Any feedback?
Please rate this page
(literature.php)
(0/150)

BRENDA support

Literature summary extracted from

  • Mann, P.A.; Mueller, A.; Wolff, K.A.; Fischmann, T.; Wang, H.; Reed, P.; Hou, Y.; Li, W.; Mueller, C.E.; Xiao, J.; Murgolo, N.; Sher, X.; Mayhood, T.; Sheth, P.R.; Mirza, A.; Labroli, M.; Xiao, L.; McCoy, M.; Gill, C.J.; Pinho, M.G.; Schneider, T.; Roemer, T.
    Chemical genetic analysis and functional characterization of staphylococcal wall teichoic acid 2-epimerases reveals unconventional antibiotic drug targets (2016), PLoS Pathog., 12, e1005585 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
5.1.3.14 drug development Staphylococcus aureus is a leading cause of hospital and community-acquired infections by Gram-positive bacteria and Staphylococcus epidermidis has emerged as the most common cause of biofilm infections on medical implant devices. Enzyme MnaA serves as a Staphylococcal antibiotic target with cognate inhibitors predicted to possess dual therapeutic benefit: as combination agents to restore beta-lactam efficacy against MRSA and MRSE and as non-bioactive prophylactic agents to prevent Staphylococcal biofilm formation Staphylococcus epidermidis
5.1.3.14 drug development Staphylococcus aureus is a leading cause of hospital and community-acquired infections by Gram-positive bacteria and Staphylococcus epidermidis has emerged as the most common cause of biofilm infections on medical implant devices. Enzyme MnaA serves as a Staphylococcal antibiotic target with cognate inhibitors predicted to possess dual therapeutic benefit: as combination agents to restore beta-lactam efficacy against MRSA and MRSE and as non-bioactive prophylactic agents to prevent Staphylococcal biofilm formation Staphylococcus aureus

Cloned(Commentary)

EC Number Cloned (Comment) Organism
5.1.3.14 gene mnaA, genotyping and mutation identification Staphylococcus epidermidis
5.1.3.14 gene mnaA, genotyping and mutation identification Staphylococcus aureus

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
5.1.3.14 purified enzyme MnaA, hanging drop vapor diffusion method, mixing of 31 mg/ml protein solution with crystallization solution containing 0.1 M Tris-HCl, pH 8.0, 0.1 M Na2SO4, 52% PEG 400, 22°C, method optimization, X-ray diffraction structure determination and analysis at 1.9 A resolution, molecular replacement using structure PDB ID 1F6D as template Staphylococcus aureus

Protein Variants

EC Number Protein Variants Comment Organism
5.1.3.14 additional information gene mnaA, genotyping and mutation identification. Mapping of MnaA LOF mutations into the MnaA crystal structure revealing key residues for substrate binding site stability and charge. To determine whether L638R mnaA LOF mutants are not identified in MRSA COL due to a functional redundancy between Cap5P and MnaA, a cap5P deletion mutant is constructed and the L638R studies are repeated. Under these conditions, in addition to identifying the expected tarG L638R mutations as well as tarO and tarA LOF mutations, multiple (n = 11) independent resistor isolates obtained uniquely possess distinct mutations that map to mnaA and are predicted to inactivate gene function as well as directly confer L638R drug resistance based on the absence of additional non-synonymous mutations in their genome following WGS analysis. While MRSA COL DELTAcap5P exhibits no wall teichoic acid (WTA) depletion phenotype and remains resistant to beta-lactams, MRSA COL mnaA, DELTAcap5P double mutants are completely devoid of WTA and are also highly sensitive to beta-lactams. MRSA COL mnaA, cap5P double mutants and MRSE mnaA single mutants reveal morphological phenotypes consistent with WTA depletion, including increased cell size heterogeneity and septation defects. Complementing DELTAcap5P mnaASa P12L and DELTAcap5P mnaASa Y194* with either cap5P or mnaASa reintroduced on an inducible plasmid restores WTA polymer levels, resistance to each of the beta-lactams tested, and wild-type sensitivity to L638 Staphylococcus aureus
5.1.3.14 additional information gene mnaA, genotyping and mutation identification. MRSA COL mnaA, cap5P double mutants and MRSE mnaA single mutants reveal morphological phenotypes consistent with WTA depletion, including increased cell size heterogeneity and septation defects Staphylococcus epidermidis
5.1.3.14 additional information to determine whether L638R mnaA LOF mutants are not identified in MRSA COL due to a functional redundancy between Cap5P and MnaA, a cap5P deletion mutant is constructed and the L638R studies are repeated. Under these conditions, in addition to identifying the expected tarG L638R mutations as well as tarO and tarA LOF mutations, multiple (n = 11) independent resistor isolates obtained uniquely possess distinct mutations that map to mnaA and are predicted to inactivate gene function as well as directly confer L638R drug resistance based on the absence of additional non-synonymous mutations in their genome following WGS analysis. While MRSA COL DELTAcap5P exhibits no wall teichoic acid (WTA) depletion phenotype and remains resistant to beta-lactams, MRSA COL mnaA, DELTAcap5P double mutants are completely devoid of WTA and are also highly sensitive to beta-lactams. MRSA COL mnaA, cap5P double mutants and MRSE mnaA single mutants reveal morphological phenotypes consistent with WTA depletion, including increased cell size heterogeneity and septation defects Staphylococcus aureus
5.1.3.14 P12L site-diected mutagenesis Staphylococcus aureus
5.1.3.14 Y194X site-directed mutagenesis Staphylococcus aureus

