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Unformatted text preview: for diagnosis of parasites in CNS Sleeping sickness is caused by a unicellular eukarytote: Trypanosoma brucei – a “Trypanosomatid”.
Other pathogenic trypanosomatids are a whole set of Leishmania species.
These cause a spectrum of different tropical diseases, called “leishmaniasis”.
Many enzymes in Trypanosoma brucei and Leishmania species are very similar in amino acid sequence.
With thanks to Wes Van Voorhis Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
is essential for the Sleeping Sickness Parasite and differs from the
Trypanosomal GAPDH Cofactor (co-substrate) NAD Note the difference in conformation near the ribose of the NAD cofactor
in the homologous proteins of host and parasite. Adenosine – the starting point (IC50= inhibitor concentration which
inhibits the enzyme by 50%) - Adenosine is part of the cofactor (co-substrate) NAD of the enzyme GAPDH
- It is by itself a poor inhibitor of mammalian and T. brucei parasite GAPDH
- Moreover, it inhibits the sleeping sickness parasite enzyme slighty worse
than the mammalian enzyme. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
Human GAPDH : NO groove near 2’OH of Adenosine 2’-OH Randy Read, Christophe Verlinde, Herman Watson Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
Sleeping sickness parasite GAPDH : Hydrophobic Groove near 2’OH of Adenosine 2’-OH Fred Vellieux, Christophe Verlinde, Fred Opperdoes , Paul Michels Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
Sleeping sickness parasite GAPDH : Substituent modeled in Hydrophobic Groove near
2’OH of Adenosine Previous
the 2’-OH Christophe Verlinde, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH)
Selectivity of Structure-based Designed Inhibitors Don’t worry: you only need to remember that inspection of the structure of a
drug target resulted in a new compound with ~ 500-fold better inhibition of the
parasite enzyme than of the homologous human enzyme Exploring additional hydrophobic grooves near the adenosine
binding pocket of Leishmania mexicana GAPDH
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This note was uploaded on 10/20/2013 for the course BIOCHEM 405 taught by Professor Hol during the Fall '08 term at University of Washington.
- Fall '08