Literature summary for 2.4.1.129 extracted from

Mesleh, M.F.; Rajaratnam, P.; Conrad, M.; Chandrasekaran, V.; Liu, C.M.; Pandya, B.A.; Hwang, Y.S.; Rye, P.T.; Muldoon, C.; Becker, B.; Zuegg, J.; Meutermans, W.; Moy, T.I.
Targeting bacterial cell wall peptidoglycan synthesis by inhibition of glycosyltransferase activity (2016), Chem. Biol. Drug Des., 87, 190-199.

Search for more literature for 2.4.1.129

Application

Application	Comment	Organism
medicine	PGT activity can be a useful target for antibiotic therapies because the enzymatic site of the enzyme is highly conserved and inhibition of PGT activity results in the inhibition of bacterial growth	Escherichia coli

Cloned(Commentary)

Cloned (Comment)	Organism
enzyme overexpression in Escherichia coli imp mutant strain	Escherichia coli

Protein Variants

Protein Variants	Comment	Organism
additional information	ponA is synthesized with the addition of ribosome binding site (AGGAGGT) and linker (AAAACAT) upstream of the Met1 codon. This construct is inserted at the XbaI and HindIII sites of pACT3 (21), generating pMCC1, with PBP1a expression under control of the tac promoter. pMCC1 and pACT3 are transformed into hyperpermeable Escherichia coli isolate generating CBS-3546 and CBS-3567, respectively	Escherichia coli

Inhibitors

Inhibitors	Comment	Organism
4-[3-amino-3-([1,1'-biphenyl]-4-yl)propanamido]-1,5-anhydro-2,4-dideoxy-3-O-[2-deoxy-2-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)-beta-D-glucopyranosyl]-2-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)-D-galactitol	-	Escherichia coli
4-[3-amino-3-([1,1'-biphenyl]-4-yl)propanamido]-1,5-anhydro-2,4-dideoxy-3-O-[2-deoxy-2-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)-beta-D-glucopyranosyl]-2-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)-D-galactitol	-	Staphylococcus aureus
ACL19098	-	Escherichia coli
ACL19098	-	Staphylococcus aureus
ACL19109	-	Escherichia coli
ACL19109	-	Staphylococcus aureus
ACL19110	-	Escherichia coli
ACL19110	-	Staphylococcus aureus
ACL19243	-	Escherichia coli
ACL19243	-	Staphylococcus aureus
ACL19273	-	Escherichia coli
ACL19273	-	Staphylococcus aureus
ACL19336	-	Escherichia coli
ACL19336	-	Staphylococcus aureus
mersacidin	a lantibiotic	Escherichia coli
mersacidin	a lantibiotic	Staphylococcus aureus
moenomycin A	moenomycins are phosphoglycolipid antibiotics that directly bind to PGT enzymes. Moenomycins are produced by certain Streptomyces species as a complex of related compounds in which moenomycin A is the major form	Escherichia coli
moenomycin A	moenomycins are phosphoglycolipid antibiotics that directly bind to PGT enzymes. Moenomycins are produced by certain Streptomyces species as a complex of related compounds in which moenomycin A is the major form	Staphylococcus aureus
additional information	molecular docking and modelling study using the structure of PBP1b, PDB ID 3VMA. NMR and mass spectrometric analysis of enzyme-inhibitor binding; PGT enzymes can be inhibited directly by compounds binding to the enzyme and indirectly by compounds binding to the lipid II substrate. Development of glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors. Design of a library of disaccharide compounds based on the minimum moenomycin fragment with peptidoglycan glycosyltransferase inhibitory activity and based on a more drug-like and synthetically versatile disaccharide building block. A subset of these disaccharide compounds bind and inhibit the glycosyltransferase enzyme. Inhibitor-enzyme binding structure analysis by 1H NMR spectral data and using crystal structure PDB ID 3VMA. MIC values with strain imp mutant BAS849	Escherichia coli
additional information	molecular docking and modelling study using the structure of MGT, PDB ID 3HZS. NMR and mass spectrometric analysis of enzyme-inhibitor binding. IC50 Inhibitory curves for MGT against moenomycin complex and vancomycin, overview; PGT enzymes can be inhibited directly by compounds binding to the enzyme and indirectly by compounds binding to the lipid II substrate. Development of glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors. Design of a library of disaccharide compounds based on the minimum moenomycin fragment with peptidoglycan glycosyltransferase inhibitory activity and based on a more drug-like and synthetically versatile disaccharide building block. A subset of these disaccharide compounds bind and inhibit the glycosyltransferase enzyme. Inhibitor-enzyme binding structure analysis by 1H NMR spectral data and using crystal structure PDB ID 3HZS. MIC values with strain ATCC 29213	Staphylococcus aureus
TS30153	-	Escherichia coli
TS30153	-	Staphylococcus aureus
Vancomycin	a glycopeptide	Escherichia coli
Vancomycin	a glycopeptide	Staphylococcus aureus

