University of Groningen

Inhibition of Kynurenine aminotransferase

Dijkman, Ulrike

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Dijkman, U. (2010). Inhibition of Kynurenine aminotransferase: a potential new drug target for the treatment
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Inhibition of Kynurenine Aminotransferase
A Potential New Drug Target for the
Treatment of Schizophrenia

2010
 RIJKSUNIVERSITEIT GRONINGEN

Inhibition of Kynurenine Aminotransferase

A Potential New Drug Target for the
Treatment of Schizophrenia

Proefschrift

ter verkrijging van het doctoraat in de

Wiskunde en Natuurwetenschappen
aan de Rijksuniversiteit Groningen
op gezag van de
Rector Magnificus, dr. F. Zwarts,
in het openbaar te verdedigen op
vrijdag 9 juli 2010
om 13.15 uur

door

Ulrike Dijkman
geboren op 22 december 1979
te Halle, DDR
Promotor: Prof. dr. B.H.C. Westerink

Copromotor: Dr. C.J. Grol

Beoordelingscommissie: Prof. dr. J. Zaagsma

Prof. dr. C. Kruse
Prof. dr. G. Engberg
 “My insides are smiling.
And I have the impression that all is well with the world.”

Pihkal – A Chemical Love Story

Alexander Shulgin & Ann Shulgin
Paranimfen: Jan-Ger Knot
Joost Folgering

Colophon

Copyright © 2010 by U. Dijkman. All rights reserved. No part of this book may
be reproduced in any manner or by any means without written permission from
the author.

The research project described in this thesis was performed within the
framework of the research school GUIDE.

Published by: Uitgeverij BOXPress, Oisterwijk

Printed by: Proefschriftmaken.nl || Printyourthesis.com
Cover illustration: Ulrike Dijkman, based on ‘Che Guevara’ by Andy Warhol

ISBN: 978-90-367-4393-8 (printed version)

978-90-367-4394-5 (electronic version)
Table of contents
Chapter 1
Introduction: The kynurenine pathway

1.1! Kynurenine pathway ...................................................................................2!

1.1.1! Kynurenine production: Indole-2,3-dioxygenase, tryptophan-2,3-
dioxygenase and kynurenine formamidase .........................................................4!
1.1.2! Kynurenine .........................................................................................5!
1.1.3! Kynurenine 3-hydroxylase ....................................................................6!
1.1.4! Kynureninase .................................................................................... 10!
1.1.5! Kynurenine aminotransferase .............................................................. 14!
1.1.6! Kynurenic acid .................................................................................. 18!
1.1.7! Regulation of KYNA levels ................................................................... 18!
1.1.7.1! Transporters .............................................................................. 18!
1.1.7.2! Ionic concentrations, cell energy status ......................................... 19!
1.1.7.3! KAT activity – pH, co-enzyme, co-substrates .................................. 20!
1.1.7.4! Competing reactions ................................................................... 20!
1.1.7.5! Direct KAT inhibition ................................................................... 20!
1.1.7.6! Mechanism based inhibitor: Vinylglycine ........................................ 25!
1.1.7.7! Influx and efflux of KYNA ............................................................. 25!
1.1.7.8! Neurotransmitters....................................................................... 26!
1.1.7.9! Pharmacological compounds that influence KYNA levels ................... 27!
1.1.8! KYNA physiology ............................................................................... 27!
1.1.8.1! Regulation at the neuronal level: KYNA effects on neuronal activity ... 27!
1.1.8.2! Region specific KYNA effects: KYNA regulated acetylcholine release ... 28!
1.1.8.3! KYNA effects on glutamate, norepinephrine and dopamine ............... 28!
1.1.9! Xanthurenic acid................................................................................ 30!
1.1.10! 3-Hydroxyanthranilic acid and quinolinic acid ....................................... 31!
1.2! Balances within the kynurenine pathway...................................................... 32!
1.3! Indolepyruvic acid pathway........................................................................ 33!
1.4! Kynurenine pathway: Pathology ................................................................. 34!
1.4.1! Immune related disorders................................................................... 34!
1.4.2! AIDS-dementia complex ..................................................................... 35!
1.4.3! Huntington’s disease .......................................................................... 35!
1.4.4! Alzheimer’s disease and cognitive function ............................................ 35!
1.4.5! Parkinson’s disease, epilepsy............................................................... 36!
1.4.6! Schizophrenia ................................................................................... 37!
1.4.7! Other disorders ................................................................................. 38!
1.5! Conclusion............................................................................................... 38!
1.6! Aim of thesis............................................................................................ 39!
1.7! References .............................................................................................. 40!

