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Document and inhibition mechanisms and provided a clarification for the mechanism by which inhibitors of both the carboxylate [28] and spirohydantoin [29] classes bind at the active site of ALR2. V. Aldo-Keto Reductase Family A. Effects of Sequence on Drug Design Page 239 The problem of structure-based drug design for ALR2 and the drug-design effort in general is compounded by the fact that this enzymes is a member of a large family of aldo-keto reductases with overlapping substrate specificity. In humans at least three such enzymes have been found: ALR2 [30], aldehyde reductase (ALR1) [30], and chlordecone reductase [31]. Other members of the family that have been isolated in other species include rat 3α-hydroxysteroid dehydrogenase [32], murine fibroblast growth factor induced protein [33], bovine prostagladin F synthase [34], murine vas deferens protein [35], frog ρ-crystallin [36], the P100/11E gene product in Leishmania major [37], and Corynebactium diketogluconate reductase [38]. This large number suggests that there may be more such enzymes to be found in humans. The similarities between the proteins with respect to both the sequence and substrate specificity implies that the nature of the substrate binding sites are similar across the family. This has indeed been the case in all the structures determined from this family to date (see below). While detailed binding studies of various inhibitors with all the different enzymes have not been conducted, it is likely that drugs intended for ALR2 are likely to “cross react” with many of the other enzymes within the family. One such case that has recently been studied both crystallographically and biochemically is the murine FR-1 protein described below. The binding sites of all of these enzymes are characterized by their large size and hydrophobicity suggesting that ideal substrates may be steroids or molecules of a similar size and nature. Sequence comparisons of all the proteins, including those whose structure has not yet been determined, show that there is a large amount of similarity involving residues implicated in substrate binding (see Figure 8). One region that diverges somewhat is the 15-amino acid segment at the carboxy terminus of the protein. This segment is likely to be responsible for what little differences in substrate specificity exhibited by the enzymes. It is the same segment that is seen adopting a different conformation upon zopolrestat binding to ALR2. It may then be possible that it is not only the chemical nature of this loop that—in making positive and negative interactions with the substrate/inhibitor—modulates specificity, but also the flexibility conferred by the amino acid sequence. Such a difference is seen when contrasting the structures of ALR2 and FR-1 bound to zopolrestat. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_239.html [4/5/2004 5:09:05 PM]
Document B. Structures Figure 8 Sequence alignment of several members of the aldo-keto reductase family. Abbreviations used are HALR2, human aldose reductase (30); HALR1, human aldehyde reductase [30]; 3α-HSD, 3α-hydroxysteroid dehydrogenase [32]; FR-1, murine FR-1 [33]; BPGFS, bovine prostaglandin F synthase [34]; CCDR12, human chlordecone reductase [31]; CDGR, Corynebacterium diketogluconate reductase [38]; MVDP, murine vas deferens protein [35], JFRC, Japanese frog ρ crystallin [36]. Page 240 Structures of several other members of the aldo-keto reductase family have also been determined. These include aldehyde reductase [39,40], FR-1 [41] and 3α-hydroxysteroid dehydrogenase [42]. Since each of these proteins retain a large amount of sequence identity and homology with human ALR2, it is not surprising to note that the overall tertiary structures are very similar. Root-meansquare C α deviations between the human ALR2 holoenzyme structure and the rest of the family are in the range of 1–2Å http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_240.html (1 of 2) [4/5/2004 5:09:22 PM]
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Document Table 3 HIV-1 RT Amino Aci
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Document Page 72 16. Goldman ME, Nu
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Document 106. Cirino NM, Cameron CE
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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 receptor, it has not yet b
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Document Figure 6 Rat and human B2
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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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Page 251 and 252: Document Page 205 enzyme and of phe
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Page 257 and 258: Document 29. Baker ME. Genealogy of
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Document Table 1 Approval Indicatio
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Document Page 438 proteins. One pot
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Document Page 441 sequence of the m
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Document Page 495 of the RNA and pr
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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 [Human immunodeficiency vi
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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