KM Value [mM]

KM Value [mM]	KM Value Maximum [mM]	Substrate	Comment	Organism	Structure
0.002	-	GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	lipid II, pH 7.5, 25°C	Escherichia coli
0.002	-	GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	lipid II, pH 8.0, 20°C	Staphylococcus aureus

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
cell surface	-	Staphylococcus aureus	9986	-
cell surface	-	Escherichia coli	9986	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Ca2+	required	Escherichia coli
Mn2+	required	Staphylococcus aureus

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.
[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n-diphosphoundecaprenol + GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	Staphylococcus aureus	i.e. lipid II	[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n+1-diphosphoundecaprenol + undecaprenyl diphosphate	-	?
[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n-diphosphoundecaprenol + GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	Escherichia coli	i.e. lipid II	[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n+1-diphosphoundecaprenol + undecaprenyl diphosphate	-	?
[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n-diphosphoundecaprenol + GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	Escherichia coli imp	i.e. lipid II	[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n+1-diphosphoundecaprenol + undecaprenyl diphosphate	-	?
[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n-diphosphoundecaprenol + GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	Staphylococcus aureus ATCC 29213	i.e. lipid II	[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n+1-diphosphoundecaprenol + undecaprenyl diphosphate	-	?

Organism

Organism	UniProt	Comment	Textmining
Escherichia coli	-	-	-
Escherichia coli imp	-	-	-
Staphylococcus aureus	-	-	-
Staphylococcus aureus	-	MRSA	-
Staphylococcus aureus ATCC 29213	-	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
additional information	development of glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors	Staphylococcus aureus	?	-	?
additional information	NMR and mass spectrometric analysis of enzyme-substrate binding	Staphylococcus aureus	?	-	?
additional information	NMR and mass spectrometric analysis of enzyme-substrate binding	Escherichia coli	?	-	?
additional information	PGT enzymes contain two substrate binding pockets flanking the enzymatic center. For a PGT enzyme in the process of extending the peptidoglycan chain, lipid II occupies the acceptor site, and the growing chain occupies the donor site and may extend through the enzyme's exit tunnel. Each round of catalysis results in the extension of the peptidoglycan chain by two saccharides and in the release of undecaprenyl diphosphate. Development of glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors	Escherichia coli	?	-	?
additional information	NMR and mass spectrometric analysis of enzyme-substrate binding	Escherichia coli imp	?	-	?
additional information	PGT enzymes contain two substrate binding pockets flanking the enzymatic center. For a PGT enzyme in the process of extending the peptidoglycan chain, lipid II occupies the acceptor site, and the growing chain occupies the donor site and may extend through the enzyme's exit tunnel. Each round of catalysis results in the extension of the peptidoglycan chain by two saccharides and in the release of undecaprenyl diphosphate. Development of glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors	Escherichia coli imp	?	-	?
additional information	development of glycosyltransferase enzymatic activity and binding assays using the natural products moenomycin and vancomycin as model inhibitors	Staphylococcus aureus ATCC 29213	?	-	?
additional information	NMR and mass spectrometric analysis of enzyme-substrate binding	Staphylococcus aureus ATCC 29213	?	-	?
[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n-diphosphoundecaprenol + GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	i.e. lipid II	Staphylococcus aureus	[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n+1-diphosphoundecaprenol + undecaprenyl diphosphate	-	?
[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n-diphosphoundecaprenol + GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	i.e. lipid II	Escherichia coli	[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n+1-diphosphoundecaprenol + undecaprenyl diphosphate	-	?
[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n-diphosphoundecaprenol + GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	i.e. lipid II	Escherichia coli imp	[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n+1-diphosphoundecaprenol + undecaprenyl diphosphate	-	?
[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n-diphosphoundecaprenol + GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)-diphosphoundecaprenol	i.e. lipid II	Staphylococcus aureus ATCC 29213	[GlcNAc-(1->4)-Mur2Ac(oyl-L-Ala-gamma-D-Glu-L-Lys-D-Ala-D-Ala)]n+1-diphosphoundecaprenol + undecaprenyl diphosphate	-	?

