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Literature summary 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

Application

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

Inhibitors

EC Number Inhibitors Comment Organism Structure
4.1.3.36 2-CoA-4-(2,4-dichlorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 2-CoA-4-(2-bromophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 2-CoA-4-(2-chlorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 2-CoA-4-(2-fluorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 2-CoA-4-(2-iodophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 2-CoA-4-(2-methoxyphenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 2-CoA-4-(2-nitrophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 2-CoA-4-(3-chlorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 2-CoA-4-(4-dichlorophenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 2-CoA-4-(4-methoxyphenyl)-4-oxobutanoic acid
-
 Mycobacterium tuberculosis
4.1.3.36 3-(2,4-dichlorophenyl)-3-oxopropyl-CoA weak inhibition Mycobacterium tuberculosis
4.1.3.36 4-(2,4-dichlorophenyl)-4-oxobutanoyl-CoA
-
 Mycobacterium tuberculosis
4.1.3.36 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
4.1.3.36 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
4.1.3.36 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
4.1.3.36 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
4.1.3.36 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
4.1.3.36 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
4.1.3.36 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
4.1.3.36 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

EC Number Organism UniProt Comment Textmining
4.1.3.36 Mycobacterium tuberculosis P9WNP5
-
-
4.1.3.36 Mycobacterium tuberculosis H37Rv P9WNP5
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
4.1.3.36 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
-
 ?
4.1.3.36 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

EC Number Synonyms Comment Organism
4.1.3.36 DHNA-CoA synthase
-
 Mycobacterium tuberculosis
4.1.3.36 MenB
-
 Mycobacterium tuberculosis

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
4.1.3.36 25
-
 assay at Mycobacterium tuberculosis

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
4.1.3.36 7.4
-
 assay at Mycobacterium tuberculosis

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
4.1.3.36 0.000049
-
 2-CoA-4-(2,4-dichlorophenyl)-4-oxobutanoic acid pH 7.4, 25°C Mycobacterium tuberculosis
4.1.3.36 0.000097
-
 2-CoA-4-(2-chlorophenyl)-4-oxobutanoic acid pH 7.4, 25°C Mycobacterium tuberculosis
4.1.3.36 0.00035
-
 2-CoA-4-(4-dichlorophenyl)-4-oxobutanoic acid pH 7.4, 25°C Mycobacterium tuberculosis

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
4.1.3.36 0.000103
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-chlorophenyl)-4-oxobutanoic acid
4.1.3.36 0.000106
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2,4-dichlorophenyl)-4-oxobutanoic acid
4.1.3.36 0.000135
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-bromophenyl)-4-oxobutanoic acid
4.1.3.36 0.000154
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-nitrophenyl)-4-oxobutanoic acid
4.1.3.36 0.000204
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-fluorophenyl)-4-oxobutanoic acid
4.1.3.36 0.000421
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-iodophenyl)-4-oxobutanoic acid
4.1.3.36 0.00047
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(4-dichlorophenyl)-4-oxobutanoic acid
4.1.3.36 0.0022
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(2,4-dichlorophenyl)-4-oxobutanoyl-CoA
4.1.3.36 0.0032
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-oxo-2-[[(1S)-1-phenylethyl]amino]-4-[2-(trifluoromethyl)phenyl]butanoic acid
4.1.3.36 0.0084
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(2-chlorophenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid
4.1.3.36 0.0121
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(2-methoxyphenyl)-4-oxobutanoic acid
4.1.3.36 0.0141
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(3-chlorophenyl)-4-oxobutanoic acid
4.1.3.36 0.0144
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(4-fluorophenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid
4.1.3.36 0.0335
-
 pH 7.4, 25°C Mycobacterium tuberculosis 2-CoA-4-(4-methoxyphenyl)-4-oxobutanoic acid
4.1.3.36 0.0527
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-oxo-4-phenyl-2-[[(1S)-1-phenylethyl]amino]butanoic acid
4.1.3.36 0.12
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(2-methoxyphenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid
4.1.3.36 0.4
-
 above, pH 7.4, 25°C Mycobacterium tuberculosis 3-(2,4-dichlorophenyl)-3-oxopropyl-CoA
4.1.3.36 117
-
 pH 7.4, 25°C Mycobacterium tuberculosis 4-(4-chlorophenyl)-4-oxo-2-[[(1S)-1-phenylethyl]amino]butanoic acid