Chapter 2
Synthesis and biological evaluation of kynurenine derivatives as KAT inhibitors:
Conformationally restricted carboxylic acids

2.1! Introduction............................................................................................. 54!

2.2! Chemistry ............................................................................................... 55!
2.3! Enzyme inhibition ..................................................................................... 60!
2.4! Discussion and conclusion.......................................................................... 61!
2.5! Experimental section................................................................................. 67!
2.6! References .............................................................................................. 75!
Chapter 3
Synthesis and biological evaluation of kynurenine derivatives as KAT inhibitors:
Conformationally restricted amino acids

3.1! Introduction............................................................................................. 80!

3.2! Chemistry ............................................................................................... 84!
3.3! Enzyme inhibition ..................................................................................... 87!
3.4! Discussion and conclusion.......................................................................... 88!
3.5! Experimental section................................................................................. 91!
3.6! References .............................................................................................. 97!

Chapter 4
Synthesis and biological evaluation of kynurenine derivatives as KAT inhibitors:
Quinolinones

4.1! Introduction........................................................................................... 102!

4.2! Chemistry ............................................................................................. 103!
4.2.1! Synthesis of 2,3-dihydro-4(1H)-quinolinone ........................................ 103!
4.2.2! Synthesis of amino-(4-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-acetic acid .. 104!
4.2.3! Synthesis of (4-oxo-1,2,3,4,-tetrahydroquinolin-3-yl)-acetic acid ........... 110!
4.3! Enzyme inhibition ................................................................................... 110!
4.4! Conformational analysis and docking studies in kynureninase ....................... 111!
4.4.1! Structures ...................................................................................... 111!
4.4.2! Conformational analysis ................................................................... 113!
4.4.3! Docking in kynureninase................................................................... 116!
4.5! Discussion and conclusion........................................................................ 120!
4.5.1! Compound design and in vitro activity ................................................ 120!
4.5.2! Conformational analysis ................................................................... 121!
4.5.3! Docking.......................................................................................... 122!
4.5.3.1! Docking of kynurenine............................................................... 122!
4.5.3.2! Docking of 4.2 and 4.3 ............................................................. 123!
4.5.4! Summary and conclusion .................................................................. 125!
4.6! Experimental section............................................................................... 126!
4.7! References ............................................................................................ 136!

Chapter 5
Synthesis and biological evaluation of kynurenine derivatives as KAT inhibitors:
Flexible analogs

5.1! Introduction........................................................................................... 140!

5.2! Chemistry ............................................................................................. 141!
5.3! Enzyme inhibition ................................................................................... 148!
5.4! Discussion ............................................................................................. 148!
5.5! Experimental section............................................................................... 154!
5.6! References ............................................................................................ 160!

Chapter 6
Molecular modeling: Kynurenine aminotransferase II

6.1! Introduction........................................................................................... 166!

6.2! PLP dependent enzymes: Position of kynurenine aminotransferase ................ 167!
 6.2.1! The subdivision of PLP dependent enzymes ......................................... 167!
6.2.2! Aminotransferases: Common enzyme properties.................................. 169!
6.2.3! Aminotransferases: Common interactions between substrate and enzyme172!
6.2.4! Kynurenine aminotransferases .......................................................... 173!
6.3! Structural examination of kynurenine aminotransferases ............................. 175!
6.3.1! Results........................................................................................... 176!
6.3.1.1! Sequences and crystal structures of kynurenine aminotransferases . 176!
6.3.1.2! Sequence comparison and evaluation of evolutionary relationships .. 179!
6.3.1.3! Human KAT II homology modeling .............................................. 183!
6.3.1.4! Docking of kynurenine............................................................... 187!
6.3.2! Discussion ...................................................................................... 190!
6.3.2.1! Sequence comparison and evolutionary relationships ..................... 190!
6.3.2.2! Homology models ..................................................................... 191!
6.3.2.3! Docking studies ........................................................................ 195!
6.3.2.4! General discussion and conclusion............................................... 197!
6.4! Experimental section............................................................................... 198!
6.5! References ............................................................................................ 200!

Chapter 7
Summary, general discussion and conclusion

7.1! Summary, general discussion and conclusion ............................................. 206!

Appendix

List of abbreviations ............................................................................................ 212!

Samenvatting ..................................................................................................... 215!
Dankwoord......................................................................................................... 220!