Complementarity of substrate

Both in nature and in test tubes many complicated reactions take place with apparent ease. Highly specific enzymatic reactions involving complementarity of substrate and receptor both with respect to their spatial structure and electrostatic fields lie outside the scope of this book. Here we would like only to mention a few... 

Once the protein interaction pattern is translated from Cartesian coordinates into distances from the reactive center of the enzyme and the structure of the ligand has been described with similar fingerprints, both sets of descriptors can be compared [25]. The hydrophobic complementarity, the complementarity of charges and H-bonds for the protein and the substrates are all computed using Carbo similarity indices [26]. The prediction of the site of metabolism (either in CYP or in UGT) is based on the hypothesis that the distance between the reactive center on the protein (iron atom in the heme group or the phosphorous atom in UDP) and the interaction points in the protein cavity (GRID-MIF) should correlate to the distance between the reactive center of the molecule (i.e. positions of hydrogen atoms and heteroatoms) and the position of the different atom types in the molecule [27]. 

Obviously, strong binding of the substrate to the catalyst may distort the structure of S towards that of TS, thereby making reaction easier. However, such distortion simply reflects the complementarity of the catalyst and the transition state (Fersht, 1985). From a purely thermodynamic point of view, the formation of a strong S-catalyst complex lowers free energy by an additional amount that must be overcome in the process of activation of the kc process (3) (Fig. 2). Living organisms and their enzymes have evolved so... 

Figure 3/ for example/ places the lanosterol so as the 3f hydroxyl polar group lies over the propionate side chains. To reduce the complexity of this picture one can now replace the lanosterol structure by a surface canopy to represent the extent of the hydrophobic substrate binding site. There is also the facility to code this surface to signify the electronic properties of the substrates such as their electron density/ electrostatic potential/ or HOMO/LUMO values. Theoretical work of this type is currently suggesting quite remarkable complementarity of electron properties between bound substrates and protein binding sites. (10). 

The original concept offered to explain why enzymes exhibit such a high degree of substrate specificity. The active site of an enzyme was viewed as a topological template for a particular reactant hence, there is an enzyme-substrate complementarity . See Induced-Fit Model Ligand-Induced Conformational Change E. Fischer (1894) Ber. 27, 2985. 

A new model for enzyme catalysis that challenges the long-standing concept of transition state complementarity as the sole source of enzymatic catalytic efficacy. This shifting model states that (a) enzymes evolved to bind substrates (b) enzyme-substrate complexes have evolved to bind transition states and (c) stronger interactions of substrate with the enzyme facilitate rapid conversion to product. This model questions the concept that strong interactions of enzyme and substrate reduce catalytic efficiency. 

C relaxation experiments are useful in studying the molecular motions of crown ethers and cryptands. Uncomplexed dibenzo[18]crown-6 shows a segmental mobility which disappears on complexation. Similarly, alkyldiammonium salts have shorter relaxation times when complexed by large cylindrical cryptands (Figure 15). The dynamic coupling of the molecular motions of substrate and receptor increases with their structural complementarity in the complex (81CC833). 

Although enzyme-transition state complementarity maximizes kcJKM, this is not a sufficient criterion for the maximization of the overall reaction rate. The reason is that the maximum reaction rate for a particular concentration of substrate depends on the individual values of cat and KM. It can be seen in Table 12.3, where some rates are calculated for various values of kcaX and KM (subject to kc.JKM being kept constant), that maximum rates are obtained for KM greater... 

Building on an idea of Haldane (Chapter 5) advanced in the 1920s, in 1944 Pauling and Pressmann formulated the hypothesis of complementarity of the catalyst with the transition state of a reaction. Until then it was assumed that the ground state of a substrate was bound most tightly to the enzyme molecule. 

Dietrich, B., Guilhem, J., Lehn, J.-M., Pascard, C., Sonveaux, E., 11. Molecular recognition in anion coordination chemistry. Structure, binding constants and receptor-substrate complementarity of a series of anion cryptates of a macrobicyclic receptor molecule. Helv. Chlm. Acta 1984, 67, 91-104. 

Recently, pharmacophores have been defined from homology models of CYP isoforms in the ALMOND program (Pastor et al., 2000). This method is based on an assessment of complementarity between binding properties of substrates and the enzymic binding sites. It assumes that within the enzyme-substrate complex, the site of reaction in the enzyme (the reactive oxygen atom) coincides... 

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