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

DOI: 10.1371/journal.pbio.3003514

Authors: Chao Li (Leiden University) , Mia Urem (Leiden University) , Ioli Kotsogianni (Leiden University) , Josephine Lau (University of Edinburgh) , Chao Du (Leiden University) , Somayah S. Elsayed (Leiden University) , Nathaniel I. Martin (Leiden University) , Iain W. Mcnae (University of Edinburgh) , Patrick Voskamp (Leiden Institute of Chemistry) , Christoph Mayer (University of Tübingen) , Sébastien Rigali (University of Liège) , Navraj Pannu (Leiden Institute of Chemistry) , Jan P. Abrahams (Basel University) , Lennart Schada Von Borzyskowski (Leiden University) , Gilles P. Van Wezel (Leiden University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Biology , VOL 23

State: Published (Approved)
Published: November 2025
Diamond Proposal Number(s): 18515

Abstract: 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.

Journal Keywords: Toxicity; Antibiotics; Streptomyces; Dehydration (medicine); Enzyme metabolism; Enzymes; Monomers; Phylogenetic analysis

Diamond Keywords: Bacteria; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I04-Macromolecular Crystallography

Added On: 30/11/2025 09:08

Documents:
journal.pbio.3003514.pdf

Discipline Tags:

Antibiotic Resistance Health & Wellbeing Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)