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- Heinrich Heine University cooperates with numerous research institutions and networks beyond the boundaries of the faculties. The HHU's affiliated institutes in particular act as a link to industry. As independent institutions, they maintain close contact with research in the faculties and participate in the training of young academics.
- One of our foci today, linking all faculties, are the Life Sciences. Cross-departmental, joint study programmes (such as Business Chemistry) are one of our major strengths.
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Recent Submissions
Overcoming bottlenecks for microbial production of the low-caloric sweetener D-allulose from D-glucose by evolutionary engineering
(2026) Gentile, Rocco; Gohlke, Holger
The low-calorie sugar D-allulose is a promising alternative to D-sucrose and high-fructose corn syrup, but its microbial production from D-glucose at mesophilic temperatures is limited by insufficient D-glucose isomerase (XylA) activity. Here, we overcome this bottleneck by evolving a Corynebacterium glutamicum selection strain whose growth strictly depends on XylA function. This strategy yielded a XylA variant with a nine-fold higher catalytic efficiency, sugar transporter variants (IolT1) with ten-fold increased activity for D-glucose and D-fructose, and hints for co-transport of these sugars by the D-sucrose transporter PtsS. Molecular dynamics simulations provided mechanistic explanations for the adaptive mutations. Combining the evolved enzymes with a suitable D-allulose 3-epimerase in a highly engineered chassis strain enabled whole-cell conversion of D-glucose to D-allulose with a 15% yield at 30 °C. This performance rivals high-temperature immobilized enzyme processes while avoiding enzyme purification and immobilization, offering an alternative for low-calorie sweetener production.
Data for "LignAmb25: A Comprehensive AMBER Force Field Addressing Lignin’s Structural and Chemical Diversity"
(2026) Lapsien, Marco; Bonus, Michele; Greb, Julian; Gohlke, Holger
LignAmb25 is a comprehensive force field for lignin molecular dynamics simulations implemented natively within the AMBER package. The force field includes parameters for all common monolignol units (p-coumaryl, coniferyl, caffeyl, and sinapyl alcohol) and their associated linkages (β O4, β 5, β β, β 1, 5 5, 5 O4, α-O4, BDO, and DBDO), along with less commonly encountered units such as tricin, spirodienones, and hydroxystilbenes. This enables simulations of both softwood and hardwood lignin structures with compositions that would be difficult to isolate experimentally. Force field parameters were initially derived from the GAFF2 force field and systematically optimized using quantum mechanical calculations at the ωB97X D4/def2 TZVPP level of theory on conformer ensembles derived via the CREST/CENSO conformational sampling toolchain. Partial atomic charges were derived using the RESP methodology, consistent with AMBER conventions. Experimentally measured crystal structures of lignin simulated with LignAmb25 accurately retain their packing based on calculations of the RMSD and density error compared to the deposited crystal structure, thereby exceeding the performance of the lignin force field for CHARMM. Additionally, LignAmb25 is shown to reliably estimate the enthalpy of vaporization and the absolute hydration free energy of lignin-related compounds. The LignAmb25 force field is provided in two variants: LignAmb25Solo, a standalone version not meant for use with other biomolecular force fields that focuses on accurate modelling of lignin solvent interactions, and LignAmb25HF, a version that is compatible with all other major biomolecular force fields in the AMBER molecular dynamics suite. This includes force fields of the GLYCAM (carbohydrates), ff19SB (proteins), and LIPID (lipids) families, as well as the DNA and RNA force fields routinely used in AMBER. The LignAmb25 force field will be distributed as of AMBER 26.
Heterogeneity of astrocyte density, morphology and connexins in the mouse hippocampus
(2025-12-19) Uelwer, Annika; Sivakumar, Mamitha; Umirdinov, Khojimurod; Purath, Fathima Faiba A.; Oluma, Lensa; Anstötz, Max; von Gall, Charlotte; Ali, Amira A. H.
The hippocampal formation is crucial for episodic learning and memory. In addition to neurons, astrocytes have also received increasing attention in recent years as essential components of brain networks by regulating the blood-brain barrier, eliminating waste products via the glymphatic system, supporting neuronal activity by providing energy supply and metabolic substrates, and regulating extracellular neurotransmitter levels. Astrocytes are heterogeneous and highly dynamic cells that respond to neuronal activity and dysfunction via morphological and functional changes. Astrocytic connexins (Cx) 30 and 43 form the molecular basis for gap junctions and hemichannels and are, thus, central to the coupling, intercellular communication and network integration of astrocytes in the brain. However, little is known about the spatial heterogeneity of astrocyte density, morphology and Cx expression in the subregions and layers of the hippocampus.
Therefore, in this study, we used immunohistochemistry to analyze the density and detailed morphological features of astrocytes and the spatial distribution of Cx30 and Cx43 in the layers of CA1, CA3 and dentate gyrus (DG). Astrocyte density correlated positively with the intensity of Cx30- and Cx43-immunoreaction (Ir). The stratum lacunosum moleculare (SLM) of CA1 and CA3 and the subgranular zone (SGZ) of DG showed the highest density of GFAP-positive (+) astrocytes and the strongest Cx30- and Cx43-Ir. The GFAP+ astrocytic processes had the largest radial extent in the pyramidal layer of CA1 and CA3 and in the granular layer of the DG.
