Circe-effect

Jencks, W.P. Binding energy, specificity, and enzymatic catalysis the Circe effect. Adv. Enzymol. 43 219-410, 1975. 

Some enzymes are so fast and so selective that their k2/Km ratio approaches the molecular diffusion rates (108-109m s-1). Such enzymes are called kinetically perfect [21]. With these enzymes, the reaction rate is diffusion controlled, and every collision is an effective one. However, since the active site is very small compared to the entire enzyme, there must be some extra forces which draw the substrate to the active sites (otherwise, there would be many fruitless collisions). The work of these forces was dubbed by William Jencks in 1975 as the Circe effect [22], after the mythological sorceress of the island of Aeaea, who lured Odysseus men to a feast and then turned them into pigs [23,24]. 

Toney, M.D. and Kirsch, J.F. (1993) Lysine 258 in aspartate aminotransferase enforcer of the Circe effect for amino acid substrates and the general-base catalyst for the 1,3-prototropic shift. Biochemistry, 32, 1471. 

Warshel, A., Florian, J., Strajbl, M. and Villa, J. (2001) Circe effect versus enzyme preorganization what can be learned from the structure of the most proficient enzyme ChemBioChem, 2, 109. 

This proposal of a ground state destabilization mechanism for ODCase (this type of mechanism was referred to earlier by Fersht as electrostatic stress 81 and by Jencks as the Circe effect ) sparked considerable controversy. In some circles it was seen as a prime example of the catalytic power of ground state destabilization,83 but several groups immediately questioned its validity on the basis of theoretical objections and apparent inconsistencies with biochemical experiments.23 26... 

Binding of substrate(s) to an enzyme has two important effects, (i) The substrate is positioned or oriented properly for reaction, both with respect to functional groups in the active site and to other substrates, (ii) In cases where more than one substrate is involved (e.g. A + B C + DorA + B=f C), the enzyme can assemble or collect the substrates from solution and place them in close proximity. Studies on cleverly-designed synthetic systems have clearly demonstrated that proximity effects alone can result in tremendous rate enhancements, as shown in Figure 4.70 for selected systems. Formation of an eirzyme-substrate complex is, however, entropically unfavourable (AS < 0) and therefore costs energy. Typically, enzymes use the favourable enthalpic change (AH < 0) of substrate binding to overcome the unfavourable entropic term and to place the substrate in au environment in which it can be transformed, a phenomenon sometimes referred to as the "Circe effect" [66]. 

The idea that polysaccharide-polysaccharidase interaction could be treated simply as the sum of the interactions of various subsites is intuitively attractive. Hiromi first tackled the algebra, but made the assumption, now known to be implausible, that the microscopic rate constant for bond cleavage in the ES complex was independent of subsite occupancy. This is very unlikely for enzymes in general terms, since it is now accepted that they exploit interactions with the substrate remote from the site of bond cleavage to lower the free energy for the catalysed reaction (the Circe effect, Section 5.4.5.3). The Hiromi assumption was shown to be incorrect by direct experiments with an endoxylanase. A better fit to experimental data was obtained if the subsite affinities were calculated for the first irreversible transition state i.e. on kcat/A)n and cleavage patterns of oligosaccharides), but careful analysis in some systems indicated that even this approximation failed. ... 

The fecat/J M ratios of the enzymes superoxide dismutase, acetylcholinesterase, and triosephosphate isomerase are between 10 and lO" s Enzymes such as these that have fecat/ M ratios at the upper limits have attained kinetic perfection. Their catalytic velocity is restricted only by the rate at which they encounter substrate in the solution (Table 8.8). Any further gain in catalytic rate can come only by decreasing the time for diffusion. Remember that the active site is only a small part of the total enzyme structure. Yet, for catalytically perfect enzymes, every encounter between enzyme and substrate is productive. In these cases, there may be attractive electrostatic forces on the enzyme that entice the substrate to the active site. These forces are sometimes referred to poetically as Circe effects. 

Fersht, A. R., Leatherbarrow, R. J., and Wells, T. N. C., 1986. Binding energy and catalysis A lesson from protein engineering of the tyrosyl-tRNA synthetase. Trends Biochem. Sd. 11 321-325. Jencks, W. P., 1975. Binding energy, specificity, and enzymic catalysis The Circe effect. Adv. Enzymol. 43 219-410. 

Hur and Bruice carried out classical molecular dynamics on the complex of ODCase with OMP before decarboxylation, as well as the putative intermediate (the C6 anion) formed by decarboxylation [39]. Based on these calculations, it was proposed that loop movement in ODCase may play a key role in catalysis a stable p hairpin structure appeared to form during decarboxylation that was not present before decarboxylation. In addition, the structure of OMP in aqueous solution was also simulated, and the similarity of the conformations of OMP in water and in the ODCase active site suggested that OMP is not bound in a particularly strained fashion, further arguing against a Circe effect. 

This phenomenon is denoted as electrostatic catalysis and was coined as Circe-effect by WP Jencks. 

Jencks WP (1975) Binding energy, specificity, and enzymic catalysis the circe effect. Adv Enzymol Relat Areas Mol Biol 43 219 10... 

Gas phase analogy Torsional strain Circe effect... 

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