PhD aminosugar metabolism

The Faculty of Science / the Institute for Biology is looking for a :

PhD Candidate , Aminosugar metabolism and control of growth and development in bacteria
Vacancy number: 15487

PhD project description
Sugars, such as glucose, are commonly assimilated by microorganisms as preferred sources of carbon and energy. The same is true for amino sugars, such as glucosamine (GlcN) and N-acetylglucosamine (GlcNAc). While the general biochemical characterization of (amino) sugar assimilation pathways is well established, there are still important knowledge gaps. Notably, the toxic effects exerted by (amino) sugars have been reported in many organisms, but are poorly understood. The glucose derivative 2-deoxyglucose (2-DOG) is investigated as anticancer compound due to its cytotoxicity, but despite extensive studies, its mode of action is still unclear. At the same time, it has been known for decades that the accumulation of amino sugars is lethal in bacterial cells, again without a clear rationale.

We recently obtained important new insights into the toxicity mechanism of GlcNAc in the bacterial model organism Streptomyces coelicolor. GlcNAc is converted into a toxic ribose analog via the newly discovered enzyme NagS (GlcNAc 6-phosphate dehydratase) [https://doi.org/10.1101/2024.07.14.603434]. GlcN toxicity was relieved by expression of the exporter SCO1448 [https://doi.org/10.1128/aem.01674-23]. Intriguingly, transporter SCO1448 not only relieves toxicity of GlcN but also of 2-DOG (but not of GlcNAc). This linkage between two toxicity pathways requires further investigation.

The general aim of this project is to fully elucidate the toxicity mechanisms for the three toxicity pathways related to 2-DOG, GlcN and GlcNAc in microorganisms. Specific aims are:

• to gain mechanistic understanding of the impact of GlcNAc conversion products on ribose metabolism, using S. coelicolor as the model organism;
• to understand the linkage between the pathways related to GlcN and 2-DOG;
• to biochemically characterize the transporter protein SCO1448 in S. coelicolor, and to elucidate its dual role in relieving toxicity to both 2-DOG-6P and GlcN-6P;
• to investigate (amino) sugar toxicity in other model bacteria (E. coli, B. subtilis, P. denitrificans), allowing a comparison of toxicity pathways in diverse single-celled bacteria and the multicellular streptomycetes.

Methods
This project will involve diverse experiments in microbial genetics and protein biochemistry. Furthermore, the fate of (amino) sugars and their breakdown products in central carbon metabolism shall be traced via 13C-based metabolomics. RNA sequencing and phylogenomics will be applied to analyze co-expression or co-occurrence, respectively, of the relevant genes, to establish direct correlations between them.

Impact
This project will generate new fundamental knowledge on the diversity of bacterial metabolism. Additionally, a better understanding of amino sugar metabolism in the prolific antibiotics producer S. coelicolor and the mode of action of the anticancer compound 2-DOG will contribute to advancing translational research.

Selection Criteria

• MSc degree in biochemistry, molecular biology or related field
• Strong background in genetics and protein chemistry
• Preferably a background in the field of microbiology
• A strong interest in biochemical pathways and primary metabolism
• Proficiency in spoken and written English.
• Desire to work in a multinational/multicultural environment.
• Excellent communication skills and a collaborative attitude.

Research at our faculty
The Faculty of Science is a world-class faculty where staff and students work together in a dynamic international environment. It is a faculty where personal and academic development are top priorities. Our people are committed to expand fundamental knowledge by curiosity and to look beyond the borders of their own discipline; their aim is to benefit science, and to make a contribution to addressing the major societal challenges of the future.

The research carried out at the Faculty of Science is very diverse, ranging from mathematics, information science, astronomy, physics, chemistry and bio-pharmaceutical sciences to biology and environmental sciences. The research activities are organised in eight institutes. These institutes offer eight bachelor’s and twelve master’s programmes. The faculty has grown strongly in recent years and now has more than 2300 {see https://www.universiteitleiden.nl/wiskunde-en-natuurwetenschappen} staff and almost 5000 {see https://www.universiteitleiden.nl/wiskunde-en-natuurwetenschappen} students. We are located at the heart of Leiden’s Bio Science Park, one of Europe’s biggest science parks, where university and business life come together.

For more information, see www.universiteitleiden.nl/en/science and https://workingat.leiden.edu/

The Institute for Biology
The research within the Institute of Biology Leiden (IBL) aims to work on the science base of biodiversity and health, which is reflected in our leading principle Harnessing Biodiversity for Health. We perform innovative curiosity-driven research to answer fundamental questions, and solutions-driven research to help solving major societal challenges. The latter include protecting nature’s biodiversity, creating sustainable biotechnology and agriculture and increasing good health. Our research focuses on four Research Themes: Bioactive Molecules, Host-Microbe Interactions, Development & Disease and Evolution & Biodiversity. Located in a thriving scientific environment with our Faculty of Sciences, Naturalis Biodiversity Centre, the Leiden University Medical Centre and the Leiden Bioscience Park, IBL offers an exciting, internationally oriented and inclusive place to work and study.

Terms and conditions
We offer a full-time 1 year term position for initially one year. After a positive evaluation of the progress of the thesis, personal capabilities and compatibility the appointment will be extended by a further three years. Salary range from €2.901,- to € 3.707,-gross per month (pay scale P in accordance with the Collective Labour Agreement for Dutch Universities).

Leiden University offers an attractive benefits package with additional holiday (8%) and end-of-year bonuses (8.3 %), training and career development and sabbatical leave. Our individual choices model gives you some freedom to assemble your own set of terms and conditions. Candidates from outside the Netherlands may be eligible for a substantial tax break.

All our PhD students are embedded in the Leiden University Graduate School of Science www.graduateschools.leidenuniv.nl. Our graduate school offers several PhD training courses at three levels: professional courses, skills training and personal effectiveness. In addition, advanced courses to deepen scientific knowledge are offered by the research school.

Leiden University is strongly committed to diversity within its community and especially welcomes applications from members of underrepresented groups.

Information
Enquiries can be made to Dr. Lennart Schada von Borzyskowski, l.schada.von.borzyskowski@biology.leidenuniv.nl or Prof. dr. Gilles P van Wezel, g.wezel@biology.leidenuniv.nl. If you have any questions about the procedure, please contact Christina Kamerman (HR@biology.leidenuniv.nl).

Applications
Applications for this vacancy can be submitted via the blue button of our online system. Please ensure that you upload the following additional documents quoting the vacancy number:

• A letter of motivation including research interests and highlighting fit for the position (max. 2 pages)
• Curriculum vitae
• Relevant certificates (e.g. degree certificate)
• Contact details of two references

Only applications received before 14 March 2025 can be considered.

38 hours per week

Rapenburg 70