Inhibitors

EC Number Inhibitors Comment Organism Structure
5.1.3.14 additional information WTA 2-epimerases are dual beta-lactam potentiation and antibiofilm drug targets; WTA 2-epimerases are dual beta-lactam potentiation and antibiofilm drug targets Staphylococcus aureus
5.1.3.14 additional information WTA 2-epimerases are dual beta-lactam potentiation and antibiofilm drug targets Staphylococcus epidermidis
5.1.3.14 tunicamycin the natural product antibiotic physically binds Cap5P and inhibits 2-epimerase activity, NMR study, reversible inhibition; the natural product antibiotic physically binds MnaA and inhibits 2-epimerase activity, NMR study, reversible inhibition Staphylococcus aureus
5.1.3.14 tunicamycin the natural product antibiotic physically binds MnaA and inhibits 2-epimerase activity, NMR study, reversible inhibition Staphylococcus epidermidis

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
5.1.3.14 cell wall
-
 Staphylococcus epidermidis 5618
-
5.1.3.14 cell wall
-
 Staphylococcus aureus 5618
-

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine Staphylococcus epidermidis
-
 UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine Staphylococcus aureus
-
 UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine Staphylococcus aureus COL
-
 UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine Staphylococcus epidermidis CLB26329
-
 UDP-N-acetyl-alpha-D-mannosamine
-
 r

Organism

EC Number Organism UniProt Comment Textmining
5.1.3.14 Staphylococcus aureus P95709 MRSA
-
5.1.3.14 Staphylococcus aureus Q9REV4 MRSA
-
5.1.3.14 Staphylococcus aureus COL P95709 MRSA
-
5.1.3.14 Staphylococcus aureus COL Q9REV4 MRSA
-
5.1.3.14 Staphylococcus epidermidis
-
 MRSE
-
5.1.3.14 Staphylococcus epidermidis CLB26329
-
 MRSE
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine
-
 Staphylococcus epidermidis UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine
-
 Staphylococcus aureus UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine interconversion Staphylococcus epidermidis UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine interconversion Staphylococcus aureus UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine
-
 Staphylococcus aureus COL UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine interconversion Staphylococcus aureus COL UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine
-
 Staphylococcus epidermidis CLB26329 UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-glucosamine interconversion Staphylococcus epidermidis CLB26329 UDP-N-acetyl-alpha-D-mannosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-mannosamine interconversion Staphylococcus epidermidis UDP-N-acetyl-alpha-D-glucosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-mannosamine interconversion Staphylococcus aureus UDP-N-acetyl-alpha-D-glucosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-mannosamine interconversion Staphylococcus aureus COL UDP-N-acetyl-alpha-D-glucosamine
-
 r
5.1.3.14 UDP-N-acetyl-alpha-D-mannosamine interconversion Staphylococcus epidermidis CLB26329 UDP-N-acetyl-alpha-D-glucosamine
-
 r

