Effect of various analogues of D-glutamic acid on the D-glutamate-adding enzyme fromEscherichis coli

Abstract

Twenty-four analogues of D-glutamic acid were tested as substrates or inhibitors of the D-glutamate-adding enzyme from Escherichia coli. The best substrates were, in decreasing order of specific activity, D-erythro-4-methylglutamic acid, D-erythro-3-methylglutamic acid, DL-homocysteic acid, (+/-)-trans-1-amino-3-carboxy-cyclopentanecarboxylic acid and (+/-)-trans-1-amino-3-carboxy-cyclohexanecarboxylic acid. Among the different stereoisomers, only the D-erythro isomers for methylglutamic acids, and the trans isomers for the cyclic analogs, were substrates. Apart from the D-erythro-3- and 4-methylglutamic acids and DL-homocysteic acid, none of the examined compounds significantly inhibited the addition of radioactive D-glutamic acid to UDP-N-acetylmuramyl-L-alanine.

Novel Naphthalene-N-sulfonyl-d-glutamic Acid Derivatives as Inhibitors of MurD, a Key Peptidoglycan Biosynthesis Enzyme,

“…Furthermore, the dimethyl ester derivative 16c proved to be inactive, further confirming the importance of the free carboxylate groups of d -Glu. On the other hand, we were surprised by the small difference in potency between the enantiomeric compounds 17c ( d -Glu derivative) and 20 ( l -Glu derivative) (Table ), which is somewhat contradictory to the high stereospecificity of MurD for the d -Glu substrate . It was unexpected that a compound containing the l -Glu moiety would act as an inhibitor of this enzyme.…”

“…On the other hand, we were surprised by the small difference in potency between the enantiomeric compounds 17c (D-Glu derivative) and 20 (L-Glu derivative) (Table 3), which is somewhat contradictory to the high stereospecificity of MurD for the D-Glu substrate. 39 It was unexpected that a compound containing the L-Glu moiety would act as an inhibitor of this enzyme. Steady-state kinetics and X-ray diffraction studies unambiguously demonstrated that the L-Glu moiety of compound 20 binds into the D-Glu-binding site of MurD in a manner similar to that of D-Glu in UMAG or in compound 17c.…”

Novel Naphthalene-N-sulfonyl-d-glutamic Acid Derivatives as Inhibitors of MurD, a Key Peptidoglycan Biosynthesis Enzyme,

“…Furthermore, the dimethyl ester derivative 16c proved to be inactive, further confirming the importance of the free carboxylate groups of d -Glu. On the other hand, we were surprised by the small difference in potency between the enantiomeric compounds 17c ( d -Glu derivative) and 20 ( l -Glu derivative) (Table ), which is somewhat contradictory to the high stereospecificity of MurD for the d -Glu substrate . It was unexpected that a compound containing the l -Glu moiety would act as an inhibitor of this enzyme.…”

“…On the other hand, we were surprised by the small difference in potency between the enantiomeric compounds 17c (D-Glu derivative) and 20 (L-Glu derivative) (Table 3), which is somewhat contradictory to the high stereospecificity of MurD for the D-Glu substrate. 39 It was unexpected that a compound containing the L-Glu moiety would act as an inhibitor of this enzyme. Steady-state kinetics and X-ray diffraction studies unambiguously demonstrated that the L-Glu moiety of compound 20 binds into the D-Glu-binding site of MurD in a manner similar to that of D-Glu in UMAG or in compound 17c.…”

Conformational Study in Water by NMR and Molecular Modeling of α-Methyl-α-Amino Acid: Differential Conformational Properties of α-Cyclic and α-Methylglutamic Acid

“…This experiment was the unique possibility to explore the position of the different substituents about the torsion angle χ1. The 3 J H3aC1 ) 1.4 Hz, 3 J H3aC(2Me)…”

“…) 2.6 Hz and in another part 3 J H3bC1 ) 5.2 Hz, 3 J H3bC(2Me) ) 1.5 Hz should include a large participation of conformation C for this torsion angle χ1 (Figure 2).…”

“…Discussing rotation about sp 3 -sp 3 carbon-carbon bonds, two degrees of conformational freedom are apparent (Figure 1b These conformers are designated according to the trans orientation relative to each other of the backbone chain and one R-group: respectively, the R-carboxylate group (A), the R-amino group (B), and the R-methyl group (C). In the system C(3)-C(4) (Figure 2b), the torsion angle about C(3)-C(4) is defined according to the disposition of the γ-carboxylate group relative to the side chain, trans (t-a) or gauche (g + -b and g --c).…”

