Dissociative transition state

The aqueous methanolysis of 3,4-dihydro-27f-pyrano[3,2-(r]pyridinium a-D-A -acetylneuraminoate has been studied and is believed to proceed via dissociative transition states with no intramolecular nucleophilic participation by the anomeric carboxylate group <2004JP0478>. The synthesis of the starting substituted sugar is also reported. 

However, it has been suggested that a-deuterium isotope effects of 1 23 must involve a more dissociated transition state, and rate-... 

Peptide substrate then docJcs onto the protein kinase, in general presumably occupying a cleft along the C-terminal lobe, as exemplified by the peptide inhibitor in the PKA-AMPPNP-PKI and IRK-ATP structures. Catalysis appears to be via a dissociative transition state mecdianism and a planar phosphate intermediate [20, 22]. The incoming peptide hydroxyl is oriented via Asp-127, which is in turn further stabilized via a hydrogen bond to Asn-132. These latter two residues that... 

The crystal structures of 9 (R = CH3) and 10 (R = CH3) bound to MTAN at 2.2 A resolution revealed a new ion pair between the positive charge on the ring and the nucleophilic water (hydroxide ion) (58). Based on the distances of these interacting atoms, 9 (R = CH3) appears to be a mimic of an early transition state, and 10 (R = CH3) mimics a highly dissociated transition state, for the MTAN-catalyzed reaction. 

M-OH2 bond to reach a dissociative transition state is much smaller than would be the case for the ground-state labilisation arising from the effect of the presence of the Cp moiety. Taken together these factors do not permit the exclusion of a limiting D mechanism. The volume profiles for reactions of chloride ion, bromide ion, 4-cyanopyridine (py-CN) and nicotinamide (py-nia) with Cp Rh(H20)2+ are displayed in Fig. 14. 

The results summarized in Table III suggest that the enzymes that catalyze phosphoryl transfer via an inversion of configuration do so with an in-line transfer in a sequential mechanism. The mechanistic pathway is prevalent in the phosphokinases. Although this information does not provide direct evidence for an associative or Sn2 mechanism in contrast to a dissociative mechanism, if the latter process does occur then there is insufficient room at the catalytic site for the metaphosphate to rotate or dissociate and to cause racemization. The observation of a secondary 0 isotope effect less than 1.00 indicates that a dissociative transition state occurs with yeast hexokinase (57). The enzymes that demonstrate retention of configuration do so via double-displacement reactions. Mutases exclusively use this mechanistic pathway. 

Fig. 7.2-13 Synthetic scheme for the generation of a protein kinase A selective bisubstrate analog inhibitor based on a dissociative transition state.

An effort is underway in our laboratory to determine transition state structures for phosphoryl transfer reactions by the use of secondary 0 isotope effects measured by the remote label method. The hypothesis is that an associative mechanism would have single bonds from phosphorus to the nonbridge oxygens in the transition state, whereas a dissociative mechanism would have enhanced bond order. So far we have determined the secondary 0 isotope effects on glucose-6-P hydrolysis at pH 4.5, 100°C (112), and by alkaline phosphatase (128). The chemical hydrolysis showed no isotope effect on P-O bond cleavage, which is consistent with a largely dissociative transition state without total conservation of bond order to phosphorus (i.e., a partial positive change exists on phosphorus). 

A further study by Ramirez et al. (1982) also utilized the effect of solvent and ionic state in controlling reactivity patterns. A number of reactions, including the decomposition and nucleophilic substitution processes of p-nitrophenyl phosphate in acetonitrile, were examined. In the absence of added nucleophiles cyclic trimetaphosphate is produced. Both t-butyl alcohol and phenol are phosphorylated under these conditions. A nonaqueous solvent of low polarity should be better than water in promoting the conversion of the highly ionic product to the less polar transition state that would produce metaphosphate. The low steric sensitivity of the reaction and the increased rate of the dianion relative to the monoanion are consistent with either any extended associative transition state or the dissociative transition state. Stereochemical studies of these reactions by Knowles... 

Correction for the isotope effect on deprotonation (which is the subject of another study) gives a net isotope effect for cleavage of the P—O bridge of 1.0004 for three substitutions. This is interpreted as supporting a dissociative transition state based on comparison of calculated models. 

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