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Literature summary for 4.1.3.36 extracted from

  • Li, X.; Liu, N.; Zhang, H.; Knudson, S.E.; Li, H.J.; Lai, C.T.; Simmerling, C.; Slayden, R.A.; Tonge, P.J.
    CoA adducts of 4-oxo-4-phenylbut-2-enoates: inhibitors of MenB from the M. tuberculosis menaquinone biosynthesis pathway (2011), ACS Med. Chem. Lett., 2, 818-823.
    View publication on PubMedView publication on EuropePMC
Search for more literature for 4.1.3.36

Application

Application Comment Organism
drug development the enzyme is a target for development of antibacterial agents Mycobacterium tuberculosis

Inhibitors

Inhibitors Comment Organism Structure
2-CoA-4-(2,4-dichlorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
2-CoA-4-(2-bromophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
2-CoA-4-(2-chlorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
2-CoA-4-(2-fluorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
2-CoA-4-(2-iodophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
2-CoA-4-(2-methoxyphenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
2-CoA-4-(2-nitrophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
2-CoA-4-(3-chlorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
2-CoA-4-(4-dichlorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
2-CoA-4-(4-methoxyphenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
3-(2,4-dichlorophenyl)-3-oxopropyl-CoA weak inhibition Mycobacterium tuberculosis
4-(2,4-dichlorophenyl)-4-oxobutanoyl-CoA
-
 Mycobacterium tuberculosis
4-(2-chlorophenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid half-life at 25°C, pH 7.4, is 0.4 h Mycobacterium tuberculosis
4-(2-methoxyphenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid half-life at 25°C, pH 7.4, is 11.6 h Mycobacterium tuberculosis
4-(4-chlorophenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid half-life at 25°C, pH 7.4, is 6.8 h Mycobacterium tuberculosis
4-(4-fluorophenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid half-life at 25°C, pH 7.4, is 12.2 h Mycobacterium tuberculosis
4-oxo-2-[[(1S)-1-phenylethyl]amino]-4-[2-(trifluoromethyl)phenyl]butanoic acid half-life at 25°C, pH 7.4, is 0.2 h Mycobacterium tuberculosis
4-oxo-4-chlorophenylbutenoyl methyl ester penetrates the cell where it is hydrolyzed and reacts with CoA to generate the active antibacterial compound, mechanism, overview Mycobacterium tuberculosis
4-oxo-4-phenyl-2-[[(1S)-1-phenylethyl]amino]butanoic acid half-life at 25°C, pH 7.4, is 11.6 h Mycobacterium tuberculosis
additional information 2-amino-4-oxo-4-phenylbutanoate inhibitors are unstable in solution and eliminate to form the corresponding 4-oxo-4-phenylbut-2-enoates that then react with CoA in situ to form nanomolar inhibitors of MenB. The potency of these compounds results from interaction of the CoA adduct carboxylate with the MenB oxyanion hole, a conserved structural motif in the crotonase superfamily. No inhibition by 1548L21 at 0.3 mM Mycobacterium tuberculosis

Organism

Organism UniProt Comment Textmining
Mycobacterium tuberculosis P9WNP5
-
-
Mycobacterium tuberculosis H37Rv P9WNP5
-
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
o-succinylbenzoate + CoA catalyzes an intramolecular Claisen condensation reaction leading to the formation of 1,4-dihydroxy-2-naphthoyl-CoA from o-succinylbenzoate, the enzyme substrate is chemically unstable Mycobacterium tuberculosis 1,4-dihydroxy-2-naphthoyl-CoA + H2O
-
 ?
o-succinylbenzoate + CoA catalyzes an intramolecular Claisen condensation reaction leading to the formation of 1,4-dihydroxy-2-naphthoyl-CoA from o-succinylbenzoate, the enzyme substrate is chemically unstable Mycobacterium tuberculosis H37Rv 1,4-dihydroxy-2-naphthoyl-CoA + H2O
-
 ?

Synonyms

Synonyms Comment Organism
DHNA-CoA synthase
-
 Mycobacterium tuberculosis
MenB
-
 Mycobacterium tuberculosis

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
25
-
 assay at Mycobacterium tuberculosis

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.4
-
 assay at Mycobacterium tuberculosis

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.000049
-
 2-CoA-4-(2,4-dichlorophenyl)-4-oxobutanoic acid pH 7.4, 25°C Mycobacterium tuberculosis
0.000097
-
 2-CoA-4-(2-chlorophenyl)-4-oxobutanoic acid pH 7.4, 25°C Mycobacterium tuberculosis
0.00035
-
 2-CoA-4-(4-dichlorophenyl)-4-oxobutanoic acid pH 7.4, 25°C Mycobacterium tuberculosis

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.000103
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-chlorophenyl)-4-oxobutanoic acid
0.000106
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2,4-dichlorophenyl)-4-oxobutanoic acid
0.000135
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-bromophenyl)-4-oxobutanoic acid
0.000154
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-nitrophenyl)-4-oxobutanoic acid
0.000204
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-fluorophenyl)-4-oxobutanoic acid
0.000421
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-iodophenyl)-4-oxobutanoic acid
0.00047
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(4-dichlorophenyl)-4-oxobutanoic acid
0.0022
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(2,4-dichlorophenyl)-4-oxobutanoyl-CoA
0.0032
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-oxo-2-[[(1S)-1-phenylethyl]amino]-4-[2-(trifluoromethyl)phenyl]butanoic acid
0.0084
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(2-chlorophenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid
0.0121
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-methoxyphenyl)-4-oxobutanoic acid
0.0141
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(3-chlorophenyl)-4-oxobutanoic acid
0.0144
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(4-fluorophenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid
0.0335
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(4-methoxyphenyl)-4-oxobutanoic acid
0.0527
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-oxo-4-phenyl-2-[[(1S)-1-phenylethyl]amino]butanoic acid
0.12
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(2-methoxyphenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid
0.4
-
 above, pH 7.4, 25°C Mycobacterium tuberculosis 3-(2,4-dichlorophenyl)-3-oxopropyl-CoA
117
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(4-chlorophenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid