Other pathogenic trypanosomatids are a whole set of

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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 human host Human GAPDH 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 position of 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 Hydrophobic Groove: F...
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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.

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