Prof. Anne-Marie Lambeir is well recognized for her expertise in enzymology. She accepted invitations not only for teaching enzyme kinetics, but also to participate in multidisciplinary projects on protein engineering, enzyme design and drug development. We are open for collaborations with academic groups and pharmaceutical and biotech companies.

Structure-activity relationships, binding mode and mechanism of enzyme inhibitors 

Optimalisation of lead compounds is an important phase in drug development. To optimally derive structure-activity relationships (SAR) in groups of compounds it is necessary to determine their binding mode and to identify suitable experimental parameters to correlate with activity.

  • For example, SAR data were collected for a family of prolyl oligopeptidase inhibitors. Their binding mode was confirmed by X-ray crystallography. In addition cell penetration properties and biological activity was determined in a cellular model of synucleinopathy.
  • In another study we showed that Vildagliptin is a covalent, slow binding but tight inhibitor of dipeptidyl peptidase 4 (DPP4). To complement data of the initial screening of Vildagliptin, which was done with a synthetic substrate, we determined inhibition parameters using natural substrates of DPP4: incretins, neuropeptides and chemokines.

Substrate specificity and structure-function relationships in peptidases

When studying proline specific peptidases and basic carboxypeptidases, there often is an overlap between de substrates of these peptidases. Whether a particular substrate is cleaved in vivo by a particular peptidase depends on at least these two parameters:

  • the substrate is cleaved efficiently in vitro, and
  • substrate and peptidase are in contactin vivo.

Determining substrate specificity of peptidases towards bioactive peptides is a speciality of our lab. Examples are given for carboxypeptidase M  and dipeptidyl peptidase 4. Substrate specificity reflects structure-function relationships in the active site of the peptidase.

Enzyme conformations and stability

Enzymes are dynamic structures. Conformational flexibility is an aspect of catalysis. Conformation is related to stability in proteins. A good example thereof is the stabilization of Leishmania triosephosphate isomerase by removing a negative charge buried in the interdimer interface.

Assay development

In one particular study we developed an assay to measure intracellular activity of prolyl oligopeptidase. When assessing inhibition levels of dipeptidyl peptidase 4 in vivo, methods need to allow for the difference between reversible and slow-binding or irreversible inhibitors.

Good enzymatic assays are needed to screen inhibitors and to determine structure-function relationships in the active sites. In our laboratory we also develop assays for measuring activity in complex biological samples.

Protein and enzyme engineering

Glucose isomerase provides an early example of the use of protein engineering to improve performance in an industrial application.

Prof. A.M. Lambeir also participated in a project aiming to alter substrate specificity in triosephosphate isomerase.

The interest in enzyme engineering is increasing in the context of durable chemistry. We welcome collaborations in this field.