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Literature summary extracted from

  • Hughes, S.J.; Barnard, L.; Mottaghi, K.; Tempel, W.; Antoshchenko, T.; Hong, B.S.; Allali-Hassani, A.; Smil, D.; Vedadi, M.; Strauss, E.; Park, H.W.
    Discovery of potent pantothenamide inhibitors of Staphylococcus aureus pantothenate kinase through a minimal SAR study inhibition is due to trapping of the product (2016), ACS Infect. Dis., 2, 627-641 .
    View publication on PubMed

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.7.1.33 gene coaW, recombinant expression of C-terminally His6-tagged enzyme in Escherichia coli strain BL21(DE3) Staphylococcus aureus

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
2.7.1.33 purified recombinant enzyme SaPanKII in complex with inhibitors N-pentylpantothenamide, N-heptylpantothenamide, N-(5-methoxypentyl)pantothenamide, and N-(benzo[d][1,3]dioxol-5-ylmethyl)pantothenamide, sitting drop vapor diffusion method, 500 nl of 20-30 mg/ml protein in 20 mM Tris-HCl, pH 8.0, 200 mM NaCl, and 10 mM dithiothreitol, and addition of 1.1% w/v cyclohexylethanoyl-N-hydroxyethylglucamide, ligand, and ATP, is mixed with 500 nl of well solution containing 25-35% PEG 4000, 0.2 M MgCl2, and 0.1 M Tris, pH 8.5, X-ray diffraction structure determination and analysis at 1.40-1.80 A resolution Staphylococcus aureus

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.7.1.33 additional information the potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) exhibit inhibition of Staphylococcus aureus atypical type II pantothenate kinase (SaPanKII). The PanAms are phosphorylated by SaPanKII but remain bound at the active site. This occurs primarily through interactions with Tyr240' and Thr172'. Kinetic analysis shows a strong correlation between kcat (slow PanAm turnover) and IC50 (inhibition of pantothenate phosphorylation) values, suggesting that SaPanKII inhibition occurs via a delay in product release. The two PanAms, N-(benzo[d][1,3]dioxol-5-ylmethyl)pantothenamide and N-(5-methoxypentyl)pantothenamide, effectively combine both hydrogen bonding and hydrophobic interactions, resulting in the most potent SaPanKII inhibition described to date. Design and synthesis of a series of N-substituted pantothenamides, analysis of the PanAm binding mode and interaction with the N-substituent binding site, structure-activity realtionships, MIC values, overview Staphylococcus aureus
2.7.1.33 N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)pantothenamide
-
 Staphylococcus aureus
2.7.1.33 N-(3-methoxyphenethyl)pantothenamide
-
 Staphylococcus aureus
2.7.1.33 N-(5-methoxypentyl)pantothenamide
-
 Staphylococcus aureus
2.7.1.33 N-(benzo[d][1,3]dioxol-5-ylmethyl)pantothenamide
-
 Staphylococcus aureus
2.7.1.33 N-heptylpantothenamide
-
 Staphylococcus aureus
2.7.1.33 N-pentylpantothenamide
-
 Staphylococcus aureus
2.7.1.33 N-phenethylpantothenamide
-
 Staphylococcus aureus
2.7.1.33 pantothenamide
-
 Staphylococcus aureus

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.7.1.33 Mg2+ required Staphylococcus aureus

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.7.1.33 ATP + (R)-pantothenate Staphylococcus aureus
-
 ADP + (R)-4'-phosphopantothenate
-
 ?
2.7.1.33 ATP + (R)-pantothenate Staphylococcus aureus RN4220
-
 ADP + (R)-4'-phosphopantothenate
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.7.1.33 Staphylococcus aureus A0A167Z3Z6
-
-
2.7.1.33 Staphylococcus aureus RN4220 A0A167Z3Z6
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
2.7.1.33 recombinant C-terminally His6-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography, desalting gel filtration, anion exchange chromatography, gel filtration, and ultrafiltration Staphylococcus aureus

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.7.1.33 ATP + (R)-pantothenate
-
 Staphylococcus aureus ADP + (R)-4'-phosphopantothenate
-
 ?
2.7.1.33 ATP + (R)-pantothenate
-
 Staphylococcus aureus RN4220 ADP + (R)-4'-phosphopantothenate
-
 ?

Subunits

EC Number Subunits Comment Organism
2.7.1.33 homodimer the subunit of the homodimers is composed of two domains (domains I and II) and the binding cap (residues 153-173), with a dimerization interface along helix alpha6 Staphylococcus aureus

Synonyms

EC Number Synonyms Comment Organism
2.7.1.33 coaW
-
 Staphylococcus aureus
2.7.1.33 PanK
-
 Staphylococcus aureus
2.7.1.33 type III pantothenate kinase
-
 Staphylococcus aureus

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
2.7.1.33 25
-
 assay at Staphylococcus aureus

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
2.7.1.33 7.6
-
 assay at Staphylococcus aureus

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
2.7.1.33 0.00013
-
 pH 7.6, 25°C Staphylococcus aureus N-(5-methoxypentyl)pantothenamide
2.7.1.33 0.00046
-
 pH 7.6, 25°C Staphylococcus aureus N-(benzo[d][1,3]dioxol-5-ylmethyl)pantothenamide
2.7.1.33 0.006
-
 pH 7.6, 25°C Staphylococcus aureus N-pentylpantothenamide
2.7.1.33 0.01
-
 pH 7.6, 25°C Staphylococcus aureus N-(3-methoxyphenethyl)pantothenamide
2.7.1.33 0.018
-
 pH 7.6, 25°C Staphylococcus aureus N-heptylpantothenamide
2.7.1.33 0.02
-
 pH 7.6, 25°C Staphylococcus aureus N-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)pantothenamide
2.7.1.33 0.036
-
 pH 7.6, 25°C Staphylococcus aureus N-phenethylpantothenamide

General Information

EC Number General Information Comment Organism
2.7.1.33 malfunction the potent antistaphylococcal activity of N-substituted pantothenamides (PanAms) exhibit inhibition of Staphylococcus aureus's atypical type II pantothenate kinase (SaPanKII), the first enzyme of coenzyme A biosynthesis. The mechanism of action follows from SaPanKII having a binding mode for PanAms that is distinct from those of other PanKs. Molecular interactions responsible for PanAm inhibitory activity, overview. The PanAms are phosphorylated by SaPanKII but remain bound at the active site, SaPanKII inhibition occurs via a delay in product release Staphylococcus aureus
2.7.1.33 metabolism CoA biosynthesis and salvage pathways, overview. The Staphylococcus aureus atypical type II pantothenate kinase (SaPanKII) is active in bothe pathways Staphylococcus aureus