A new pathway in central metabolism mediates nutrient control of development and antibiotic production by streptomyces

Li, C.; Urem, M.; Kotsogianni, A.I.; Lau, J.; Elsayed, S.S.M.A.; Martin, N.I; ... ; Wezel, G.P. van (2024)

Research paper

The amino sugar N-acetylglucosamine (GlcNAc) plays a central role in primary metabolism and is a key signaling molecule for the onset of morphological and chemical differentiation of Streptomyces. The global nutrient-sensory regulator DasR acts as the gatekeeper of development in streptomycetes, and its activity is modulated by aminosugar phosphates. Here, we report the discovery of a novel pathway in aminosugar metabolism that governs GlcNAc sensing. GlcNAc-6P is converted into a toxic metabolite via two new enzyme functions, namely dehydration of N-acetylglucosamine-6-phosphate by NagS to form 6P-Chromogen I, a reaction that has not yet been described in the textbooks, and its subsequent deacetylation by NagA producing a cytotoxic structural analogue of ribose. The latter reveals an unexpected promiscuous activity for GlcNAc-6P deacetylase NagA. The crystal structures of NagS apoenzyme and NagS in complex with its substrate GlcNAc-6P or its inhibitor 6-phosphogluconate were resolved at 2.3 Å, 2.6 Å, and 1.7 Å resolution, respectively. Detailed in vivo and in vitro studies resolved the key residues of the NagS catalytic site. Thus, we have uncovered a novel pathway in aminosugar metabolism that sheds new light on nutrient-mediated control of development and antibiotic production in Streptomyces.

• All authors: Li, C.; Urem, M.; Kotsogianni, A.I.; Lau, J.; Elsayed, S.S.M.A.; Martin, N.I; McNae, I.W.; Voskamp, P.; Mayer, C.; Rigali, S.; Pannu, N.; Abrahams, J.P.; Schada von Borzyskowski, L.; Wezel, G.P. van
• Date: 2024-07-14
• Title of host publication: bioRxiv
• DOI: doi:10.1101/2024.07.14.603434