Catalytic mechanism secondary structures

There is also great similarity between aspartic proteinases in terms of interactions with the transition-state analog inhibitors at the catalytic center. The catalytic aspartyl side chains and the inhibitor hydroxyl group are essentially superimposable in both renin complexes. The isostere C-OH bonds lie at identical positions when the structures of inhibitor complexes of several aspartic proteinases are superposed, in spite of the differences in the sequence and secondary structure. Most of the complex array of hydrogen bonds found in endothiapepsin complexes are formed in renin with the exception of that to the threonine or serine at 218, which is replaced by alanine in human renin. The similarity can be extended to all other pepsin-like aspartic proteinases and even to the retroviral proteinases [44,45]. This implies that the recognition of the transition state is conserved in evolution, and the mechanisms of this divergent group of proteinases must be very similar. 

RNA is chemically very similar to DNA but differs in important ways. The sugar miit is ribose with an added hydroxyl group at the 2 position, and the methylated pyrim-idine uracil (U) replaces thymine. RNA exists in various functional forms but typically as a single-stranded polymer that is much shorter than DNA and that has an irregular three-dimensional structure. Research from recent years has revealed that RNA conformations are not random structures and the folding mechanism of RNA molecules is complex. The secondary structure adopted by an RNA molecule is to a large extent related to its nucleotide sequence. The secondary structure for particular RNA sequences can be as regular as the secondary structure of a protein. It is now known that RNA molecules can further interact to form complex tertiary structures, which are intimately related to novel functions of RNA, such as the catalytic activity of ribozymes, ... 

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. 

Nonenzymatic hydrolysis of RNA assisted by metals (312-316) as well as by some ribozymes (317, 318) presumably follows the mechanism described above. Metals may be involved in the deprotonation of the 2 -OH group (319). Ribozymes, now recognized as metalloenz5mies (318,320,321), correspond to selected sequences of RNA able to cleave the same strand (intramolecular process) or an RNA sequence on a different strand (intermolecular process). Metal ions are necessary to ribozymal activity (318). They promote the folding of the secondary structure of RNA into an active tertiary structure, and it is difficult to discriminate between their structural and/or catalytic role (322, 323). 

Figure 6.7 Catalyst engineering involves an optimal combination of interdependent structural elements that yields the catalytic, mechanical, and physicochemical (specific surface area and pore size distribution, density, surface functionality, and acidity) properties desired for successful industrial applications. Solid arrows indicate primary contributions of catalyst components to the desired properties. Dashed arrows indicate secondary influences of these components via the interdependent nature of some properties.

The third folding unit is the catalytic domain of about 450 amino acid residues in length. The catalytic domain is encoded by the fifth to eleventh exons of the COX-1 gene or by the fourth to the tenth exons of the COX-2 gene. As described above, COX has two catalytic activities cyclooxygenase and peroxidase activity. The domain carries the active sites for the two functions. Fig. 8 shows a proposed scheme for the catalytic mechanism to explain the relationship between the two activities [59,60]. The secondary structure of the catalytic domain is predominantly a-helical with very little -sheet [48], The tertiary structure comprises two distinct lobes that are intertwined with each other (Fig. 9). The larger lobe is composed of seven helices (H2, H3, H5, H6, HIO, H18 and H19), while the smaller domain is... 

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