PhD ceremony: Ms. U. Dijkman, 13.15 uur, Academiegebouw, Broerstraat 5, Groningen
Thesis: Inhibition of kynurenine aminotransferase. A potential new drug target for the treatment of schizophrenia
Promotor(s): prof. B.H.C. Westerink
Faculty: Mathematics and Natural Sciences
The kynurenine pathway is the main route for tryptophan metabolism. The most important intermediate is kynurenine. Kynurenine (KYN) is converted to kynurenic acid (KYNA) by the enzyme kynurenine aminotransferase (KAT). KYN can also be converted to anthranilic acid (AA) and 3-hydroxykynurenine (3-OH-KYN) by kynureninase (KYNase) and kynurenine mono-oxygenase (KMO), respectively.
Elevated levels of KYNA have been found in patients with schizophrenia. A straightforward way to decrease KYNA levels is inhibition of the biosynthetic enzyme KAT. It is important to inhibit KAT selectively over KYNase and KMO. If the latter two enzymes are inhibited, increased availability of KYN would lead to enhanced synthesis of KYNA.
In her thesis Ulrike Dijkman has described the synthesis and biological evaluation of a series of KYN analogs. The analogs consist of a bicyclic core, which locks the KYN scaffold in a rigid structure. Evaluation of the bicyclic structures and several flexible analogs in KAT, KYNase and KMO assays provided interesting information regarding selectivity profiles.
In addition, the characterization of KAT is described by Dijkman. The evolutionary position of the enzyme within the group of vitamin B6 dependent enzymes was studied. Furthermore, the substrate binding site of KAT enzymes was studied by Dijkman by means of homology modeling, docking and comparison of results to available crystal structures. The knowledge she gathered is important for the rational design of pharmacologically active compounds.
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