Synonyms

Synonyms	Comment	Organism
bacterial cell wall glycosyltransferase	-	Staphylococcus aureus
bacterial cell wall glycosyltransferase	-	Escherichia coli
bifunctional penicillin-binding protein	-	Staphylococcus aureus
bifunctional penicillin-binding protein	-	Escherichia coli
MGT	-	Staphylococcus aureus
monofunctional glycosyltransferase	-	Staphylococcus aureus
monofunctional glycosyltransferase	-	Escherichia coli
PBP1a	-	Escherichia coli
PBP1b	-	Escherichia coli
PBP1c	-	Escherichia coli
peptidoglycan transglycosylase	-	Staphylococcus aureus
peptidoglycan transglycosylase	-	Escherichia coli
PGT	-	Staphylococcus aureus
PGT	-	Escherichia coli

Temperature Optimum [°C]

Temperature Optimum [°C]	Temperature Optimum Maximum [°C]	Comment	Organism
20	-	assay at	Staphylococcus aureus
25	-	assay at	Staphylococcus aureus
25	-	assay at	Escherichia coli

pH Optimum

pH Optimum Minimum	pH Optimum Maximum	Comment	Organism
7.5	-	assay at	Staphylococcus aureus
7.5	-	assay at	Escherichia coli
8	-	assay at	Staphylococcus aureus

IC50 Value

IC50 Value	IC50 Value Maximum	Comment	Organism	Inhibitor
0.0000076	-	pH 8.0, 20°C	Staphylococcus aureus	moenomycin A
0.00054	-	pH 7.5, 25°C	Escherichia coli	Vancomycin
0.000685	-	pH 8.0, 20°C	Staphylococcus aureus	Vancomycin
0.0062	-	pH 7.5, 25°C	Escherichia coli	ACL19098
0.0062	-	pH 7.5, 25°C, PBP1b	Escherichia coli	ACL19098
0.0073	-	pH 8.0, 20°C	Staphylococcus aureus	ACL19098
0.0073	-	pH 7.5, 25°C, MGT	Staphylococcus aureus	ACL19098
0.019	-	pH 7.5, 25°C	Escherichia coli	moenomycin A
0.0346	-	pH 7.5, 25°C	Escherichia coli	ACL19109
0.0346	-	pH 7.5, 25°C, PBP1b	Escherichia coli	ACL19109
0.0362	-	pH 7.5, 25°C	Escherichia coli	ACL19336
0.0362	-	pH 7.5, 25°C, PBP1b	Escherichia coli	ACL19336
0.0365	-	pH 7.5, 25°C	Escherichia coli	ACL19110
0.0365	-	pH 7.5, 25°C, PBP1b	Escherichia coli	ACL19110
0.0382	-	pH 8.0, 20°C	Staphylococcus aureus	ACL19109
0.0382	-	pH 7.5, 25°C, MGT	Staphylococcus aureus	ACL19109
0.04	-	pH 7.5, 25°C	Escherichia coli	ACL19273
0.04	-	pH 7.5, 25°C, PBP1b	Escherichia coli	ACL19273
0.0497	-	pH 7.5, 25°C	Escherichia coli	ACL19243
0.0497	-	pH 7.5, 25°C, PBP1b	Escherichia coli	4-[3-amino-3-([1,1'-biphenyl]-4-yl)propanamido]-1,5-anhydro-2,4-dideoxy-3-O-[2-deoxy-2-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)-beta-D-glucopyranosyl]-2-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)-D-galactitol
0.05	-	pH 8.0, 20°C	Staphylococcus aureus	ACL19273
0.05	-	pH 7.5, 25°C, MGT	Staphylococcus aureus	ACL19273
0.0732	-	pH 8.0, 20°C	Staphylococcus aureus	ACL19243
0.0732	-	pH 7.5, 25°C, MGT	Staphylococcus aureus	4-[3-amino-3-([1,1'-biphenyl]-4-yl)propanamido]-1,5-anhydro-2,4-dideoxy-3-O-[2-deoxy-2-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)-beta-D-glucopyranosyl]-2-({[3-(trifluoromethyl)phenyl]carbamoyl}amino)-D-galactitol
0.075	-	pH 8.0, 20°C	Staphylococcus aureus	ACL19336
0.075	-	pH 7.5, 25°C, MGT	Staphylococcus aureus	ACL19336
0.0905	-	pH 8.0, 20°C	Staphylococcus aureus	ACL19110
0.0905	-	pH 7.5, 25°C, MGT	Staphylococcus aureus	ACL19110

