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
Artikel, Zweitveröffentlichung, Verlagsversion
Kurzbeschreibung (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.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2022 |
| Autor(en): | Purder, Patrick L. ; Meyners, Christian ; Krysenko, Sergii ; Funk, Jonathan ; Wohlleben, Wolfgang ; Hausch, Felix |
| Art des Eintrags: | Zweitveröffentlichung |
| Titel: | Mechanism‐Based Design of the First GlnA4‐Specific Inhibitors |
| Sprache: | Englisch |
| Publikationsjahr: | 2022 |
| Ort: | Darmstadt |
| Publikationsdatum der Erstveröffentlichung: | 2022 |
| Verlag: | Wiley-VCH |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | ChemBioChem |
| Jahrgang/Volume einer Zeitschrift: | 23 |
| (Heft-)Nummer: | 19 |
| Kollation: | 8 Seiten |
| DOI: | 10.26083/tuprints-00022898 |
| URL / URN: | https://tuprints.ulb.tu-darmstadt.de/22898 |
| Zugehörige Links: | |
| Herkunft: | Zweitveröffentlichung DeepGreen |
| Kurzbeschreibung (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. |
| Freie Schlagworte: | amino acids, antibiotics, glutamine synthetase, sulfoximine, Streptomyces coelicolor |
| Status: | Verlagsversion |
| URN: | urn:nbn:de:tuda-tuprints-228984 |
| Sachgruppe der Dewey Dezimalklassifikatin (DDC): | 500 Naturwissenschaften und Mathematik > 540 Chemie 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie |
| Fachbereich(e)/-gebiet(e): | 07 Fachbereich Chemie 07 Fachbereich Chemie > Clemens-Schöpf-Institut > Fachgebiet Biochemie |
| Hinterlegungsdatum: | 23 Dez 2022 13:25 |
| Letzte Änderung: | 28 Dez 2022 07:18 |
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