The novel GlcNAc 6-phosphate dehydratase NagS governs a metabolic checkpoint that controls nutrient signaling in Streptomyces

TY - JOUR

T1 - The novel GlcNAc 6-phosphate dehydratase NagS governs a metabolic checkpoint that controls nutrient signaling in Streptomyces

AU - Li, Chao

AU - Urem, Mia

AU - Kotsogianni, Ioli

AU - Lau, Josephine

AU - Du, Chao

AU - Elsayed, Somayah S.

AU - Martin, Nathaniel I.

AU - McNae, Iain W.

AU - Voskamp, Patrick

AU - Mayer, Christoph

AU - Rigali, Sébastien

AU - Pannu, Navraj

AU - Abrahams, Jan Pieter

AU - Schada von Borzyskowski, Lennart

AU - van Wezel, Gilles P.

N1 - Publisher Copyright: Copyright: © 2025 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2025/11/1

Y1 - 2025/11/1

N2 - Streptomyces bacteria are renowned for their multicellular lifestyle and as Nature's medicine makers, producing the majority of the clinical antibiotics. A landmark event during early development is the lytic dismantling of the substrate mycelium. Degradation of the hyphal cell-wall leads to the accumulation of N-acetylglucosamine (GlcNAc) in the colonies, which is a metabolic checkpoint during the onset of development and antibiotic production. Here, we show that GlcNAc sensing requires a toxicity pathway dependent on the enzyme GlcNAc-6P dehydratase (NagS). Dehydration of GlcNAc-6P by NagS to 6P-chromogen I is an unprecedented reaction in central metabolism that is highly conserved in - and limited to - the Streptomycetaceae. 6P-chromogen I is metabolized into a structural analogue of ribose by a promiscuous activity of GlcNAc-6P deacetylase NagA. Toxicity is relieved by supplementing the growth media with ribose. Structure-function analysis of NagS not only highlighted key residues in the active site of the enzyme in interaction with its substrate GlcNAc-6P, but also revealed 6-phosphogluconate as its catalytic inhibitor. Our work uncovers a conserved metabolic toxicity pathway in Streptomyces that revolves around a novel enzyme that plays a key role in nutrient signaling.

AB - Streptomyces bacteria are renowned for their multicellular lifestyle and as Nature's medicine makers, producing the majority of the clinical antibiotics. A landmark event during early development is the lytic dismantling of the substrate mycelium. Degradation of the hyphal cell-wall leads to the accumulation of N-acetylglucosamine (GlcNAc) in the colonies, which is a metabolic checkpoint during the onset of development and antibiotic production. Here, we show that GlcNAc sensing requires a toxicity pathway dependent on the enzyme GlcNAc-6P dehydratase (NagS). Dehydration of GlcNAc-6P by NagS to 6P-chromogen I is an unprecedented reaction in central metabolism that is highly conserved in - and limited to - the Streptomycetaceae. 6P-chromogen I is metabolized into a structural analogue of ribose by a promiscuous activity of GlcNAc-6P deacetylase NagA. Toxicity is relieved by supplementing the growth media with ribose. Structure-function analysis of NagS not only highlighted key residues in the active site of the enzyme in interaction with its substrate GlcNAc-6P, but also revealed 6-phosphogluconate as its catalytic inhibitor. Our work uncovers a conserved metabolic toxicity pathway in Streptomyces that revolves around a novel enzyme that plays a key role in nutrient signaling.

U2 - 10.1371/journal.pbio.3003514

DO - 10.1371/journal.pbio.3003514

M3 - Article

C2 - 41289323

AN - SCOPUS:105024127068

SN - 1544-9173

VL - 23

SP - e3003514

JO - PLoS Biology

JF - PLoS Biology

IS - 11

ER -