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Dr. Ulla Gerling-Driessen

Phd students:

M. Sc. Simon Walber

M. Sc. Georgia Partalidou

M.Sc. Frauke Stoelting

Master students: 

B. Sc. Marc Pallaske

B. Sc. Sören Nagel

Bachelor student:

Marc Tackmann


M. Sc.  Hauke Junghans

M. Sc. Dominik Mierswa

M. Sc. Thorben Köhler

B. Sc. Lukas Zeipelt

B. Sc. Marie Dulder

B. Sc. Julian Peters

B. Sc. Dilan Yildirim


Understanding the pathology of aberrant protein glycosylation

Our research occurs at the interface of chemistry and biology with a special focus on solving disease-related questions in the field of glycobiology. In particular, we aim at elucidating the role that abnormal protein glycosylation plays in the pathology and progression of certain human diseases.

Glycans are key players in many cellular processes. As abundant components on the cell surface, glycans are exposed to the environment, act as mediators of intercellular interactions and participate in the pathogen recognition by components of the immune system. Due to their crucial role in many important processes, abnormal glycosylation has been linked to the pathology of many diseases, such as the malignant transformation of cancer cells, certain neurodegenerative diseases, inflammation or autoimmune diseases. The biological role of altered protein glycosylation in these human diseases is still not well understood. However, basis for the development of suitable therapeutic strategies is a better understanding of how abnormal glycosylation affect the structure and function of glycoproteins and influences their network of interaction partners in biological pathways.  These systematic studies require excellent model systems and the development of new strategies and analytical tools that enable a better investigation of this class of biomolecules.


Chemical tools for improved glycoanalysis

Given that the characterization of glycans and glycoproteins is still very challenging, there is a huge need for molecular tools that allow a better analysis of these molecules. As a non-templated, posttranslational modification, glycans are not amenable to investigations by traditional genetic techniques. Metabolic oligosaccharide engineering and bioorthogonal chemistry alleviate some of these problems by incorporating chemical handles into glycoproteins and utilizing them to attach probes in a way that does not exhibit cross reactivity with the natural environment.

To better analyze glycans and glycoproteins in our research, we develop new bioorthogonal probes with a broad application spectrum. By using the principle of solid phase peptide synthesis, we combine different bioorthogonal handles with multiple analytical tools (i.e., fluorophores, isotopic labels, cleavable linkers and affinity tags) in a building block fashion. This fast and easy synthesis strategy offers a free choice of combining a huge variety of analytical labels with every available bioorthogonal attachment chemistry. Our probes can be used for qualitative and quantitative analysis of glycoproteins and other biomolecules in multiple applications such as imaging, mass spectrometry, isolation and purification. We will use these probes to analyze glycans and glycoproteins in diverse disease backgrounds, such as genetic glycosylation defects (CDGs) and the infection processes of certain pathogens as part of the research consortium GlycoPathogens. Universität Düsseldorf: GlycoPathogens (hhu.de)

Congenital Disorders of Glycosylation (CDG)

Congenital disorders of glycosylation (CDGs), are rare genetic diseases affecting enzymes involved in the assembly and processing of glycans. The clinical spectrum is broad, ranging from severe multisystemic phenotypes to symptoms restricted to specific organs. Today more than 100 district CDGs have been identified in humans, most of which affect the N-glycan biosynthesis, an essential process for the survival of all eukaryotes. However, little is known about the glycobiology underlying the pathology of CDGs, such as proteins and pathways that are impaired due to altered or truncated glycosylation. We aim to understand cause and consequences of altered protein glycosylation on a molecular level. Therefore, we are investigating selected CDGs as model systems to understand the consequences of a disrupted N-Glycan biosynthesis at different stages (early vs. late stage; glycan assembly vs. glycan transfer). We are elucidating crucial functions of glycoproteins and unravel their role in essential biological pathways. Our goal is to understand the diverse clinical phenotypes in CDGs by linking aberrantly glycosylated proteins to impaired biological functions and pathways.

Schematic representation of genes encoding enzymes involved in particular steps of the N-glycan biosynthesis (yellow) and CDGs identified in humans affecting these genes (red x).

