BRENDA - Enzyme Database show
show all sequences of 2.5.1.96

A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence

Liu, C.; Liu, G.; Song, Y.; Yin, F.; Hensler, M.; Jeng, W.; Nizet, V.; Wang, A.; Oldfield, E.; Science 319, 1391-1394 (2008)

Data extracted from this reference:

Cloned(Commentary)
Commentary
Organism
-
Staphylococcus aureus
Crystallization (Commentary)
Crystallization
Organism
native protein to 1.58 A resolution. CrtM crystallizes in the P3221 space group and there is one molecule per asymmetric unit. The overall fold shows similarity to that seen in human squalene synthase. In the complex with substrate analogue farnesyl thiodiphosphate, two farnesyl thiodiphosphate molecules are found in the large central cavity. Their diphosphate head groups interact with three Mg2+ ions, which in turn interact with Asp residues in two conserved Asp-X-X-X-Asp repeats. The space group of the complex is P3121, and there are two molecules per asymmetric unit. In docking studies with phosphonosulfonate inhibitors, only one phosphonosulfonate is bound per CrtM. All three inhibitors tested have different binding modes. 4-(3-phenoxyphenyl)-1-phosphonobutane-1-sulfonic acid binds into the farnesyl thiodiphosphate-1 site with two Mg2+, 4-(4'-butylbiphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid binds into the farnesyl thiodiphosphate-2 site with only one Mg2+, and 4-(biphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid binds into the farnesyl thiodiphosphate-2 site with no Mg2+. The phosphonosulfonate side chains do closely track the locations of the two farnesyl thiodiphosphate inhibitor side chains
Staphylococcus aureus
Inhibitors
Inhibitors
Commentary
Organism
Structure
4-(3-phenoxyphenyl)-1-phosphonobutane-1-sulfonic acid
i.e. BPH-652
Staphylococcus aureus
4-(4'-butylbiphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid
i.e. BPH-698
Staphylococcus aureus
4-(4-biphenyl)butyldiphosphonic acid
i.e. BPH-674
Staphylococcus aureus
4-(biphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid
i.e. BPH-700
Staphylococcus aureus
Organism
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
Staphylococcus aureus
A9JQL9
-
-
Ki Value [mM]
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
0.0000002
-
4-(4-biphenyl)butyldiphosphonic acid
pH not specified in the publication, temperature not specified in the publication
Staphylococcus aureus
0.0000015
-
4-(3-phenoxyphenyl)-1-phosphonobutane-1-sulfonic acid
pH not specified in the publication, temperature not specified in the publication
Staphylococcus aureus
0.000006
-
4-(biphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid
pH not specified in the publication, temperature not specified in the publication
Staphylococcus aureus
0.000135
-
4-(4'-butylbiphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid
pH not specified in the publication, temperature not specified in the publication
Staphylococcus aureus
Cloned(Commentary) (protein specific)
Commentary
Organism
-
Staphylococcus aureus
Crystallization (Commentary) (protein specific)
Crystallization
Organism
native protein to 1.58 A resolution. CrtM crystallizes in the P3221 space group and there is one molecule per asymmetric unit. The overall fold shows similarity to that seen in human squalene synthase. In the complex with substrate analogue farnesyl thiodiphosphate, two farnesyl thiodiphosphate molecules are found in the large central cavity. Their diphosphate head groups interact with three Mg2+ ions, which in turn interact with Asp residues in two conserved Asp-X-X-X-Asp repeats. The space group of the complex is P3121, and there are two molecules per asymmetric unit. In docking studies with phosphonosulfonate inhibitors, only one phosphonosulfonate is bound per CrtM. All three inhibitors tested have different binding modes. 4-(3-phenoxyphenyl)-1-phosphonobutane-1-sulfonic acid binds into the farnesyl thiodiphosphate-1 site with two Mg2+, 4-(4'-butylbiphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid binds into the farnesyl thiodiphosphate-2 site with only one Mg2+, and 4-(biphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid binds into the farnesyl thiodiphosphate-2 site with no Mg2+. The phosphonosulfonate side chains do closely track the locations of the two farnesyl thiodiphosphate inhibitor side chains
Staphylococcus aureus
Inhibitors (protein specific)
Inhibitors
Commentary
Organism
Structure
4-(3-phenoxyphenyl)-1-phosphonobutane-1-sulfonic acid
i.e. BPH-652
Staphylococcus aureus
4-(4'-butylbiphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid
i.e. BPH-698
Staphylococcus aureus
4-(4-biphenyl)butyldiphosphonic acid
i.e. BPH-674
Staphylococcus aureus
4-(biphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid
i.e. BPH-700
Staphylococcus aureus
Ki Value [mM] (protein specific)
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
0.0000002
-
4-(4-biphenyl)butyldiphosphonic acid
pH not specified in the publication, temperature not specified in the publication
Staphylococcus aureus
0.0000015
-
4-(3-phenoxyphenyl)-1-phosphonobutane-1-sulfonic acid
pH not specified in the publication, temperature not specified in the publication
Staphylococcus aureus
0.000006
-
4-(biphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid
pH not specified in the publication, temperature not specified in the publication
Staphylococcus aureus
0.000135
-
4-(4'-butylbiphenyl-4-yl)-1-phosphonobutane-1-sulfonic acid
pH not specified in the publication, temperature not specified in the publication
Staphylococcus aureus
Other publictions for EC 2.5.1.96
No.
1st author
Pub Med
title
organims
journal
volume
pages
year
Activating Compound
Application
