Hydrolysis associative pathway

The pathway of exchangeable-site GTP hydrolysis associated with bovine brain microtubule polymerization was... 

Mg2+ is associated with a large number of enzymes involving the hydrolysis and transfer of phosphates. The MgATP complex serves as the substrate in many cases. As noted in Section 62.1.2.2.2, the interaction of Mg2+ with the ATP enhances the transfer (to a substrate or water) of the terminal phosphoryl group. The results of many studies with model compounds lead to the postulate of an SN2 mechanism for this reaction.125 Associative pathways allow greater control of the stereochemistry of the substitution, and the rates of such processes are accelerated more effectively by metal ions. 

Kinetic data indicate that the hydrolysis of 5-2,4-dinitrophenyl 4,-hydroxythioben-zoate (61) in mild alkaline solutions (pH 8-11) most likely follows a dissociative, ElcB pathway, through a p-oxoketene intermediate, whereas at higher pH values an associative mechanism carries the reaction flux (Scheme 18). LFER relationships obtained from a kinetic study on the alkaline hydrolyses of substituted 5-aryl 4 -hydroxythiobenzoates seem to suggest that the associative pathway is a concerted, one-step process, rather than the classical mechanism via a tetrahedral intermediate.51... 

In contrast to the speciation work there have only been a modest number of reports on kinetic and mechanistic details. The formation of Zn" complexes of GSH proceeds by two pH-dependent mechanisms involving coordination at the thiol group, although no thiol involvement is apparent in Ni" complex formation. Different behaviom is found again with MeHg", which binds to GSH by an associative pathway. The Cu"-GSH system is further complicated by the observation that the disulfide hydrolysis in alkaline solution is accelerated by Cu" ions (equations 3-5). 

Hydrolysis of phosphate monoesters may proceed by either the associative or dissociative pathway depending on the type of phosphate ester (including the pK values of stepwise deprotonation of the phosphate ester), the properties of the leaving group and the pH of the solution. The neutral diprotonated form of the phosphate monoesters (and other neutral phosphoramidates and polyphosphates) appears to react via the associative pathway, while the mono-and di-anionic forms react solely by the dissociative pathway (Shen and Morgan, 1973 Wijesekera, 1992). 

The reaction of cycloheptaamylose with diaryl carbonates and with diaryl methylphosphonates provides a system in which a carboxylic acid derivative can be directly compared with a structurally analogous organo-phosphorus compound (Brass and Bender, 1972). The alkaline hydrolysis of these materials proceeds in twro steps, each of which is associated with the appearance of one mole of phenol (Scheme Y). The relative rates of the two steps, however, are reversed. Whereas the alkaline hydrolysis of carbonate diesters proceeds with the release of two moles of phenol in a first-order process (kh > fca), the hydrolysis of methylphosphonate diesters proceeds with the release of only one mole of phenol to produce a relatively stable aryl methylphosphonate intermediate (fca > kb), In contrast, kinetically identical pathways are observed for the reaction of cycloheptaamylose with these different substrates—in both cases, two moles of phenol are released in a first-order process.3 Maximal catalytic rate constants for the appearance of phenol are presented in Table XI. Unlike the reaction of cycloheptaamylose with m- and with p-nitrophenyl methylphosphonate discussed earlier, the reaction of cycloheptaamylose with diaryl methylphosphonates... 

Table IV also contains results of UV absorption studies of hydroxylation effects on the DNA intercalative binding of ben-zo[a]pyrene metabolites and metabolite model compounds. The most important feature of these results is that hydrolysis of BPDE to BPT causes a four-fold reduction in the intercalation association constant. Of all the BP derivatives studied, the tetrol has the lowest binding constant for intercalation. The small binding constant of the tetrol compared with BPDE, coupled with the DNA catalyzed hydrolysis of BPDE to the tetrol may provide a detoxification pathway for removal of a portion of unreacted intercalated BPDE.

