyme mutant inhibition Mycobacterium tuberculosis
1.1.1.205 N-[4-chloro-3-(morpholine-4-carbonyl)phenyl]-N'-(2-[3-[(1Z)-N-hydroxyethanimidoyl]phenyl]propan-2-yl)urea
-
 Mycobacterium tuberculosis
1.1.1.205 N2-(2,3-dichlorophenyl)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]-L-alaninamide a competitive inhibitor versus NAD+, that has a strong preference for E-IMP, enzyme binding structure analysis, overview Mycobacterium tuberculosis
1.1.1.205 NAD+ low substrate inhibition Mycobacterium tuberculosis
1.1.1.205 N~2~-(2,3-dichlorophenyl)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]alaninamide
-
 Mycobacterium tuberculosis

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
1.1.1.205 0.041
-
 IMP recombinant MtbIMPDH2DELTACBS mutant enzyme, pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.078
-
 IMP recombinant wild-type enzyme, pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.58
-
 NAD+ recombinant MtbIMPDH2DELTACBS mutant enzyme, pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 1.005
-
 NAD+ recombinant wild-type enzyme, pH 8.0, 22°C Mycobacterium tuberculosis

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.1.1.205 IMP + NAD+ + H2O Mycobacterium tuberculosis
-
 XMP + NADH + H+
-
 ?
1.1.1.205 IMP + NAD+ + H2O Mycobacterium tuberculosis H37Rv
-
 XMP + NADH + H+
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.1.1.205 Mycobacterium tuberculosis P9WKI7
-
-
1.1.1.205 Mycobacterium tuberculosis H37Rv P9WKI7
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
1.1.1.205 recombinant wild-type and mutant enzymes from Escherichia coli strain Bl21(DE3) Mycobacterium tuberculosis

Reaction

EC Number Reaction Comment Organism Reaction ID
1.1.1.205 IMP + NAD+ + H2O = XMP + NADH + H+ the enzymatic mechanism of IMPDH consists two steps, a dehydrogenase and a hydrolase reaction. Upon binding of IMP and NAD+ cofactor, a thioimidate enzyme-substrate adduct, E-XMP*, is formed via a covalent bond to the catalytic C341 with concurrent production of NADH. Hydride transfer occurs to the pro-S position with the cofactor in the anti-conformation. The cofactor is released and an active site mobile flap moves into the NAD+ site and facilitates E-XMP* hydrolysis with a conserved R443 acting as a general base. The enzyme has two distinct conformations, an open form for the dehydrogenase reaction and a closed form for E-XMP* hydrolysis Mycobacterium tuberculosis
a

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.1.1.205 IMP + NAD+ + H2O
-
 Mycobacterium tuberculosis XMP + NADH + H+
-
 ?
1.1.1.205 IMP + NAD+ + H2O
-
 Mycobacterium tuberculosis H37Rv XMP + NADH + H+
-
 ?

Synonyms

EC Number Synonyms Comment Organism
1.1.1.205 guaB2
-
 Mycobacterium tuberculosis
1.1.1.205 IMPDH2
-
 Mycobacterium tuberculosis
1.1.1.205 inosine 5’-monophosphate dehydrogenase 2
-
 Mycobacterium tuberculosis

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
1.1.1.205 22
-
 assay at room temperature Mycobacterium tuberculosis

Turnover Number [1/s]

EC Number Turnover Number Minimum [1/s] Turnover Number Maximum [1/s] Substrate Comment Organism Structure
1.1.1.205 0.53
-
 NAD+ recombinant wild-type enzyme, pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.53
-
 IMP recombinant wild-type enzyme, pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.57
-
 NAD+ recombinant MtbIMPDH2DELTACBS mutant enzyme, pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.57
-
 IMP recombinant MtbIMPDH2DELTACBS mutant enzyme, pH 8.0, 22°C Mycobacterium tuberculosis

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.1.1.205 8
-
 assay at Mycobacterium tuberculosis

Cofactor

EC Number Cofactor Comment Organism Structure
1.1.1.205 NAD+ dependent on, binding structure to CBS domain-deleted enzyme mutant of MtbIMPDH2DELTACBS Mycobacterium tuberculosis

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
1.1.1.205 0.000013
-
 2-chloro-5-[[(2-[3-[(1Z)-N-hydroxyethanimidoyl]phenyl]propan-2-yl)carbamoyl]amino]-N,N-dimethylbenzamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.000014
-
 N2-(2,3-dichlorophenyl)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]-L-alaninamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.000017
-
 2-chloro-N,N-dimethyl-5-[([2-[3-(prop-1-en-2-yl)phenyl]propan-2-yl]carbamoyl)amino]benzamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.000035
-
 2-chloro-N,N-diethyl-5-[[(2-[3-[(1Z)-N-hydroxyethanimidoyl]phenyl]propan-2-yl)carbamoyl]amino]benzamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.000037
-
 N-[4-chloro-3-(morpholine-4-carbonyl)phenyl]-N'-(2-[3-[(1Z)-N-hydroxyethanimidoyl]phenyl]propan-2-yl)urea pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.00004
-
 (2S)-2-(2,3-dichlorophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-6-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.00004
-
 N~2~-(2,3-dichlorophenyl)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]alaninamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.000076
-
 (2S)-2-(2,3-dichlorophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.0001
-
 (2S)-2-(2-chlorophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.00013
-
 (2S)-2-(2-chloro-3-nitrophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.00015
-
 2-(4-methoxyphenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.000158
-
 2-chloro-5-[[(2-[3-[(1Z)-N-hydroxyethanimidoyl]phenyl]propan-2-yl)carbamoyl]amino]benzamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.00024
-
 2-(2-chlorophenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.00044
-
 (2R)-2-phenyl-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.00062
-
 (2S)-2-(2,3-dimethoxyphenoxy)-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.00065
-
 2-phenoxy-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.00158
-
 5'-O-([1-[(2E)-4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-methylbut-2-en-1-yl]-1H-1,2,3-triazol-4-yl]methyl)adenosine pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 0.002
-
 2-(2,4-dichlorophenoxy)-N-[2-(pyridin-2-yl)-1,3-benzoxazol-5-yl]propanamide pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 5
-
 NAD+ recombinant wild-type enzyme, pH 8.0, 22°C Mycobacterium tuberculosis
1.1.1.205 16
-
 NAD+ recombinant MtbIMPDH2DELTACBS mutant enzyme, pH 8.0, 22°C Mycobacterium tuberculosis

General Information

EC Number General Information Comment Organism
1.1.1.205 additional information determination of XMP and NAD+ substrate binding structures, overview. Active site structures of wild-type apo-enzyme and of CBS domain-deleted enzyme mutant MtbIMPDH2DELTACBS in apoform Mycobacterium tuberculosis
1.1.1.205 physiological function the enzyme IMPDH2 catalyzes the conversion of inosine 5'-monophosphate into xanthosine 5'-monophosphate with the concomitant reduction of NAD+ to NADH and controls flux into the guanine nucleotide pool Mycobacterium tuberculosis