Cloned(Commentary)
Crystallization (Commentary)
Engineering
General Stability
Inhibitors
KM Value [mM]
Localization
Metals/Ions
Molecular Weight [Da]
Natural Substrates/ Products (Substrates)
Organic Solvent Stability
Organism
Oxidation Stability
Posttranslational Modification
Purification (Commentary)
Reaction
Renatured (Commentary)
Source Tissue
Specific Activity [micromol/min/mg]
Storage Stability
Substrates and Products (Substrate)
Subunits
Temperature Optimum [C]
Temperature Range [C]
Temperature Stability [C]
Turnover Number [1/s]
pH Optimum
pH Range
pH Stability
Cofactor
Ki Value [mM]
pI Value
IC50 Value
Activating Compound (protein specific)
Application (protein specific)
Cloned(Commentary) (protein specific)
Cofactor (protein specific)
Crystallization (Commentary) (protein specific)
Engineering (protein specific)
General Stability (protein specific)
IC50 Value (protein specific)
Inhibitors (protein specific)
Ki Value [mM] (protein specific)
KM Value [mM] (protein specific)
Localization (protein specific)
Metals/Ions (protein specific)
Molecular Weight [Da] (protein specific)
Natural Substrates/ Products (Substrates) (protein specific)
Organic Solvent Stability (protein specific)
Oxidation Stability (protein specific)
Posttranslational Modification (protein specific)
Purification (Commentary) (protein specific)
Renatured (Commentary) (protein specific)
Source Tissue (protein specific)
Specific Activity [micromol/min/mg] (protein specific)
Storage Stability (protein specific)
Substrates and Products (Substrate) (protein specific)
Subunits (protein specific)
Temperature Optimum [C] (protein specific)
Temperature Range [C] (protein specific)
Temperature Stability [C] (protein specific)
Turnover Number [1/s] (protein specific)
pH Optimum (protein specific)
pH Range (protein specific)
pH Stability (protein specific)
pI Value (protein specific)
Expression
General Information
General Information (protein specific)
Expression (protein specific)
KCat/KM [mM/s]
KCat/KM [mM/s] (protein specific)
739019
Steiger
Annotation and functional assi ...
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161
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4
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2
2
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738235
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Directed evolution of squalene ...
Homo sapiens, Saccharomyces cerevisiae, Thermosynechococcus elongatus
FEBS Lett.
588
3375-3381
2014
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3
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3
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6
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3
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6
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3
3
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722759
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Binding modes of zaragozic aci ...
Staphylococcus aureus
J. Biol. Chem.
287
18750-18757
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722921
Lin
Head-to-head prenyl tranferase ...
Staphylococcus aureus
J. Med. Chem.
55
4367-4372
2012
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1
1
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3
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715199
Garrido-Fernandez
Carotenoid production in Lacto ...
Lactobacillus plantarum
Int. J. Food Microbiol.
140
34-39
2010
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715673
Kahlon
Molecular docking studies to m ...
Staphylococcus aureus
J. Biomol. Struct. Dyn.
28
201-210
2010
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716765
Lin
Mechanism of action and inhibi ...
Staphylococcus aureus
Proc. Natl. Acad. Sci. USA
107
21337-21342
2010
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1
1
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713989
Koecher
Structure, function and biosyn ...
Halobacillus halophilus, Halobacillus halophilus DSM 2266T
Arch. Microbiol.
191
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2009
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1
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4
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715841
Song
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Staphylococcus aureus
J. Med. Chem.
52
976-988
2009
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1
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7
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7
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1
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7
7
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716919
Liu
A cholesterol biosynthesis inh ...
Staphylococcus aureus
Science
319
1391-1394
2008
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1
1
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4
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713819
Ku
Preparation, characterization, ...
Staphylococcus aureus
Appl. Environ. Microbiol.
71
6578-6583
2005
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1
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715351
Umeno
Evolution of a pathway to nove ...
Staphylococcus aureus, Staphylococcus aureus ATCC 35556
J. Bacteriol.
186
1531-1536
2004
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1
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10
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715332
Wieland
Genetic and biochemical analys ...
Staphylococcus aureus, Staphylococcus aureus Newman
J. Bacteriol.
176
7719-7726
1994
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