Dopamine acts on G-protein-coupled receptors belonging to the D1 -family of receptors (so-called D1-like receptors , or DlLRs, comprised of Dl- and D5-receptors), and the D2-family of receptors ( D2-like receptors , or D2LRs comprised of D2-, D3- and D4-receptors). Dl LRs stimulate adenylate cyclase activity and, possibly, also phosphoinosit-ide hydrolysis, while D2LRs reduce adenylate cyclase activity. In the striatum, DlLRs are predominately associated with medium spiny neurons of the direct pathway, while D2LRs have been found as autoreceptors on dopaminergic terminals, as heteroreceptors on cholinergic interneurons, and on indirect pathway neurons. In the SNr, DlLRs are located on terminals of the direct pathway projection, while D2LRs appear to function as autoreceptors. 

Three different pathways are associated with the metabolism of disulfoton (I) oxidation of the thioether sulfur to produce sulfoxides and sulfones (2) oxidation of the thiono sulfur to produce the oxygen analogs and (3) hydrolysis of the P-S-C linkage to produce the corresponding phosphorothionate or phosphate (WHO 1976) (see Figure 2-3). These pathways have been elucidated from data obtained in humans exposed to disulfoton and from in vivo and in vitro metabolism studies in rats and mice. 

Many different pathways, mechanisms, and enzymes are associated with activation. These include dehalogenation, AT-nitrosation of secondary amines, epoxidation, conversion of phosphothionates to phosphate, metabolism of phen-oxyalkanoic acids, oxidation of thioethers, hydrolysis of esters and peroxides. The following is a summary. 

The metabolic fate of isoniazid and iproniazid, two isonicotinoylhydra-zides, has been extensively studied, and it has been shown that metabolic hydrolysis represents an important step in their toxification. Isoniazid (4.269) is employed as a first-line tuberculostatic drug, but prolonged therapy is associated in 1 -2% of patients with significant hepatotoxicity. Isoniazid can be metabolized by either of two primary pathways, hydrolysis and direct -acetylation. Isonicotinic acid (4.271), the product of hydrolysis, can be formed either di-... 

Furthermore, although the rates of addition and loss may differ at each end (i.e., the transition states for the individual association-dissociation reactions may depend on the polarity of protomer-polymer interactions), the initial state (protomer + MT ) and the final state (MT +i) are independent of the pathway for protomer addition. This result is true because addition or loss of a protomer at either end leads to structurally indistinguishable polymers. Thus, the energetics of the reactions at each end are the same, and Ki equals for the case of no nucleotide hydrolysis accompanying assembly. We may then reexpress the rate equations for protomer addition or loss to the two ends in the following manner ... 

A dissociative elimination-addition pathway has also been proposed to account for the kinetics of alkaline hydrolysis of 2,4-dinitrophenyl 4 -hydroxyphenylpropionitrile in 40% (v/v) dioxane-water, although participation of the associative Bac2 mechanism cannot be ruled out since it may be facilitated by the electronic effect of the triple bond. Formation of intermediate (15), having a conjugated and cumulated double-bond system, should favour the ElcB mechanism and thereby account for the contrasting entropies of activation found for hydrolysis of (14) and the corresponding 4 -methoxyphenylpropionate. 

The DAG produced by the hydrolysis of PIP2 by PLC remains in the plasma membrane where it activates a family of membrane-associated protein kinases collectively termed protein kinase C (PKC). Activated PKC produces a variety of cellular responses, including the regulation of protein synthesis and key metabolic pathways. 

To further probe this pathway, XBu,/, a cation too large to enter 1, was used to displace the ion associated iminium product. As with NMe4+, increasing the concentration of NBU4+ led to faster rates of hydrolysis with a first order dependence on [NBU4+]. With this information, the mechanistic model was proposed that incorporates an intermediate ion associated iminium cation complex (Scheme 7.4). 

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