Novel Naphthalene-N-sulfonyl-d-glutamic Acid Derivatives as Inhibitors of MurD, a Key Peptidoglycan Biosynthesis Enzyme,

“…Furthermore, the dimethyl ester derivative 16c proved to be inactive, further confirming the importance of the free carboxylate groups of d -Glu. On the other hand, we were surprised by the small difference in potency between the enantiomeric compounds 17c ( d -Glu derivative) and 20 ( l -Glu derivative) (Table ), which is somewhat contradictory to the high stereospecificity of MurD for the d -Glu substrate . It was unexpected that a compound containing the l -Glu moiety would act as an inhibitor of this enzyme.…”

“…On the other hand, we were surprised by the small difference in potency between the enantiomeric compounds 17c (D-Glu derivative) and 20 (L-Glu derivative) (Table 3), which is somewhat contradictory to the high stereospecificity of MurD for the D-Glu substrate. 39 It was unexpected that a compound containing the L-Glu moiety would act as an inhibitor of this enzyme. Steady-state kinetics and X-ray diffraction studies unambiguously demonstrated that the L-Glu moiety of compound 20 binds into the D-Glu-binding site of MurD in a manner similar to that of D-Glu in UMAG or in compound 17c.…”

Conformational Study in Water by NMR and Molecular Modeling of α-Methyl-α-Amino Acid: Differential Conformational Properties of α-Cyclic and α-Methylglutamic Acid

“…This experiment was the unique possibility to explore the position of the different substituents about the torsion angle χ1. The 3 J H3aC1 ) 1.4 Hz, 3 J H3aC(2Me)…”

“…) 2.6 Hz and in another part 3 J H3bC1 ) 5.2 Hz, 3 J H3bC(2Me) ) 1.5 Hz should include a large participation of conformation C for this torsion angle χ1 (Figure 2).…”

“…Discussing rotation about sp 3 -sp 3 carbon-carbon bonds, two degrees of conformational freedom are apparent (Figure 1b These conformers are designated according to the trans orientation relative to each other of the backbone chain and one R-group: respectively, the R-carboxylate group (A), the R-amino group (B), and the R-methyl group (C). In the system C(3)-C(4) (Figure 2b), the torsion angle about C(3)-C(4) is defined according to the disposition of the γ-carboxylate group relative to the side chain, trans (t-a) or gauche (g + -b and g --c).…”

Novel Naphthalene-N-sulfonyl-d-glutamic Acid Derivatives as Inhibitors of MurD, a Key Peptidoglycan Biosynthesis Enzyme,

“…Furthermore, the dimethyl ester derivative 16c proved to be inactive, further confirming the importance of the free carboxylate groups of d -Glu. On the other hand, we were surprised by the small difference in potency between the enantiomeric compounds 17c ( d -Glu derivative) and 20 ( l -Glu derivative) (Table ), which is somewhat contradictory to the high stereospecificity of MurD for the d -Glu substrate . It was unexpected that a compound containing the l -Glu moiety would act as an inhibitor of this enzyme.…”

“…On the other hand, we were surprised by the small difference in potency between the enantiomeric compounds 17c (D-Glu derivative) and 20 (L-Glu derivative) (Table 3), which is somewhat contradictory to the high stereospecificity of MurD for the D-Glu substrate. 39 It was unexpected that a compound containing the L-Glu moiety would act as an inhibitor of this enzyme. Steady-state kinetics and X-ray diffraction studies unambiguously demonstrated that the L-Glu moiety of compound 20 binds into the D-Glu-binding site of MurD in a manner similar to that of D-Glu in UMAG or in compound 17c.…”

Conformational Study in Water by NMR and Molecular Modeling of α-Methyl-α-Amino Acid: Differential Conformational Properties of α-Cyclic and α-Methylglutamic Acid

“…This experiment was the unique possibility to explore the position of the different substituents about the torsion angle χ1. The 3 J H3aC1 ) 1.4 Hz, 3 J H3aC(2Me)…”

“…) 2.6 Hz and in another part 3 J H3bC1 ) 5.2 Hz, 3 J H3bC(2Me) ) 1.5 Hz should include a large participation of conformation C for this torsion angle χ1 (Figure 2).…”

“…Discussing rotation about sp 3 -sp 3 carbon-carbon bonds, two degrees of conformational freedom are apparent (Figure 1b These conformers are designated according to the trans orientation relative to each other of the backbone chain and one R-group: respectively, the R-carboxylate group (A), the R-amino group (B), and the R-methyl group (C). In the system C(3)-C(4) (Figure 2b), the torsion angle about C(3)-C(4) is defined according to the disposition of the γ-carboxylate group relative to the side chain, trans (t-a) or gauche (g + -b and g --c).…”