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Literature summary for 3.5.1.108 extracted from

  • Barb, A.W.; Leavy, T.M.; Robins, L.I.; Guan, Z.; Six, D.A.; Zhou, P.; Hangauer, M.J.; Bertozzi, C.R.; Raetz, C.R.
    Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC (2009), Biochemistry, 48, 3068-3077.
    View publication on PubMedView publication on EuropePMC

Protein Variants

Protein Variants Comment Organism
C125A as sensitive to 2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime as the wild-type enzyme Escherichia coli
C207A much less sensitive to 2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime inhibition, suggesting that Cys-207 is necessary to form the E-I complex Escherichia coli
C214N as sensitive to 2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime as the wild-type enzyme Escherichia coli
C250A as sensitive to 2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime as the wild-type enzyme Escherichia coli
C63S as sensitive to 2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime as the wild-type enzyme Escherichia coli
C65A as sensitive to 2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime as the wild-type enzyme Escherichia coli
Q202W/G210S mutant loses the time-dependence of N-((2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl)-4-((4-(morpholinomethyl)phenyl)ethynyl)benzamide inhibition. Still sensitive to inhibition by 2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime in a time-dependent manner Escherichia coli

Inhibitors

Inhibitors Comment Organism Structure
(R)-3-(5,8-dihydronaphthalen-2-yl)-N-hydroxy-2-(naphthalene-2-sulfonamido)propanamide
-
Escherichia coli
(S)-N-(1-(2-(3,4-dimethoxy-5-propylphenyl)-4,5-dihydrooxazol-4-yl)vinyl)hydroxylamine
-
Escherichia coli
2,3-dihydroxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime weak inhibitor Escherichia coli
2,4-dihydroxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime
-
Escherichia coli
3,4,5-trihydroxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime weak inhibitor, contains a 5 position hydroxyl and exhibits greatly reduced inhibitory potency Escherichia coli
3,4-dihydroxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime 50 microM, 49% inhibition Rhizobium leguminosarum
5'-O-[(E)-(2,3,4-trihydroxybenzylidene)amino]uridine 50 microM, 80% inhibition, pH-dependent, two-step, covalent inhibitor. 2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime represents a new class of LpxC inhibitors that exploit the uridine binding site to form a covalent complex. While not antibiotic, it may provide a new scaffold for extension of existing LpxC-inhibiting antibiotics to target the UDP binding pocket Escherichia coli
5'-O-[(E)-(2,3,4-trihydroxybenzylidene)amino]uridine 50 microM, 21% inhibition, pH-dependent, two-step, covalent inhibitor. 2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime represents a new class of LpxC inhibitors that exploit the uridine binding site to form a covalent complex. While not antibiotic, it may provide a new scaffold for extension of existing LpxC-inhibiting antibiotics to target the UDP binding pocket Helicobacter pylori
5'-O-[(E)-(3,4-dihydroxybenzylidene)amino]uridine 50 microM, 60% inhibition, inhibitor as potent as (E)-2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime Escherichia coli
5'-O-[(E)-(3,4-dihydroxybenzylidene)amino]uridine 50 microM, 41% inhibition Helicobacter pylori
additional information dithiothreitol, glutathione and the C207A mutant prevent the formation of a covalent complex by (E)-2,3,4-trihydroxybenzaldehyde O-((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl oxime; no inhibitory effect by 2,4-dihydroxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime, 3,4-dimethoxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime, and 2,3,4-trimethoxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime Escherichia coli
N-(((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-((Z)-2,3,4-trihydroxybenzylideneaminooxy)acetamide
-
Escherichia coli
N-((2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl)-4-((4-(morpholinomethyl)phenyl)ethynyl)benzamide
-
Escherichia coli

Organism

Organism UniProt Comment Textmining
Escherichia coli
-
-
-
Helicobacter pylori
-
-
-
Rhizobium leguminosarum
-
-
-

Purification (Commentary)

Purification (Comment) Organism
-
Escherichia coli
-
Helicobacter pylori
-
Rhizobium leguminosarum

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine + H2O
-
Escherichia coli UDP-3-O-((R)-3-hydroxymyristoyl)-D-glucosamine + acetate
-
?

Synonyms

Synonyms Comment Organism
LpxC
-
Escherichia coli
LpxC
-
Helicobacter pylori
LpxC
-
Rhizobium leguminosarum
UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase
-
Escherichia coli
UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase
-
Helicobacter pylori
UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase
-
Rhizobium leguminosarum

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
30
-
assay at Escherichia coli

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.4
-
assay at Escherichia coli

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.054
-
5'-O-[(E)-(2,3,4-trihydroxybenzylidene)amino]uridine
-
Escherichia coli

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
additional information
-
above 500 microM Escherichia coli 2,4-dihydroxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime
additional information
-
above 500 microM Escherichia coli 2,3-dihydroxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime
additional information
-
above 500 microM Escherichia coli 3,4,5-trihydroxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime
0.027
-
-
Escherichia coli 5'-O-[(E)-(2,3,4-trihydroxybenzylidene)amino]uridine
0.03
-
-
Escherichia coli 3,4-dihydroxy-benzaldehyde O-[5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-3,4-dihydroxy-tetrahydro-furan-2-ylmethyl]-oxime
0.12
-
-
Escherichia coli N-(((2R,3R,4S,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)-2-((Z)-2,3,4-trihydroxybenzylideneaminooxy)acetamide