Oxyanion geometry

Table 3.36. Geometries and NBO/NRT descriptors of common oxyanions XOmn (see Fig. 3.91), showing symmetry, bond length Rxo, NRT bond order bxo and central-atom valency Vx, atomic charges Qx and Qo, and d-orbital occupancy dx for representative first- and second-row species...

The importance of oxyanion holes in enzymes was first discovered in chymot-rypsin by David Blow and co-workers and in subtihsin by Jo Kraut and co-workers [39]. In these enzymes, a tetrahedral intermediate is generated after nucleophilic attack of a deprotonated serine side chain on the peptide carbonyl group. It was recognized from the begirming that the geometry of the active site complexes was possibly better complementary to the tetrahedral intermediate than to the planar peptide substrate [40]. 

Table 4.3 The oxyanion hole geometry for selected tetrahedral intermediates and enolate intermediates. 

The oxyanion hole geometry of three complexes is visuahzed in Figures 4.2. 4. Figure 4.2 displays the active site of trypsin complexed with a peptide inhibitor [41]. In Figure 4.3, the active site of chymotrypsin complexed with a neutral aldehyde adduct is displayed [43], and in Figure 4.4, cutinase (a lipase) with a covalently bound phosphate, a transition state analog is depicted [63]. 

Figure 4.2 Structure of the oxyanion hole of the active site of trypsin, complexed with a peptide inhibitor (PDB IPPE). The hydrogen atoms (in white) are only included when relevant for the hydrogen bonding geometry of the oxyanion hole. The dotted lines highlight the key interactions in the oxyanion hole.

Three factors constrain the role of oxyanions as ligands (a) their size (Table 2) s (b) their relatively rigid geometry (trigonal planar, pyramidal, tetrahedral or octahedral) 5 and (c) their weak donor properties9"11 relative to nitrogen donors and especially relative to that of water. 

Phosphonates (Fig. 8) and sulfonates represent a third class of covalent irreversible inhibitors. These inhibitors adopt a stable tetrahedral geometry and are covalently bound transition-state analogs. They often have a peptide-like specificity element, and the electrophilicity of the leaving groups can be modified to mne the reactivity of the inhibitor. These inhibitors are specific for serine proteases, because the serine protease active site has a well-defined oxyanion hole, which stabilizes the transition-state mimic. 

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