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Figure 7<br />

Comparison of the binding modes of the adenosine moiety of NAD to GAPDH:<br />

(left) in T.brucei,(right) in the human enzyme. Note the identical hydrogen bonds to<br />

the purine N6 and the ribosyl hydroxyls. The purine ring is embraced <strong>by</strong><br />

hydrophobic residues that are not conserved. Also, a unique cleft near O2', which we<br />

called the selectivity cleft, is present in the T.brucei enzyme. (From Ref. 13.Copyright<br />

1994 <strong>by</strong> the American Chemical Society.)<br />

Page 375<br />

Other differences in the vicinity of the adenosine portion of the NAD + cofactor are prime targets for<br />

selective inhibitor design. Close to C8 of the adenine ring, the trypanosomal GAPDH exhibits a Leu<br />

while its human counterpart has a smaller residue, namely Val (Figure 7). Also, the parasite enzyme<br />

possesses a hydrophobic cleft near the 2' -hydroxyl of the adenosine ribose. This cleft, termed the<br />

“selectivity cleft” is almost absent in the human enzyme due to a different local backbone conformation<br />

and the presence of the Ile37 side chain. In conclusion, the adenosine binding region looks like an<br />

excellent target for selective inhibitor design.<br />

It is exciting that the residues responsible for binding adenosine in T. brucei GAPDH are identical to<br />

their counterparts in glycosomal GAPDH of Leishmania mexicana, another trypanosomatid [31]. L.<br />

mexicana is one of the most common species of Leishmania throughout Central and South America and<br />

the southern United States. In humans it hides as amastigotes in the macrophages and causes hideous<br />

skin lesions. Together with about twenty other species of Leishmania these parasites infect about twelve<br />

million people annually [63]. Though they are less dependent on glycolysis than T. brucei there is<br />

evidence that stibogluconate, a well-known drug for treating leishmaniasis, specifically inhibits<br />

glycolysis in these parasites [64]. Therefore, we decided to study GAPDH of L. mexicana in parallel<br />

with the T. brucei enzyme. Its structure<br />

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