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Mechanism‐Based Design of the First GlnA4‐Specific Inhibitors

Purder, Patrick L. ; Meyners, Christian ; Krysenko, Sergii ; Funk, Jonathan ; Wohlleben, Wolfgang ; Hausch, Felix (2022)
Mechanism‐Based Design of the First GlnA4‐Specific Inhibitors.
In: ChemBioChem, 2022, 23 (19)
doi: 10.26083/tuprints-00022898
Article, Secondary publication, Publisher's Version

Abstract

γ‐Glutamylamine synthetases are an important class of enzymes that play a key role in glutamate‐based metabolism. Methionine sulfoximine (MSO) is a well‐established inhibitor for the archetypal glutamine synthetase (GS) but inhibitors for most GS‐like enzymes are unknown. Assuming a conserved catalytic mechanism for GS and GS‐like enzymes, we explored if subtype‐selective inhibitors can be obtained by merging MSO with the cognate substrates of the respective GS‐like enzymes. Using GlnA4Sc from Streptomyces coelicolor, an enzyme recently shown to produce γ‐glutamylethanolamine, we demonstrate that MSO can be reengineered in a straightforward fashion into potent and selective GlnA4Sc inhibitors. Linkage chemistry as well as linker length between the MSO moiety and the terminal hydroxyl group derived from ethanolamine were in agreement with the postulated phosphorylated catalytic intermediate. The best GlnA4 inhibitor 7 b potently blocked S. coelicolor growth in the presence of ethanolamine as the sole nitrogen source. Our results provide the first GlnA4Sc‐specific inhibitors and suggest a general strategy to develop mechanism‐based inhibitors for GS‐like enzymes.

Item Type: Article
Erschienen: 2022
Creators: Purder, Patrick L. ; Meyners, Christian ; Krysenko, Sergii ; Funk, Jonathan ; Wohlleben, Wolfgang ; Hausch, Felix
Type of entry: Secondary publication
Title: Mechanism‐Based Design of the First GlnA4‐Specific Inhibitors
Language: English
Date: 2022
Place of Publication: Darmstadt
Year of primary publication: 2022
Publisher: Wiley-VCH
Journal or Publication Title: ChemBioChem
Volume of the journal: 23
Issue Number: 19
Collation: 8 Seiten
DOI: 10.26083/tuprints-00022898
URL / URN: https://tuprints.ulb.tu-darmstadt.de/22898
Corresponding Links:
Origin: Secondary publication DeepGreen
Abstract:

γ‐Glutamylamine synthetases are an important class of enzymes that play a key role in glutamate‐based metabolism. Methionine sulfoximine (MSO) is a well‐established inhibitor for the archetypal glutamine synthetase (GS) but inhibitors for most GS‐like enzymes are unknown. Assuming a conserved catalytic mechanism for GS and GS‐like enzymes, we explored if subtype‐selective inhibitors can be obtained by merging MSO with the cognate substrates of the respective GS‐like enzymes. Using GlnA4Sc from Streptomyces coelicolor, an enzyme recently shown to produce γ‐glutamylethanolamine, we demonstrate that MSO can be reengineered in a straightforward fashion into potent and selective GlnA4Sc inhibitors. Linkage chemistry as well as linker length between the MSO moiety and the terminal hydroxyl group derived from ethanolamine were in agreement with the postulated phosphorylated catalytic intermediate. The best GlnA4 inhibitor 7 b potently blocked S. coelicolor growth in the presence of ethanolamine as the sole nitrogen source. Our results provide the first GlnA4Sc‐specific inhibitors and suggest a general strategy to develop mechanism‐based inhibitors for GS‐like enzymes.

Uncontrolled Keywords: amino acids, antibiotics, glutamine synthetase, sulfoximine, Streptomyces coelicolor
Status: Publisher's Version
URN: urn:nbn:de:tuda-tuprints-228984
Classification DDC: 500 Science and mathematics > 540 Chemistry
500 Science and mathematics > 570 Life sciences, biology
Divisions: 07 Department of Chemistry
07 Department of Chemistry > Clemens-Schöpf-Institut > Fachgebiet Biochemie
Date Deposited: 23 Dec 2022 13:25
Last Modified: 28 Dec 2022 07:18
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