Investigating the NGLY1/NRF1 axis

N-Glycanase 1 (NGLY1) is an enzyme that removes glycans from glycoproteins that are targeted to ER-associated degradation (ERAD). The heterozygous inactivating mutations in the ngly1 gene causes a rare genetic disease, called NGLY1 deficiency, which represents a special type of a CDG as in this case a de-glycosylating enzyme is affected by the genetic mutation. Patients exhibit a spectrum of severe symptoms, such as developmental delay, hypotonia, seizures, and peripheral neuropathy. Recently, we were able to show that NGLY1 is essential for activating an important transcription factor Nuclear Factor, Erythroid 2 Like 1 (NFE2L1, also called Nrf1), which responds to proteasome insufficiency or pharmacological inhibition by upregulating proteasome subunit gene expression. Chemical or genetic disruption of NGLY1 activity results in the accumulation of misprocessed Nrf1 that shows no activation of target genes upon proteasome inhibition. Nrf1 is also an attractive but inaccessible target for the therapy of multiple myeloma (MM) that shows a high tendency for resistance mechanisms, involving this transcription factor. Through a small molecule screen, we identified a cell-active NGLY1 inhibitor (WRR139) that disrupts the processing and function of Nrf1. The compound potentiates the cytotoxicity of carfilzomib, a clinically used proteasome inhibitor, against MM and T cell-derived acute lymphoblastic leukemia (T-ALL) cell lines. NGLY1 inhibition prevents Nrf1 activation and represents a new therapeutic approach for cancers that depend on proteasome homeostasis.

 Activation of Nrf1 via the ERAD pathway involves de-N-glycosylation by NGLY1.


23. U. I. M. Gerling-Driessen, M. Hoffmann, S.  Schmidt, N. L. Snyder, L. Hartmann  "Glycopolymers against pathogen infection"Chem. Soc. Rev., 2023, 52, 2617-2642, Journal Cover


22. M. D. Driessen§, H. L. Junghans§, L. Hartmann, U. I. M. Gerling-Driessen* "Multi-Tag: A modular platform of bioorthogonal probes for multi-modal (glyco)protein analysis" bioRxiv, 2022§ Contributed equally


21. S. Walber, G. Partalidou, U. I. M. Gerling-Driessen*  "NGLY1 Deficiency: A Rare Genetic Disorder Unlocks Therapeutic Potential for Common Diseases" Isr. J. Chem., 2022


20. P. B. Konietzny, H. Peters, M. L. Hofer, U. I. M. Gerling-Driessen, R. P. de Vries, T. Peters, L. Hartmann, "Enzymatic Sialylation of Synthetic Multivalent Scaffolds: From 3′-Sialyllactose Glycomacromolecules to Novel Neoglycosides" Macromol. Biosci., 2022


19. M. Santos de Freitasa, R. Rezaei Araghi, E. Brandenburg, J. Leitererd, F. Emmerling, K. Folmert, U. I. M. Gerling-Driessen, B. Bardiaux, C. Böttcher, K. Pagel, A. Diehl, H. v. Berlepsch, H. Oschkinat, B. Koksch, “The protofilament architecture of a de novo designed coiled coil-based amyloidogenic peptideJ. Struct. Biol., 2018, 203, 263–272.


18. F. M. Tomlin§, U. I. M. Gerling-Driessen§, Y-C. Liu, R. A. Flynn, J. R. Vangala, C. S. Lentz, S Clauder-Muenster, P. Jakob, W. F. Mueller, D. Ordonez, M. Paulsen, N. Matsui, D. Foley, A. Rafalko, T. Suzuki, M. Bogyo, L. M. Steinmetz, S. K. Radhakrishnan, C. R. Bertozzi; “Inhibition of NGLY1 inactivates the transcription factor Nrf1 and potentiates proteasome inhibitor cytotoxicity ACS Cent. Sci. 2017, 3, 1143-1155. § Contributed equally


17. J. D. Castillo Gomez, A. Hagenbach, U. I. M. Gerling-Driessen, B. Koksch, N. Beindorff, W. Brenner, U. Abram; “Thiourea derivatives as chelating agents for bioconjugation of rhenium and technetiumDalton Trans. 2017, 46, 14602-14611.


16. J-S. Völler, M. Dulic, U. I. M. Gerling-Driessen, H. Biava, T. Baumann, N. Budisa, I. Gruic-Sovulj, B. Koksch; “Discovery and Investigation of Natural Editing Function against Artificial Amino Acids in Protein Translation” ACS Cent. Sci. 2017, 3, 73-80.


15.  U. I. M. Gerling-Driessen, N. Mujkic-Ninnemann, D. Ponader, D. Schöne, L. Hartmann, B. Koksch; “Exploiting Oligo(amido amine) Backbones for the Multivalent Presentation of Coiled-Coil Peptides” Biomacromolecules, 2015, 16, 2394-2402.