Subunits

EC Number Subunits Comment Organism
5.1.3.14 dimer
-
 Staphylococcus aureus

Synonyms

EC Number Synonyms Comment Organism
5.1.3.14 Cap5P
-
 Staphylococcus aureus
5.1.3.14 MnaA
-
 Staphylococcus epidermidis
5.1.3.14 MnaA
-
 Staphylococcus aureus
5.1.3.14 teichoic acid 2-epimerase
-
 Staphylococcus epidermidis
5.1.3.14 teichoic acid 2-epimerase
-
 Staphylococcus aureus
5.1.3.14 UDP-GlcNAc:UDP-ManNAc 2-epimerase
-
 Staphylococcus epidermidis
5.1.3.14 UDP-GlcNAc:UDP-ManNAc 2-epimerase
-
 Staphylococcus aureus
5.1.3.14 WTA 2-epimerase
-
 Staphylococcus epidermidis
5.1.3.14 WTA 2-epimerase
-
 Staphylococcus aureus

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
5.1.3.14 30
-
 assay at Staphylococcus epidermidis
5.1.3.14 30
-
 assay at Staphylococcus aureus

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
5.1.3.14 8
-
 assay at Staphylococcus epidermidis
5.1.3.14 8
-
 assay at Staphylococcus aureus

General Information

EC Number General Information Comment Organism
5.1.3.14 malfunction deletions of early wall teichoic acid (WTA) biosynthetic enzymes are nonlethal, but cause diverse attenuated virulence phenotypes, deletions of later steps in WTA biosynthesis are not generally tolerated and the enzymes are normally essential for growth, an essential gene paradox. The beta-lactam antibiotic imipenem exhibits restored bactericidal activity against mnaA mutants in vitro and concomitant efficacy against 2-epimerase defective strains in a mouse thigh model of MRSA infection. Complementing DELTAcap5P mnaASa P12L and DELTAcap5P mnaASa Y194* with either cap5P or mnaASa reintroduced on an inducible plasmid restores WTA polymer levels, resistance to each of the beta-lactams tested, and wild-type sensitivity to L638 Staphylococcus aureus
5.1.3.14 malfunction deletions of early wall teichoic acid (WTA) biosynthetic enzymes are nonlethal, but cause diverse attenuated virulence phenotypes, deletions of later steps in WTA biosynthesis are not generally tolerated and the enzymes are normally essential for growth, an essential gene paradox. The beta-lactam antibiotic imipenem exhibits restored bactericidal activity against mnaA mutants in vitro and concomitant efficacy against 2-epimerase defective strains in a mouse thigh model of MRSE infection Staphylococcus epidermidis
5.1.3.14 physiological function 2-epimerase MnaA interconverts UDP-GlcNAc and UDP-ManNAc to modulate substrate levels of TarO and TarA wall teichoic acid (WTA) biosynthesis enzymes. Besides MnaA, Staphylococcus aureus maintains a second 2-epimerase involved in serotype 5 capsular polysaccharide (CP5) synthesis, Cap5P. MnaA and Cap5P provide compensatory WTA functional roles in Staphylococcus aureus. MnaA and other enzymes of WTA biosynthesis are required for biofilm formation in MRSA. Overlapping functional activity of MnaA and Cap5P in Staphylococci Staphylococcus aureus
5.1.3.14 physiological function 2-epimerase MnaA interconverts UDP-GlcNAc and UDP-ManNAc to modulate substrate levels of TarO and TarA wall teichoic acid (WTA) biosynthesis enzymes. MnaA serves as the sole 2-epimerase required for WTA biosynthesis in Staphylococcus epidermidis. MnaA and other enzymes of WTA biosynthesis are required for biofilm formation in MRSE Staphylococcus epidermidis