Exploring the metabolism and toxicity of amino sugars and 2-deoxyglucose in Streptomyces

Li, C. (2024)

Doctoral Thesis

Streptomyces are prolific producers of enzymes and secondary metabolites, including more than 50% of all clinical antibiotics. This makes them highly attractive for medical, biotechnological, and industrial purposes. Amino sugars, such as GlcN and GlcNAc, are vital for streptomycetes, as they are important carbon and nitrogen sources, and GlcNAc is involved in nutrient-mediated signalling that controls Streptomyces development and antibiotic production. In my thesis, the metabolism and toxicity of three glucose analogues, including GlcN, GlcNAc, and 2-deoxyglucose, are studied in Streptomyces coelicolor. We investigated the functions of two newly conserved proteins (RokL6 and NagS), aiming to work out their roles in GlcN(Ac) toxicity. We identified a transporter protein SCO1448, which is proposed to exports the toxic intermediates produced by GlcN and 2-deoxyglucose. Besides, we determined that NagS acts as a phosphosugar dehydratase, an activity has never been reported in any organism. With this, we propose a new model that explains the role of GlcNAc in streptomycetes morphological and chemical differentiation. We also found that pentose phosphate pathway is the key reaction for 2-deoxyglucose toxicity in S. coelicolor, shedding new lights on the mode of action of 2-deoxyglucose in bacteria.

• Streptomyces biology
• Antibiotic production
• Central metabolism
• Amino sugar sensitivity
• ROK-family transcriptional regulator
• Sugar dehydratase
• 2-deoxyglucose toxicity

• All authors: Li, C.
• Supervisor: Wezel, G.P. van: Claessen, D.
• Co-supervisor: Schade von Borzyskowski, L.
• Committee: Meijer, A.H.; Spaink, H.P.; Winde, J.H. de; Rigali, S.; Titgemeyer, F.
• Qualification: Doctor (dr.)
• Awarding Institution: Institute of Biology Leiden (IBL), Faculty of Science, Leiden University
• Date: 2024-10-30