Enzyme transition state analog

Although this comparison of reaction coordinate diagrams provides an intuitive argument for the synthesis of transition state analog enzyme inhibitors, in a quantitative sense it is applicable only to unimolecular S -> P... 

Wolfenden, R. Transition state analogs and enzyme catalysis. Ann. Rev. Biophys. Bioeng. 1976, 5, 271-306. 

TRANSITION-STATE ANALOGS are stable molecules that are designed to look more like the transition state than like the substrate or product. Transition-state analogs usually bind to the enzyme they re designed to inhibit much more tightly (by 1000-fold or more) than the substrate does. 

Different oxidation states of sulfur have also been explored, particularly sulf-ones and sulfonamides as transition state analogs of lysine deacetylation, but without much success. The monodentate SAHA-like methyl sulfoxide 7 proved most potent, but still with an enzyme IC50 of only 48 pM and indications of HDAC/TDAC selectivity in cellular assays [28]. 

Keywords Catalysis a Enzyme a Transition State Analog a RNA Catalysis a DNA catalysis a Catalytic Antibodies... 

The transition state analog (TSA) approach1651 which has proved so successful in the design of enzyme inhibitors and catalytic antibodies lends itself nicely, at least in principle, to the molecular imprinting of polymers. Polymerization carried out in the presence of the TSA, or with the TSA covalently but readily reversibly bound to a monomer, produces a polymer with a number of embedded TSA molecules. If these can be removed under rea-... 

Concept A new approach to the rational design of enzyme inhibitors has emerged in the last ten to fifteen years that incorporates a substrate (or transition state) analog "core" molecule with additional binding determinants spanning beyond the immediate... 

Interestingly, although many transition state analogs bind noncovalently to the target enzyme s active site via a one-step kinetic mechanism (Scheme la) and would therefore be expected to exhibit no time-dependent properties of inhibition, inhibitors with Kj values of < 10 10 M (like coformy-cin) usually have a slow onset of inhibition kobserved < 10 2 s 1 (i.e., an approach to equilibrium inhibition of > 1 min).161 This is merely an assay artifact due to... 

Bartlett has derived a method181 for proving that a putative transition state analog exerts its inhibitory power from successfully mimicking the transition state. If a series of structurally-related inhibitors (all containing the identical core chemical structure meant to simulate the transition state) bind to the target enzyme with log (fQ) values that linearly correlate (slope = 1) with the log (KMlkcai) values of the same series of structurally-related substrates, then... 

This analysis reveals that enzymes bind the transition state more tightly than the ground state by a factor approximately equal to the rate of acceleration (ie, Kjs/Ks kuncaJkcat)- This method has been used to show, for example, that the peptide phos-phonate inhibitors of carboxypeptidase A are true transition state analogs. 

R. H. Abeles, Enzyme Inhibitors Ground State/ Transition-State Analogs , Drug, Dev. Res. 1987, 10, 221-234. 

Popovitz-Biro, R. Chang, H. C. Tang, C. P. Shochet, N. Lahav, M. Leiserowitz, L. In Chemical Approaches to Understanding Enzyme Catalysis Biomimetic Chemistry and Transition-State Analogs Green, B. S. Ashani, Y. Chipman, D., Eds. Elsevier Amsterdam, 1982, pp. 88-105. 

In our context, an important class of reversible inhibitors are the transition state analogs [18], which are stable compounds designed to mimic the structure of an intermediate in the path of substrate s transformation by the enzyme. Such analogs are based in Pauling s postulate [19], which states that "an enzyme recognises and binds more tightly to the transition state than to the ground state of the substrate". 

Inhibition of enzymatic reactions by transition state analogs has been an extremely important approach for drug design [20], the principle underlying this is that "nature has developed enzymes for binding efficiently to the transition states of the reactions they catalyse". 

Chemical Approaches to Understanding Enzyme Catalysis Biomimetic Chemistry and Transition-State Analogs edited by B.S. Green, Y. Ashani and D.Chipman... 

The preceding summary and Fig. 20 present a frame-by-frame account of the pathway for ribonuclease catalysis, based predominandy on knowledge of the structures of the various intermediates and transition states involved. The ability to carry out such a study is dependent on three critical features (1) crystals of the enzyme which diffract sufficiently well to permit structural resolution to at least 2 A (2) compatibility of the enzyme, its crystals, and its catalytic kinetic parameters with cryoenzymology so as to permit the accumulation and stabilization of enzyme-substrate complexes and intermediates at subzero temperatures in fluid cryosolvents with crystalline enzyme and (3) the availability of suitable transition state analogs to mimic the actual transition states which are, of course, inaccessible due to their very short lifetimes. The results from this investigation demonstrate that this approach is feasible and can provide unparalleled information about an enzyme at work. 

Also a new family of inhibitors exemplified by SUAM 1221 65 [75] has been described in which a pyrrolidinylcarbonyl function at the PI site is the crucial entity for enzyme recognition, giving rise to the transition state analog of the enzyme-substrate interaction. 

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