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Document Page 234 approximately 7 by 13 Å and is lined primarily with hydrophobic side chains. This is entirely consistent with earlier experiments showing that the enzyme has a marked preference for lipophilic substrates versus polar substrates such as sugars [21]. The catalytic site also suggested a model for the enzyme's chemical mechanism, which is substantially similar to most other NAD(P)H-dependent oxido reductases. Upon binding of the reduced cofactor, the enzyme is able to form a ternary complex with the substrate. The pro-R hydride from the C-4 of the nicotinamide is transferred to the carbonyl carbon of the substrate, which in turn causes the carbonyl oxygen to abstract a proton from a general acid, which is presumably located on the protein, to form the alcoholic product. Three proton-donating side chains are located within 6 Å of the C-4 atom in the NADPH cofactor that could potentially fulfill this role: Tyr48, His110, and Cys298. Since it is not conserved in other members of the aldo-keto reductase family that exhibit enzymatic activity (Figure 8) Cys298 was unlikely as a candidate proton donor. The histidine is surrounded by several hydrophobic residues including Val47, Trp79, and Trp111, which would serve to lower the pK a of the side chain, making it less effective as a proton donor at physiological pHs. The tryrosine, which ordinarily has a pK a of approximately 11 engages in an interaction with the charged ammonium group of Lys77, which in turn charge-pairs with Asp43. This network serves to depress the pK a of the phenolic oxygen, increasing the exchangability of the proton. Subsequent activity studies involving site-directed mutants support this model [17,22]. The Tyr48 rarrow.gif Phe mutation shows a complete lack of activity while the Asp43 rarrow.gif Asn, Lys77 rarrow.gif Met, His110 rarrow.gif Asn, and Cys298 rarrow.gif Ser showed losses in catalytic efficiency of approximately 100-, 1000-, 10 6-, and 10-fold respectively when compared with the wildtype enzyme. These results correlate well with the functions predicted for each residue with the exception of the histidine. The structure of the ALR2 holoenzyme showed that the catalytic site was situated atop the nicotinamide moiety of the NADPH cofactor. The substrate binding site, which would determine the enzyme's specificity and also presumably bind inhibitors, appeared to be composed of a deep cleft (Figures 3 and 4). It extended away from the catalytic site towards the loop composed of residues between β4 and α4 and the last 20 residues of the carboxy-terminal meander. This hypothesis was supported by the appearance of poorly resolved density that occupied this region, which suggested the presence of an endogenously bound substrate or inhibitor in the structure of the holoenzyme [16]. Subsequent studies indicate that this electron density may be a citrate molecule, one of the components included in the crystallization mixture. Activity studies indicate that citrate is indeed one of the many inhibitors of the enzyme with a K i in the millimolar range [23]. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_234.html [4/5/2004 5:08:18 PM]
Document Figure 4 Surface representation of the ALR2 holoenzyme in an orientation similar to Figure 3. The nicotinamide moiety that defines the active site of the enzyme is seen in the center. The groove that extends down from it is highly hydrophobic and was initially assumed to be the inhibitor binding site. Figure prepared using the GRASP program [49]. IV. Aldose Reductase Complexed with Inhibitor Page 235 While a large number of high-potency inhibitors for ALR2 have been developed [4], a structural understanding of the exact molecular features that foster this affinity have been only vaguely understood. Several general chemical motifs such as hydrophobic ring systems, a spirohydrantoin group or carboxylate group are seen repeatedly when examining a list of known inhibitors (Figure 2) but little was known about the specific role for each in inhibitor binding. The structure of the ALR2/NADPH/zopolrestat ternary complex [18] has provided some answers about the mode of binding of zopolrestat (Figure 2), a high-affinity, carboxylate-containing compound developed by Pfizer, Inc. [13]. While the overall structure was preserved, the inhibitor binding induced a conformational change of the enzyme. This change, which involved the movement of several loops in the active site of the molecule, was large enough to cause a change in crystal packing relative to the holoenzyme. As a consequence of the shifting of the active-site loops, a cavity is created inside the protein in which the benzothiazole ring is seated and the groove that was implicated in substrate and inhibitor binding by the holoenzyme structure vanishes. This illustrates the unpredictability of conformational changes within a protein in response to substrate or inhibitor binding. It also implies that modeling compounds http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_235.html [4/5/2004 5:08:24 PM]
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Document 2 Structural Studies of HI
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Document dine) and didanosine (dide
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Document Page 108 mulate during tre
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Document 4 Bradykinin Receptor Anta
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Document We determined the structur
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Document D ddI, 152 tumour necrosis
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Document antistasin peptides, 281 c
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