Our study provides a comprehensive anatomical and comparative mapping of astrocytic density, morphology and Cx distribution in the mouse hippocampus and provides an important basis for further studies on the dynamics of neuron-glial interaction under different physiological and pathological conditions.
Data for "Mechanistic Insights into the Structural Asymmetry of the LanFEG Transporter NisFEG in Lantibiotic Immunity"
(2025) Cea, Pablo; Gohlke, Holger
Nisin is one of the best studied antimicrobial peptides. Still, how nisin-producing strains can protect themselves against nisin’s bactericidal effects is only partially understood. Located within the nisin biosynthesis operon, the heterotetrameric ABC transporter NisFEG transports nisin to the extracellular environment, granting autoimmunity to the producer strain. NisFEG belongs to the LanFEG family of ABC transporters, members of which are found in some lantibiotic-producing bacterial strains. However, their structure has not been elucidated. In this work, we constructed a full atom model of NisFEG in the ATP-bound conformation. The architecture of the complex reveals a narrow transmembrane interface with prominent lateral clefts, similar to those observed in other exporters of hydrophobic compounds. Through molecular dynamics (MD) simulations, we observed that one of the most conserved elements of the LanFEG family, the E-loop of the nucleotide binding domain, interacts preferentially with a small intracellular helix of the NisG transmembrane chain. Cosolvent MD simulations reveal the presence of a putative binding site within the lateral cleft of the transporter, next to the transmembrane chain NisE. Mutational analysis showed that large hydrophobic residues near this putative site are relevant to the transporter function, and more so than analogous residues in the opposite cleft. Our results suggest that nisin extrusion operates in an asymmetric manner, where contacts between the E-loop and NisG are the driving force for the conformational changes triggered by ATP hydrolysis, whereas the NisE subunit is the main mediator of interactions with the lantibiotic. This functional asymmetry could provide an explanation for why the LanFEG family has evolved two distinct transmembrane chains, where each one was selected to perform a single step in an optimal way, maximizing the immunity of lantibiotic-producing bacteria.
Data for "Early-stage autophagy inhibitors targeting the ATG101-ATG13 subunit of the ULK1 complex"
(2025) Mudrovcic, Korana; Gopalswamy, Mohanraj; Gohlke, Holger
Autophagy is commonly up- or down-regulated in cancer cells due to the unique metabolic needs of these cells, and small molecules modulating the autophagy pathway are already in clinical trials. However, specific autophagy-targeting compounds remain rare. A new potential mechanism for effective early-stage autophagy inhibition was described by us and others recently, involving the inhibition of the interaction between ATG101 and ATG13 subunits of the autophagy-initiating ULK1 complex. Here, we describe the discovery of two small molecules inhibiting the ATG101-ATG13 interaction, one by binding to ATG101 with micromolar affinity (EC50 = 151 µM) and the other by binding to both ATG101 and ATG13 with micromolar affinity (EC50 = 135 µM and EC50 = 107 µM, respectively). In two independent assays, both compounds inhibit autophagy. Scrutinizing the binding mechanism by molecular dynamics simulations and STD-NMR spectroscopy indicates that the compounds bind to ATG101 in an orthosteric fashion, at the interface of the protein-protein interaction, while the binding to ATG13 is allosteric. Both compounds have a favorable predicted ADME-Tox profile. The compounds can serve as tool compounds to inhibit autophagy or as candidates for further optimization toward lead structures.
Data for "Identification of autophagy inhibitors selectively targeting the ATG13-ATG101 protein-protein interaction"
(2025) Mudrovcic, Korana; Gopalswamy, Mohanraj; Gohlke, Holger
The dysregulation of autophagy promotes the development of several diseases like such as neurodegeneration, infection, or cancer. To keep up with their metabolic demand under low nutrient and/or oxygen conditions typically present in the tumor microenvironment, cancer cells can upregulate autophagy autonomously or in surrounding cells. Therefore, the inhibition of autophagy is desired in these settings. However, to date, drugs targeting autophagy selectively remain rare. The autophagy-inducing ULK1 complex comprises ULK1/2, FIP200, and a heterodimer consisting of ATG13 and ATG101. We previously showed that the ATG13-ATG101 protein-protein interaction is crucial for the assembly of the ULK1 complex and initiation of autophagic activity. Thus, targeting the ATG13-ATG101 protein-protein interaction with small molecules promises to yield new tools for the study of autophagy as well as to deliver new therapeutic starting points. By screening a diversity set of 15k compounds in a biochemical setup, followed by extensive cell-based validation studies, we identified the compounds AFS30 and AFS32. Both compounds inhibited the ATG13-ATG101 PPI in the low micromolar range and led to reduced autophagic activity in different cell lines, with IC50 values of 3-4 µM in the LC3 HiBiT reporter assay. Spectral shift assays, molecular dynamics simulations, and STD-NMR suggested that the compounds bind allosterically to ATG13. AFS30 and AFS32 also promoted apoptosis in different cancer cell lines exposed to nutrient stress. We propose that AFS30 and AFS32 are promising lead compounds for the development of PPI inhibitors that selectively inhibiting the ATG13-ATG101 interaction and thus autophagy.