Phosphonate transition state

An example of esterase behaviour is provided by a catalytic antibody developed by Tramontano et al. (1988), using a phosphonate transition state analogue [53] as the hapten. The antibody cleaves the carboxylic ester [54, R = Me] with enzyme-like efficiency (kc/ku = 6.25 X 106 = 1.5 mM ... 

Selection with transition-state analogues has also been used to extract catalytic antibodies from libraries of phage-antibodies. McCafFerty et al. [52] have shown that antibodies with nanomolar affinities for a phosphonate transition-state analogue could easily be extracted from a library derived from immunized mice. 

Applications of enzymes in preparative chemistry is largely dominated by kinetic resolutions using esterases and lipases. Due to the ease of preparation of esterase catalytic antibodies from immunization with phosphonate transition state analogs, these represent the vast majority of catalytic antibodies prepared to date, even if it is not yet clear whether they will be competitive with currently available enzymes. 

An analysis of phosphonamidate and phosphonate transition-state analogs for the thermolysin reaction was reported (95, 96) and the data were interpreted to suggest that one hydrogen bond could contribute 4 kcal/mol binding to stabilize the formation of the tetrahedral transition state. A reevaluation was re-... 

E.C. Sherer, G.M. Turner, T.N. Lively, D.W. Landry, and G.C. Shields, A semiempirical transition state structure for the first step in the alkaline hydrolysis of cocaine. Comparison between the transition state structure, the phosphonate monoester transition state analog, and a newly designed thio-phosphonate transition state analog, J. Mol. Modeling 24 (1996), pp. 62-69. 

Scanlan and coworkers reported the generation and characterization of an unusually active catalytic antibody, 17E8.249 jj raised against a phosphonate transition state analog (Figure 14) of norleucine and mediates the hydrolysis of unactivated norleucine and methionine phenyl esters. Subsequently, the structure of the antibody Fab fragment complexed with the transition state analog was solved at 2.5 A resolution. ... 

These mutants provided a unique opportunity for us to examine whether phosphonate transition state similarity extends beyond simple geometric considerations. We posed the question how will mutation at position 127 affect inhibitor binding A correlation between log(Kj) and log(Km/kcat) across a series of proteins would show whether the phosphorus oxyanion, the part of the inhibitor that interacts with the 127-side chain, and the carbonyl oxygen in the transition state respond similarly to... 

A phosphonate transition-state analogue (218) for phe-gly hydrolysis was successfully employed to generate catalytic antibodies that showed moderate rate accelerations (10 -10 ) however, the uncharged methyl phosphonamidate (219) failed to generate any catalytic activity. ... 

Figure 9.7 (a) Schematic illustration of the application of dynamic covalent capture for catalyst discovery (b) target reaction (c) selected functional group by the phosphonate transition state analog and (d) positioning of the selected group near the target bond. 

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