14. S. Huhmann, E. K. Nyakatura, H. Erdbrink, U. I. M. Gerling, C. Czekelius, B. Koksch; “Effects of single substitutions with hexafluoroleucine and trifluorovaline on the hydrophobic core formation of a heterodimeric coiled coil J. Fluor. Chem. 2015, 175, 32-35.


13. U. I. M. Gerling§, M.S. Miettinen§, B. Koksch; “Concluding the amyloid formation pathway from the size of the critical nucleusChemPhysChem 2015, 16, 108-114. § Contributed equally


12. U. I. M. Gerling, M. Salwiczek, C. D. Cadicamo, H. Erdbrink, C. Czekelius, S. L. Grage, P. Wadhwani, A. S. Ulrich, M. Behrends, G. Haufe, B. Koksch; “Fluorinated amino acids in amyloid formation: a symphony of size, hydrophobicity, and α-helix propensityChem. Sci. 2014, 5, 819-830.


11. J. Maity§, U. I. M. Gerling§, S. Vukelić, A. Schäfer, B. Koksch; “Proline-glutamate chimera’s side chain conformation directs the type of β-hairpin structureAmino Acids, 2014, 46, 177-186. § Contributed equally


10. H. Erdbrink, E. K. Nyakatura, S. Huhmann, U. I. M. Gerling, D. Lentz, B. Koksch; “Synthesis of enantiomerically pure (2S,3S)-5,5,5-trifluoroisoleucine and (2R,3S)-5,5,5-trifluoro-allo-isoleucineBeilstein J. Org. Chem. 2013, 9, 2009-2014.


9. P. D. Rakowska, H. Jiang, S. Ray, A. Pyne, B. Lamarre, M. Carr, P. J. Judge, J. Ravi, U. I. M. Gerling, B. Koksch, G. J. Martyna, B. W. Hoogenboom, A. Watts, J. Crain, C. R. M. Grovenor, M. G. Ryadnov; “Nanoscale imaging reveals laterally expanding antimicrobial pores in lipid bilayersProc. Natl. Acad. Sci. U.S.A. 2013, 110, 8918-8923.


8. H. Erdbrink, I. Peuser, U. I. M. Gerling, D. Lentz, B. Koksch, C. Czekelius; “Conjugate hydrotrifluoromethylation of α, β-unsaturated acyl-oxazolidinones: synthesis of chiral fluorinated amino acidsOrg. Biomol. Chem. 2012, 10, 8583-8586.


7. M. Salwiczek, E. K. Nyakatura, U. I. M. Gerling, S. Ye, B. Koksch; “Fluorinated Amino Acids: Compatibility with native protein structures and effects on protein-protein interactionsChem. Soc Rev. 2012, 41, 2135-2171. * Journal cover


6. J. Maity, P. Saha, U. I. M. Gerling, D. Lentz, B. Koksch; “An approach for simultaneous synthesis of cis- and trans-3-substituted proline-glutamic acid chimerasSynthesis, 2012, 44, 3063-3070.


5. R. Rezaei Araghi, C. Baldauf, U. I. M. Gerling, C. D. Cadicamo, B. Koksch; “A systematic study of fundamentals in a-helical coiled coil mimicry by alternating sequences of β- und γ-amino acidsAmino Acids, 2011, 41, 733-742.


4. E. Brandenburg, H. v. Berlepsch, U. I. M. Gerling, C. Böttcher, B. Koksch; “Inhibition of Amyloid Aggregation by Formation of Helical AssembliesChem. Eur. J. 2011, 17, 10651-10661.


3. U. I. M. Gerling, E. Brandenburg, H.v. Berlepsch, K. Pagel, B. Koksch; “Structure Analysis of an Amyloid-Forming Model Peptide by a Systematic Glycine and Proline ScanBiomacromolecules, 2011, 12, 2988-96.


2. A. Botev, L.M. Munter, R. Wenzel, L. Richter, V. Althoff, J. Ismer, U. Gerling, C. Weise, B. Koksch, P.W. Hildebrand, R. Bittl, G. Multhaup; “The Amyloid Precursor Protein C-Terminal Fragment C100 Occurs in Monomeric and Dimeric Stable Conformations and Binds γ-Secretase ModulatorsBiochemistry, 2011, 50, 828-825.


1. J.A. Falenski, U. Gerling, B. Koksch; “Multiple glycosylation of de novo designed alpha-helical coiled coil peptidesBioorg. Med. Chem. 2010, 18, 3703-3706.