Push-pull mechanisms

The HIV-1 protease, like other retroviral proteases, is a homodimeric aspartyl protease (see Fig. 1). The active site is formed at the dimer interface, with the two aspartic acids located at the base of the active site. The enzymatic mechanism is thought to be a classic acid-base catalysis involving a water molecule and what is called a push-pull mechanism. The water molecule is thought to transfer a proton to the dyad of the carboxyl groups of the aspartic acids, and then a proton from the dyad is transferred to the peptide bond that is being cleaved. In this mechanism, a tetrahedral intermediate transiently exists, which is nonconvalent and which is mimicked in most of the currently used FDA approved inhibitors. 

The mechanistic interpretation of the acid-catalyzed ring opening reaction of thiirane oxides is based on the push-pull mechanism with a transition state in which the bonded hydrogen atom plays a major role (see equation 59). 

Y Kiso, K Ukawa, T Akita. Efficient removal of /V-bcnzyloxycarbonyl group by a push-pull mechanism using thioanisole-trifluoroacetic acid, exemplified by a synthesis of Met-enkephalin. Chem Commun 101, 1980. 

This is an example of acid catalysis and the effect is to pull electrons away from the leaving group. Often both acid catalysis and nucleophilic attack are involved in enzyme-catalysed reactions in what are known as push-pull mechanisms. 

The cleavage of the 0-0 bond of the hydroperoxide is promoted by the push-pull mechanism shown in Fig. 4, in which the native HRP reacts with the unionized form of the hydroperoxide. Thus, the latter is converted into a much better nucleophile upon transfer of its proton to the distal basic group (His 42). 

The nature of the bonding in Zeise s anion and other r -olefin complexes is illustrated in Fig. 18.2. Without the push-pull mechanism, the 7r electrons of the olefin would have little or no tendency to allow themselves... 

The regiochemistry observed in the EGA-catalyzed displacement of methoxyl group with nucleophiles is promising For example, the carbenium ion formed from compound 29 in methanolic solution is trapped to produce the thermodynamically stable compound 30. However, in CHjClj, a concerted push-pull mechanism ( push by nucleophile and pull by EGA) is operative leading to the exclusive formation of 31. 1-Menthone 32 can be acetalized by EGA catalysis without epimerization at C-2... 

In the in-line push-pull mechanisms of Rabin and Roberts, the highest energy transition state may be either the pentacovalent intermediate or the alkoxide (hydroxide) state with 02 or 05" deprotonated but not bonded to P. Incipient deprotonation of 02 in an activated state is equivalent. Protonation of X or Y or nearby positive charge could stabilize the pentacovalent intermediate. Removal of either could facilitate formation of the alkoxide in the breakdown of the intermediate. Restoration of the initial state of the enzyme is required in this mechanism and could be rate limiting. In the adjacent (pseudorotation) models of Witzel, Hammes, Usher, or Wang protonation of X or Y would be required to allow one of the two pseudomers to exist. In step 1 this requirement (and thus perhaps a rate limiting process) applies to the attack by 02. Deprotonation would force or facilitate reversal or pseudorotation to... 

Quite fascinating compounds are the super-basic nitriles102. The cyanamides are the most basic nitriles presently known103,104. The high basicity of such compounds is explained by a so-called push-pull mechanism, described schematically by the resonance structures. 

In the 1950s, the push-pull mechanism whereby a proton is donated by one centre and received at another was considered as a major contributor to enzyme catalysis and to give rise to third-order terms in non-enzymic reactions. Third-order terms were observed in organic solvents but in water they are of minor importance because of the solvating power of this solvent for ions and polar centres. 

In enzymes, the active site may possess acid and base groups intimately associated with the conjugate base and acid functions, respectively, of the complexed substrate the push-pull mechanism is possible but might not be a driving force. The halogenation of acetone in the presence of aqueous solutions of carboxylic acid buffers exhibits the rate law of Equation 11.2 where the third-order term, although small, has been shown to be significant and due to bifunctional concerted acid-base catalysis (Scheme 11.13) ... 

Roberts, T. M., and Stewart, M. (2000). Acting like actin The dynamics of the nematode major sperm protein (MSP) cytoskeleton indicate a push-pull mechanism for amoeboid cell motility./ Cell Biol. 149, 7-12. 

Figure 3 Proposed difunctional or push-pull mechanism for diphenyl 4-nitrophenyl phosphate by Breslow s metallomicelle 5.

In homogeneous model systems, this mechanism is scarcely realized because of proton exchange simplicity between the donor and the acceptor. It proceeds without substrate and, therefore, the efficiency of the push-pull mechanism in solution is reduced. Moreover, both the donor and the acceptor of protons are usually located far from the places required for proton transfer in solutions. This hinders the required alignment of reacting molecules being achieved. 

While cationic ring opening of halocyclopropanes can be induced under strictly thermal conditions, it is most often performed in the presence of a Lewis acid.8 The Lewis acids commonly used in these reactions are silver(I) salts due the inherent halophilicity of the silver cation. The silver(I)-mediated reactions can be carried out at lower temperatures due to activation of the departing halide by coordination to silver in what has been described as a highly concerted push-pull mechanism.13 Under these conditions the halide-substituted carbon atom bears slightly increased positive character, which enables the cationic ring opening to proceed under mild conditions (Fig. 4.4). 

In mildly basic conditions (pyridine), a methylene group in the 2-position may react with aromatic aldehydes to give a 2-styryl-l,6,6aA4-trithiapentalene (7lAHC(l3)161, p. 194). As the trithiapentalene system is not affected in this case, it is likely that a free carbanion is not the intermediate and that a push-pull mechanism is involved. 

Furthermore, the latter reaction may involve a push-pull mechanism which could make the separated ion pair more reactive even than the free ion. It seems, indeed, that E8 < E, but the entropy of activation is more negative for the separated ion pair than for the free —S" ion. 

The catalyst diagnostician can justifiably inquire if the carbonium ion participation and migration by some push-pull mechanism is the only mechanism on which catalyst construction can be based, or do we have some alternatives. Up to the present no alternatives have been published, however, the relatively simple mechanism described above, can be modified in that the initial reaction of carbonium ion formation can be also looked upon as a two step process, whereby a paraffin is first dehydrogenated and the resulting olefin promptly forms a carbonium ion. The overall result is the same. 

Fig. 10.5. Push-pull mechanism for Compound I formation in peroxidases (adapted from [12] and [63]). Distal residues (Arg and His) work together to cleave the 0-0 bond, while proximal residues (His and Asp) assist by supplying electron density.

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