The Relationship between Substrate Structure and Selectivity of Ketoreduction in Multimodular Polyketide Synthases: A Comparative Study of A-Type Ketoreductases from Late Modules Using Complex Precursor Analogues DOI
Lan-Anh Thi Nguyen,

Sebastian Derra,

Frank Hahn

et al.

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Ketoreductases (KRs) are domains in the reductive loops of type I polyketide synthases (PKSs) and responsible for majority stereocenters reduced polyketides. Although highly stereoselective reduction ACP-bound β-ketothioester intermediates by KRs is crucial overall functioning PKSs, substrate-dependent stereoselectivity a factor that not yet fully understood, especially KR late PKS modules act on biosynthetic precursors with complex polyketidic moieties. We present studies three FosKR7, PlmKR6, EryKR6 from pathways fostriecin, phoslactomycin, erythromycin vitro assays using close surrogates octaketidic FosKR7 precursor, derivatives diketide form their biomimetic N-acetylcysteamine thioesters. Supported molecular modeling, specific interactions studied extended moieties natural were identified correlated to differences observed assays. These results reinforce importance PKSs suggest more detailed experimental structural isolated full could ultimately lead improved engineering.

Language: Английский

The Relationship between Substrate Structure and Selectivity of Ketoreduction in Multimodular Polyketide Synthases: A Comparative Study of A-Type Ketoreductases from Late Modules Using Complex Precursor Analogues DOI
Lan-Anh Thi Nguyen,

Sebastian Derra,

Frank Hahn

et al.

ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Ketoreductases (KRs) are domains in the reductive loops of type I polyketide synthases (PKSs) and responsible for majority stereocenters reduced polyketides. Although highly stereoselective reduction ACP-bound β-ketothioester intermediates by KRs is crucial overall functioning PKSs, substrate-dependent stereoselectivity a factor that not yet fully understood, especially KR late PKS modules act on biosynthetic precursors with complex polyketidic moieties. We present studies three FosKR7, PlmKR6, EryKR6 from pathways fostriecin, phoslactomycin, erythromycin vitro assays using close surrogates octaketidic FosKR7 precursor, derivatives diketide form their biomimetic N-acetylcysteamine thioesters. Supported molecular modeling, specific interactions studied extended moieties natural were identified correlated to differences observed assays. These results reinforce importance PKSs suggest more detailed experimental structural isolated full could ultimately lead improved engineering.

Language: Английский

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