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

Li, C.; Urem, M.; Kotsogianni, I.; Lau, j.; Elsayed, S. S.; Martin, N. I.; McNae, I.; Voskamp, P.; Mayer, C.; Rigali, S.; Pannu, N.; Abrahams, J.-P.; Schada von Borzyskowski, L.; van Wezel, G. P.

doi:10.1101/2024.07.14.603434

bioRxiv · 10.1101/2024.07.14.603434

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

Li, C.·Urem, M.·Kotsogianni, I.·Lau, j.·Elsayed, S. S.·Martin, N. I.·McNae, I.·Voskamp, P.·Mayer, C.·Rigali, S.·Pannu, N.·Abrahams, J.-P.·Schada von Borzyskowski, L.·van Wezel, G. P.

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Abstract

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 [A], 2.6 [A], and 1.7 [A] 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.

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Li, C., Urem, M., Kotsogianni, I., Lau, j., Elsayed, S. S., Martin, N. I., McNae, I., Voskamp, P., Mayer, C., Rigali, S., Pannu, N., Abrahams, J.-P., Schada von Borzyskowski, L., van Wezel, G. P.. 2024-07-14. A new pathway in central metabolism mediates nutrient control of development and antibiotic production by Streptomyces. https://doi.org/10.1101/2024.07.14.603434

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