Transition-state analogue

Nebularine. Nebularine(44) is a naturaHy occurring purine riboside isolated from S.jokosukanensis (1,3,4). It is phosphorylated, and inhibits purine biosynthesis and RNA synthesis, but is not incorporated into RNA by E. coli RNA polymerase. It has also found appHcation as a transition state analogue for treatment of schistosomiasis and as a substrate for the restriction endonuclease, Hindll (138—141). 

Ubenimex, [(2(3),3(R))-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine, was isolated as an inhibitor of aminopeptidases, on which it acts as a strong, reversible transition-state analogue inhibitor (293). Analogues of ubenimex have been made and some other aminopeptidase inhibitors, not all of them peptides, have been isolated from streptomycetes (294—296). 

Stmcture 8 (a charged form of (7) [124419-33-6J) represents a well designed transition-state analogue for dibydroorotase (21). 

The reaction is proposed to proceed from the anion (9) of A/-aminocatbonylaspattic acid [923-37-5] to dehydrooranate (11) via the tetrahedral activated complex (10), which is a highly charged, unstable sp carbon species. In order to design a stable transition-state analogue, the carboxylic acid in dihydrooronate (hexahydro-2,6-dioxo-4-pyrimidinecarboxylic acid) [6202-10-4] was substituted with boronic acid the result is a competitive inhibitor of dibydroorotase witb a iC value of 5 ]lM. Its inhibitory function is supposedly due to tbe formation of tbe charged, but stable, tetrabedral transition-state intermediate (8) at tbe active site of tbe enzyme. 

A Tropsha, J Hermans. Application of free energy simulations to the binding of a transition-state-analogue inhibitor to HIV protease. Protein Eng 51 29-34, 1992. 

Rittinger, K., et al. Structure at 1.65 A of RhoA and its GTPase-activating protein in complex with a transition-state analogue. Nature 389 758-762, 1997. 

Lolis, E., and Petsko, G., 1990. Transition-state analogues in protein crystallography Probes of the structural source of enzyme catalysis. Annual Review of Biochemistry 59 597—630. 

Wolfenden, R., and Kati, W. M., 1991. Testing the limits of protein-ligand binding discrimination widi transition-state analogue inhibitors. Accounts of Chemical Research 24 209-215. 

Esler,W. P.,Kimberly,W.T.,Ostaszewski,B. L. etal.Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nature Cell Biol. 2 428-434,2000. 

Farrington, G.K., Kumar, A., and Wedler, F.C., Design and synthesis of new transition-state analogue inhibitors of aspartate transcarbamylase, /. Med. Chem., 28, 1668, 1985. 

K D. Coffins, G. R. Stark, Aspartate Transcarbamylase Interadion With the Transition State Analogue N-(Phosphonacetyl)-L-Aspartate , J. Biol. Chem. 1971,246, 6599-6605. 

Design of Reaction Intermediate and Transition-State Analogue for a Target... 

DESIGN OF REACTION INTERMEDIATE AND TRANSITION-STATE ANALOGUE FOR A TARGET REACTION ON OXIDE SURFACES... 

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 ... 

As mentioned in the Introduction, various authors have been influenced (directly or indirectly) by the Kurz approach in their discussions of enzyme behaviour (e.g. Wolfenden, 1972 Lienhard, 1973 Jencks, 1975 Schowen, 1978 Fersht, 1985 Kraut, 1988 Wolfenden and Kati, 1991). Also, as noted earlier, the concepts of transition state binding and stabilization were crucial to the development of transition state analogues as enzyme inhibitors and hence as chemotherapeutic agents (Jencks, 1969 Wolfenden, 1972 Wolfenden and Frick, 1987 Wolfenden and Kati, 1991). 

---