General Information

General Information	Comment	Organism
evolution	proteins with PGT activity occur as monofunctional glycosyltransferases (MGTs) and as bifunctional penicillin-binding proteins (PBPs) designated as class A PBPs	Staphylococcus aureus
evolution	proteins with PGT activity occur as monofunctional glycosyltransferases (MGTs) and as bifunctional penicillin-binding proteins (PBPs) designated as class A PBPs	Escherichia coli
evolution	proteins with PGT activity occur as monofunctional glycosyltransferases (MGTs) and as bifunctional penicillin-binding proteins (PBPs) designated as class A PBPs. Both forms contain a single transmembrane span at the N-terminus followed by the glycosyltransferase domain. In the class A PBPs, the C-terminus contains the transpeptidase domain. Bacterial species typically have multiple forms of these enzymes. Escherichia coli has 3 class A PBPs (PBP1a, PBP1b, and PBP1c) and 2 MGT proteins	Escherichia coli
evolution	proteins with PGT activity occur as monofunctional glycosyltransferases (MGTs) and as bifunctional penicillin-binding proteins (PBPs) designated as class A PBPs. Both forms contain a single transmembrane span at the N-terminus followed by the glycosyltransferase domain. In the class A PBPs, the C-terminus contains the transpeptidase domain. Bacterial species typically have multiple forms of these enzymes. Staphylococcus aureus has a single class A PBP (PBP2) and 2 MGT proteins (SgtA, SgtB/MGT)	Staphylococcus aureus
physiological function	synthesis of bacterial cell wall requires the concerted action of peptidoglycan glycosyltransferases (PGT, also known as peptidoglycan transglycosylases) and transpeptidases. The PGT enzymes transfer the disaccharide-peptide from the lipid II substrate onto the growing glycan chain allowing TP enzymes to crosslink peptides from adjacent chains. The lipid II substrate is anchored into the cell membrane through an undecaprenyl (C55) tail. Each round of catalysis results in the extension of the peptidoglycan chain by two saccharides and in the release of undecaprenyl diphosphate (C55PP)	Staphylococcus aureus
physiological function	synthesis of bacterial cell wall requires the concerted action of peptidoglycan glycosyltransferases (PGT, also known as peptidoglycan transglycosylases) and transpeptidases. The PGT enzymes transfer the disaccharide-peptide from the lipid II substrate onto the growing glycan chain allowing TP enzymes to crosslink peptides from adjacent chains. The lipid II substrate is anchored into the cell membrane through an undecaprenyl (C55) tail. Each round of catalysis results in the extension of the peptidoglycan chain by two saccharides and in the release of undecaprenyl diphosphate (C55PP)	Escherichia coli
physiological function	the PGT enzymes transfer the disaccharide-peptide from the lipid II substrate onto the growing glycan chain allowing transpeptidase enzymes to crosslink peptides from adjacent chains. The lipid II substrate is anchored into the cell membrane through an undecaprenyl (C55) tail. The enzymatic reaction is thought to occur at the surface of the membrane	Staphylococcus aureus
physiological function	the PGT enzymes transfer the disaccharide-peptide from the lipid II substrate onto the growing glycan chain allowing transpeptidase enzymes to crosslink peptides from adjacent chains. The lipid II substrate is anchored into the cell membrane through an undecaprenyl (C55) tail. The enzymatic reaction is thought to occur at the surface of the membrane	Escherichia coli