The studies described in this thesis deal with glycosidases, in particular alpha-galactosidases.

Promotor: Prof.dr. M. Ubbink

This thesis describes the use of an activity-based proteomics method to study the endocannabinoid system.

The work in this thesis has been focused on two subjects. The first is the assembly of alginate oligosaccharides and the generation of building blocks for the enzymatic synthesis of alginate, and the second is the total synthesis of large fragments of the zwitterionic SP1 polysaccharide.

Promotor: H.S. Overkleeft, Co-promotor: M. van der Stelt

Using photosynthesis to generate energy, or using enzymes to effectively produce biofuel; Leiden chemists Huub de Groot en Hermen Overkleeft have both obtained an NWO TOP funding for their pioneering research. With the money they can take on new PhD students.

The main research theme in the group of Dennis Hetterscheid is to understand and mimic bioinorganic multi-electron processes that are relevant to our future energy infrastructure. Reduction of protons generates hydrogen that can be used as a chemical fuel. Alternatively to gaseous hydrogen, the reduction…

Science, Leiden Institute of Chemistry (LIC), Bio-organic Synthesis

Science, Leiden Institute of Chemistry (LIC), Bio-organic Synthesis

Lecture

Research aims: Identification of key genes involved in programming the cellular architecture of A. niger & Genetic engineering of A. niger in order to improve its secretory capacities and rheological behavior under industrial fermentation conditions.

This functional genomics project aims at understanding the biology of the underlying mycelium differentiation and autolysis processes in much more detail.

Bacteria are highly complex and diverse organisms that have adapted to survive in ecological niches ranging from the most extreme to the most heterogeneous environments.

Streptomyces present a valuable platform for natural product discovery. Lugdunomycin is a novel angucycline-derived polyketide from Streptomyces sp QL37, with unprecedented skeleton and antimicrobial activity.

The filamentous bacteria Streptomyces are widespread inhabitants of terrestrial soils.

Promotores: Prof.dr. H. van Veen & Prof.dr. W. de Boer (Wageningen University)

Natural product inspired antibiotics to address resistance

In neonates and infants, body size, enzyme pathways, and expression and function of receptors and (target) proteins are still developing.

Glycosidases (GHs) are enzymes responsible for the degradation of carbohydrates and play many roles in human health and pathophysiology. Often, abnormal levels of glycosidase activity are markedly linked to human pathologies.

This thesis describes biochemical investigations of glucocerebrosidase (GBA), the lysosomal β- glucosidase that is deficient in Gaucher disease (GD).

Microbial Sciences'contribution to the Development & Disease research theme is to perform world-class research to understand cellular morphogenesis, growth, development and virulence of microbes.

In this thesis, a system pharmacology approach, integrating metabolomics, pharmacology and chemical biology, was applied to understand and modulate the endocannabinoid system across different model systems (cells, zebrafish, mice and humans).

Death in all types of melanomas is generally caused by metastasis. Uveal melanoma (UM) is the most common intraocular melanoma, there are currently no (patient-derived) animal models that faithfully recapitulate metastatic dissemination of UM.

Promotores: G.W. Canters, T.J. Aartsma

Promotor: Prof.dr. G.P. van Wezel

Synthesis and application of chemical biology tools to study immunomodulatory signaling lipids.

Drug development is a time- and resource-consuming process that starts with the discovery and validation of a (protein) target that contributes to pathogenesis or disease progression.

Lysosomal glycosidases are acid hydrolases that fragment glycoconjugates in lysosomes.

The goal of target discovery is to identify and validate proteins and biological pathways that are involved in the disease process. Modulating these target proteins and pathways with small molecules, therapeutic proteins or other biomolecules (e.g. mRNA) could deliver an effective and safe drug or v…

Agrobacterium tumefaciens, a gram-negative plant pathogen belonging to the family Rhizobiaceae, is the causative agent of crown gall disease, which can affect many plant species including agronomically important ones.

Can new variants of daptomycin and the polymyxins be found?

The investigations described in this thesis lay out strategies aimed at advancing antibiotic research and development. The examples presented revolve around two main approaches: understanding drug-target interactions and target identification.

Lysosomal acid glucosylceramidase (GBA1) is a lysosomal enzyme that degrades glucolipids with its main substrate being glucosylceramide (GlcCer). Defects in the GBA1 gene lead to glycosphingolipidosis Gaucher disease (GD), in which the hydrolysis of GlcCer is impaired and therefore, it accumulates in…

Pseudomonas Aeruginosa is a Gram-negative bacterium which can form biofilms, increasing its resistance against antibiotics and the host immune system. Polysaccharides are an integral part of this biofilm, one of these polysaccharides is called Psl. PslG is a glycosidase, able to cleave this polysaccharide,…

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.

How are new drugs developed? This question is central to the Minor Modern Drug Discovery (MDD), which covers the entire trajectory from disease to drug molecule and vice versa. The various research groups involved offer a complementary and interdisciplinary perspective by connecting the diverse subjects…

What are the functions of the endocannabinoid system?

Focus in skin research

N-acylethanolamines (NAEs), including N-arachidonoylethanolamine (anandamide, AEA), N-palmitoylethanolamine (PEA) and N-oleoylethanolamine (OEA), are signaling lipids that play an important role in different physiological process.

Neurodegenerative diseases pose a large medical and societal challenge. The etiology of these diseases is still poorly understood, which makes drug discovery for these diseases difficult.

- How to deconvolute metabolic mixture of precursors and products by biontransformation? - How to optimize the reaction conditions to produce bioactive compounds in biotransformation? - What is the effect of co-treating fungi or bacteria for biotransformations?

Through metabolism, biochemical processes give rise to the complexity of life. Acquired and inborn errors in metabolism underlie many diseases occurring in man. The challenge for present day medical biochemistry is to find, and integrate, pieces of information at molecular, cell and organismal level…

Dr. at Max Planck Institute for chemical Ecology, Jena - Germany

This thesis describes the structural and biochemical characterization of the β-lactamase BlaC from Mycobacterium tuberculosis (Mtb), and the Alr and YlmE proteins from Streptomyces coelicolor A3(2).Mtb is the main cause of tuberculosis.

The lysosomal β-glucosidase named glucocerebrosidase (GCase) is a retaining β-glucosidase that hydrolyzes the glycosphingolipid glucosylceramide (GlcCer) to ceramide and glucose at acid pH.

Ceramides (CERs), cholesterol, and free fatty acids (FFAs) are the main lipid classes in human stratum corneum (SC, outermost skin layer), but no studies report on the detailed analysis of these classes in a single platform.

To this day, all cyclophellitol-based inhibitors and ABPs have been close analogues of their natural substrate counterparts. As a result, these probes showed high selectivity towards their target glycosidases.

Why do plants produces always produced so many slightly differing metabolites within a particular chemical class?

According to the amyloid cascade hypothesis, accumulation of beta-amyloid (Aβ) peptides initiates the pathological cascade in Alzheimer's disease (AD).