Secondary Amide Peptide Bond Cis-Trans Isomerases

Many mitotic proteins, transcription factors, and RNA processing proteins, apoptotic proteins, the tumor suppressor p53 and p73 as well as the cytoskeleton protein tau have been shown to be functionally linked to Pinl catalysis in cells [147]. 

on the other hand, has some specificity for arginine preceding the proline residue [139]. This enzyme seems to localize to the nucleus and the N-termi-nal extension of the catalytic domain might mediate interactions with the pre-ribo-somal nucleoprotein complex [148]. 

Secondary Amide Peptide Bond Cis-Trans Isomerases 

The dynamics of CTI demonstrate the fundamental similarity between prolyl bonds and secondary amide peptide bonds, making it probable that enzymes exist for the rate acceleration of both types of reactions. The relatively low spontaneous rates indicate the potential importance of CTI of secondary amide peptide bonds as rate-limiting step in protein backbone rearrangements preceding the formation of biologically active proteins. 

Whereas peptidyl prolyl cis-trans isomerases constitute a well-characterized enzyme class comprising well over 1000 members with small sequence variations in the proteins of different species, the discovery of secondary amide peptide bond cis-trans isomerases (APIases) had to await the development of suitable enzyme assays. Fortunately, spectral differences in the UV region between cis and trans isomers of dipeptides could be exploited to identify and quantify isomerization rate-enhancing factors in biological material [149]. 

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There is evidence that the trigger factor and the hsp70 chaperone DnaK, a PPIase and a secondary amide peptide bond cis-trans isomerase (APIase) respectively, contribute to the formation of native proteins by apparently overlapping functions with the trigger factor as the primary interaction partner of the emerging polypeptide chain [122-124]. Consequently, synthetic lethality was observed... 

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The design of selective and potent inhibitors of PPIases is of interest and numerous molecules have been designed or selected from chemical libraries with a view to curing these major diseases. The study of Pinl, which is clearly distinct from other members of the PPIase family on the basis of structure, binding site, catalytic mechanism, and biological implications, has opened up new perspectives in the biological chemistry of PPIases. The recent discoveries of the secondary amide peptide bond cis-trans isomerase (APIase) DnaK [209] and of a novel class of FK506 and cyclosporine-sensitive PPIase [210] are also major advances in this field. 

Beyond protein folding, the discovery of peptidyl prolyl isomerases (PPIases) and related proteins has opened the way to novel concepts in biology the notion of chaperone-assisted receptor binding is an emerging field of research which sheds light on receptor function and protein-protein interactions. The recent discovery of a secondary amide peptide bond cis-trans isomerase (APIase) heralds new advances in this field. 

Thrl67 bond in the cis Prol67Thr TEM-1 /J-lactamase variant is also characterized by a rate constant between 1 x 10-3 s-1 and 4 x 10 3 s-1 for the trans to cis interconversion [26]. Therefore the trans to cis isomerization can be rate-limiting in protein folding under native-like conditions, as was shown for a proline-free variant of the a-amylase inhibitor tendamistat [27]. This seems to be proven in the discovery of a novel protein dass, the secondary amide peptide cis/trans isomerases (APIases), which can accelerate interconversion of these peptide bonds conformers [28],... 

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