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Document state through the tight binding of ligands. In this way inhibitors might act at two levels, directly by blocking catalysis and indirectly by preventing proper enzyme routing in the parasite. Thus far, we have engaged in a collaborative effort to inhibit three of the glycosomal enzymes. (From Ref. 95. Copyright 1988 by Elsevier.) http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_370.html (2 of 2) [4/5/2004 5:33:24 PM]
Document II. Three Glycolytic Enzymes Of T. Brucei: Molecular Biology, Biochemistry, and X-Ray Crystallography A. Triosephosphate Isomerase (TIM) Page 371 TIM is a homodimeric enzyme that interconverts dihydroxyacetone phosphate and glyceraldehyde-3phosphate. It ensures that both trioses derived from glucose can be used for ATP production in the glycolytic pathway. Triosephosphate isomerase does not require any cofactor. Both the T. brucei and human enzymes have been overexpressed in Escherichia coli [50,25] and their crystal structures were solved in our group [24,25]. In addition, the structures of T. brucei TIM in complex with seven nonselective competitive inhibitors, with inhibition constants of 300 μM or higher were determined: monohydrogen phosphate [51], 2-phosphoglycerate [52], 3-phosphoglycerate [53], 3phosphonopropionate [53], glycerol-3-phosphate [53], 2-(N-formyl-N-hydroxyamino)-ethyl phosphonic acid [54], and N-hydroxy-4-phosphonobutanamide [55]. These studies gave an excellent picture of different ligand binding modes and of the conformational flexibility of the enzyme. All ligands interact with the main features of the catalytic machinery of the enzyme (Figure 3): (1) the phosphate is sequestered by the positive end of a 3 10-helix and Lys13; (2) polar groups on the carbon framework interact with His95 and Glu167, the catalytic electrophile and the catalytic base of the enzyme, respectively; (3) the entire inhibitor is shielded from the bulk solvent by a flexible loop, which normally closes over the substrate during catalysis to prevent phosphate elimination [56] (Figure 4). The only exception to flexible loop closure is N-hydroxy-4-phosphono-butanamide. It binds to the enzyme with the flexible loop in the open conformation because its size precludes loop closure. Thus, the crystallographic binding studies point out that it should be possible to design two very different classes of selective inhibitors: a class that binds to the enzyme in the closed loop conformation and one that binds to the open loop conformation. Selective inhibitor design in the case of TIM appears to be a formidable task. All residues within 10 Å of the active site are conserved [25]. This is also reflected in the similarity of the kinetic characteristics between trypanosomal and human TIM: for T. brucei TIM, K m (glyceraldehyde-3-phosphate) = 0.25 mM, kcat = 3.7 × 10 5min -1 [57]; for human TIM, K m = 0.49 mM, kcat = 2.7 × 10 5 min -1 [25]. There are significant differences in the surface protein of the two enzymes about 15 Å away from the substrate phosphorus atom [58]. In a shallow cleft, T. bruceiTIM has Ala100-Tyr101, while the human counterpart of these residues is His-Val (Figure 5). The cleft is formed by the flexible loop of one subunit of the enzyme and a different loop originating from another subunit. When the flexible loop changes its conformation from the closed to the open form the cleft widens substantially. Moreover, the Ala-Tyr dipeptide becomes then directly accessible from the active site, the distance being about http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_371.html [4/5/2004 5:34:04 PM]
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Structure-based Drug Design 14 Stru
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Document dine) and didanosine (dide
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Document Page 108 mulate during tre
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Document when metals are bound. Fin
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Document cubation of phosphotyrosin
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Document 4 Bradykinin Receptor Anta
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Document Page 127 The des-Arg 9 for
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Document receptor, it has not yet b
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Document Page 141 receptor with int
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Document We determined the structur
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Document Figure 3 Previously known
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Document large solvent channels and
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Document IV. Drug Design Progressio
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Document Table 1 Inhibition Data fo
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Document Page 166 As predicated, th
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Document References 1. Parks RE Jr.
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Document 17. Ealick SE, Rule SA, Ca
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Document 6 Structural Implications
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Document Page 176 0.43 Å) as the c
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Document Page 178 studies show that
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Document Figure 4 Amino acids impor
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Document Page 202 269, and valine-2
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Document Page 205 enzyme and of phe
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Page 413 and 414: Document 2. Blundell TL, Cooper J,
Page 415 and 416: Document 17. Szelke M. Chemistry of
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Page 421 and 422: Document Page 343 14 Structural Asp
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Page 451 and 452: Document Table 1 Trypanosomal Targe
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Document Cyclotheonamide A (CtA), 2
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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Document fragment-based programs, 5
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Document Kininogen, 119 high molecu
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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